Sample records for phenotypic variability due
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Katsanos, Dimitris; Koneru, Sneha L.; Mestek Boukhibar, Lamia; Gritti, Nicola; Ghose, Ritobrata; Appleford, Peter J.; Doitsidou, Maria; Woollard, Alison; van Zon, Jeroen S.; Poole, Richard J.
2017-01-01
Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens. PMID:29108019
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Hypogonadotropic Hypogonadism due to Novel FGFR1 Mutations.
Akkuş, Gamze; Kotan, Leman Damla; Durmaz, Erdem; Mengen, Eda; Turan, İhsan; Ulubay, Ayça; Gürbüz, Fatih; Yüksel, Bilgin; Tetiker, Tamer; Topaloğlu, A Kemal
2017-06-01
The underlying genetic etiology of hypogonadotropic hypogonadism (HH) is heterogeneous. Fibroblast growth factor signaling is pivotal in the ontogeny of gonadotropin-releasing hormone neurons. Loss-of-function mutations in FGFR1 gene cause variable HH phenotypes encompassing pubertal delay to idiopathic HH (IHH) or Kallmann syndrome (KS). As FGFR1 mutations are common, recognizing mutations and associated phenotypes may enhance clinical management. Using a candidate gene approach, we screened 52 IHH/KS patients. We identified three novel (IVS3-1G>C and p.W2X, p.R209C) FGFR1 gene mutations. Despite predictive null protein function, patients from the novel mutation families had normosmic IHH without non-reproductive phenotype. These findings further emphasize the great variability of FGFR1 mutation phenotypes in IHH/KS.
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Measuring the effect of inter-study variability on estimating prediction error.
Ma, Shuyi; Sung, Jaeyun; Magis, Andrew T; Wang, Yuliang; Geman, Donald; Price, Nathan D
2014-01-01
The biomarker discovery field is replete with molecular signatures that have not translated into the clinic despite ostensibly promising performance in predicting disease phenotypes. One widely cited reason is lack of classification consistency, largely due to failure to maintain performance from study to study. This failure is widely attributed to variability in data collected for the same phenotype among disparate studies, due to technical factors unrelated to phenotypes (e.g., laboratory settings resulting in "batch-effects") and non-phenotype-associated biological variation in the underlying populations. These sources of variability persist in new data collection technologies. Here we quantify the impact of these combined "study-effects" on a disease signature's predictive performance by comparing two types of validation methods: ordinary randomized cross-validation (RCV), which extracts random subsets of samples for testing, and inter-study validation (ISV), which excludes an entire study for testing. Whereas RCV hardwires an assumption of training and testing on identically distributed data, this key property is lost in ISV, yielding systematic decreases in performance estimates relative to RCV. Measuring the RCV-ISV difference as a function of number of studies quantifies influence of study-effects on performance. As a case study, we gathered publicly available gene expression data from 1,470 microarray samples of 6 lung phenotypes from 26 independent experimental studies and 769 RNA-seq samples of 2 lung phenotypes from 4 independent studies. We find that the RCV-ISV performance discrepancy is greater in phenotypes with few studies, and that the ISV performance converges toward RCV performance as data from additional studies are incorporated into classification. We show that by examining how fast ISV performance approaches RCV as the number of studies is increased, one can estimate when "sufficient" diversity has been achieved for learning a molecular signature likely to translate without significant loss of accuracy to new clinical settings.
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Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability.
Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol C; Foley, A Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Véronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell J; Winder, Thomas L; Crawford, Thomas O; Weiss, Robert B; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G
2015-01-01
Collagen 6-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter- and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. © 2014 WILEY PERIODICALS, INC.
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Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature.
Dell'Isola, A; Allan, R; Smith, S L; Marreiros, S S P; Steultjens, M
2016-10-12
Knee Osteoarthritis (KOA) is a heterogeneous pathology characterized by a complex and multifactorial nature. It has been hypothesised that these differences are due to the existence of underlying phenotypes representing different mechanisms of the disease. The aim of this study is to identify the current evidence for the existence of groups of variables which point towards the existence of distinct clinical phenotypes in the KOA population. A systematic literature search in PubMed was conducted. Only original articles were selected if they aimed to identify phenotypes of patients aged 18 years or older with KOA. The methodological quality of the studies was independently assessed by two reviewers and qualitative synthesis of the evidence was performed. Strong evidence for existence of specific phenotypes was considered present if the phenotype was supported by at least two high-quality studies. A total of 24 studies were included. Through qualitative synthesis of evidence, six main sets of variables proposing the existence of six phenotypes were identified: 1) chronic pain in which central mechanisms (e.g. central sensitisation) are prominent; 2) inflammatory (high levels of inflammatory biomarkers); 3) metabolic syndrome (high prevalence of obesity, diabetes and other metabolic disturbances); 4) Bone and cartilage metabolism (alteration in local tissue metabolism); 5) mechanical overload characterised primarily by varus malalignment and medial compartment disease; and 6) minimal joint disease characterised as minor clinical symptoms with slow progression over time. This study identified six distinct groups of variables which should be explored in attempts to better define clinical phenotypes in the KOA population.
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The role of sex and body weight on the metabolic effects of high-fat diet in C57BL/6N mice.
Ingvorsen, C; Karp, N A; Lelliott, C J
2017-04-10
Metabolic disorders are commonly investigated using knockout and transgenic mouse models on the C57BL/6N genetic background due to its genetic susceptibility to the deleterious metabolic effects of high-fat diet (HFD). There is growing awareness of the need to consider sex in disease progression, but limited attention has been paid to sexual dimorphism in mouse models and its impact in metabolic phenotypes. We assessed the effect of HFD and the impact of sex on metabolic variables in this strain. We generated a reference data set encompassing glucose tolerance, body composition and plasma chemistry data from 586 C57BL/6N mice fed a standard chow and 733 fed a HFD collected as part of a high-throughput phenotyping pipeline. Linear mixed model regression analysis was used in a dual analysis to assess the effect of HFD as an absolute change in phenotype, but also as a relative change accounting for the potential confounding effect of body weight. HFD had a significant impact on all variables tested with an average absolute effect size of 29%. For the majority of variables (78%), the treatment effect was modified by sex and this was dominated by male-specific or a male stronger effect. On average, there was a 13.2% difference in the effect size between the male and female mice for sexually dimorphic variables. HFD led to a significant body weight phenotype (24% increase), which acts as a confounding effect on the other analysed variables. For 79% of the variables, body weight was found to be a significant source of variation, but even after accounting for this confounding effect, similar HFD-induced phenotypic changes were found to when not accounting for weight. HFD and sex are powerful modifiers of metabolic parameters in C57BL/6N mice. We also demonstrate the value of considering body size as a covariate to obtain a richer understanding of metabolic phenotypes.
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Tiedt, Hannes O; Benjamin, Beate; Niedeggen, Michael; Lueschow, Andreas
2018-02-22
In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age. © 2018 S. Karger AG, Basel.
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Xu, Man K.; Gaysina, Darya; Tsonaka, Roula; Morin, Alexandre J. S.; Croudace, Tim J.; Barnett, Jennifer H.; Houwing-Duistermaat, Jeanine; Richards, Marcus; Jones, Peter B.
2017-01-01
Very few molecular genetic studies of personality traits have used longitudinal phenotypic data, therefore molecular basis for developmental change and stability of personality remains to be explored. We examined the role of the monoamine oxidase A gene (MAOA) on extraversion and neuroticism from adolescence to adulthood, using modern latent variable methods. A sample of 1,160 male and 1,180 female participants with complete genotyping data was drawn from a British national birth cohort, the MRC National Survey of Health and Development (NSHD). The predictor variable was based on a latent variable representing genetic variations of the MAOA gene measured by three SNPs (rs3788862, rs5906957, and rs979606). Latent phenotype variables were constructed using psychometric methods to represent cross-sectional and longitudinal phenotypes of extraversion and neuroticism measured at ages 16 and 26. In males, the MAOA genetic latent variable (AAG) was associated with lower extraversion score at age 16 (β = −0.167; CI: −0.289, −0.045; p = 0.007, FDRp = 0.042), as well as greater increase in extraversion score from 16 to 26 years (β = 0.197; CI: 0.067, 0.328; p = 0.003, FDRp = 0.036). No genetic association was found for neuroticism after adjustment for multiple testing. Although, we did not find statistically significant associations after multiple testing correction in females, this result needs to be interpreted with caution due to issues related to x-inactivation in females. The latent variable method is an effective way of modeling phenotype- and genetic-based variances and may therefore improve the methodology of molecular genetic studies of complex psychological traits. PMID:29075213
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Xu, Man K; Gaysina, Darya; Tsonaka, Roula; Morin, Alexandre J S; Croudace, Tim J; Barnett, Jennifer H; Houwing-Duistermaat, Jeanine; Richards, Marcus; Jones, Peter B
2017-01-01
Very few molecular genetic studies of personality traits have used longitudinal phenotypic data, therefore molecular basis for developmental change and stability of personality remains to be explored. We examined the role of the monoamine oxidase A gene ( MAOA ) on extraversion and neuroticism from adolescence to adulthood, using modern latent variable methods. A sample of 1,160 male and 1,180 female participants with complete genotyping data was drawn from a British national birth cohort, the MRC National Survey of Health and Development (NSHD). The predictor variable was based on a latent variable representing genetic variations of the MAOA gene measured by three SNPs (rs3788862, rs5906957, and rs979606). Latent phenotype variables were constructed using psychometric methods to represent cross-sectional and longitudinal phenotypes of extraversion and neuroticism measured at ages 16 and 26. In males, the MAOA genetic latent variable (AAG) was associated with lower extraversion score at age 16 (β = -0.167; CI: -0.289, -0.045; p = 0.007, FDRp = 0.042), as well as greater increase in extraversion score from 16 to 26 years (β = 0.197; CI: 0.067, 0.328; p = 0.003, FDRp = 0.036). No genetic association was found for neuroticism after adjustment for multiple testing. Although, we did not find statistically significant associations after multiple testing correction in females, this result needs to be interpreted with caution due to issues related to x-inactivation in females. The latent variable method is an effective way of modeling phenotype- and genetic-based variances and may therefore improve the methodology of molecular genetic studies of complex psychological traits.
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Age Dependent Variability in Gene Expression in Fischer 344 ...
Recent evidence suggests older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response does increase with age. However, few reports address the question of variation in gene expression as an underlying cause for increased variability of phenotypic response in the aged. In this study, we utilized global analysis to compare variation in constitutive gene expression in the retinae of young (4 mos), middle-aged (11 mos) and aged (23 mos) Fischer 344 rats. Three hundred and forty transcripts were identified in which variance in expression increased from 4 to 23 mos of age, while only twelve transcripts were found for which it decreased. Functional roles for identified genes were clustered in basic biological categories including cell communication, function, metabolism and response to stimuli. Our data suggest that population stochastically-induced variability should be considered in assessing sensitivity due to old age. Recent evidence suggests older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response does increase with age. However, few reports address the question of variation in
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Modelling the co-evolution of indirect genetic effects and inherited variability.
Marjanovic, Jovana; Mulder, Han A; Rönnegård, Lars; Bijma, Piter
2018-03-28
When individuals interact, their phenotypes may be affected not only by their own genes but also by genes in their social partners. This phenomenon is known as Indirect Genetic Effects (IGEs). In aquaculture species and some plants, however, competition not only affects trait levels of individuals, but also inflates variability of trait values among individuals. In the field of quantitative genetics, the variability of trait values has been studied as a quantitative trait in itself, and is often referred to as inherited variability. Such studies, however, consider only the genetic effect of the focal individual on trait variability and do not make a connection to competition. Although the observed phenotypic relationship between competition and variability suggests an underlying genetic relationship, the current quantitative genetic models of IGE and inherited variability do not allow for such a relationship. The lack of quantitative genetic models that connect IGEs to inherited variability limits our understanding of the potential of variability to respond to selection, both in nature and agriculture. Models of trait levels, for example, show that IGEs may considerably change heritable variation in trait values. Currently, we lack the tools to investigate whether this result extends to variability of trait values. Here we present a model that integrates IGEs and inherited variability. In this model, the target phenotype, say growth rate, is a function of the genetic and environmental effects of the focal individual and of the difference in trait value between the social partner and the focal individual, multiplied by a regression coefficient. The regression coefficient is a genetic trait, which is a measure of cooperation; a negative value indicates competition, a positive value cooperation, and an increasing value due to selection indicates the evolution of cooperation. In contrast to the existing quantitative genetic models, our model allows for co-evolution of IGEs and variability, as the regression coefficient can respond to selection. Our simulations show that the model results in increased variability of body weight with increasing competition. When competition decreases, i.e., cooperation evolves, variability becomes significantly smaller. Hence, our model facilitates quantitative genetic studies on the relationship between IGEs and inherited variability. Moreover, our findings suggest that we may have been overlooking an entire level of genetic variation in variability, the one due to IGEs.
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Phenotypic variability in monozygotic twins with neurofibromatosis 2
DOE Office of Scientific and Technical Information (OSTI.GOV)
Baser, M.E.; Ragge, N.K.; Riccardi, V.M.
Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affectedmore » organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes. 42 refs., 1 tab.« less
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The role of sex and body weight on the metabolic effects of high-fat diet in C57BL/6N mice
Ingvorsen, C; Karp, N A; Lelliott, C J
2017-01-01
Background: Metabolic disorders are commonly investigated using knockout and transgenic mouse models on the C57BL/6N genetic background due to its genetic susceptibility to the deleterious metabolic effects of high-fat diet (HFD). There is growing awareness of the need to consider sex in disease progression, but limited attention has been paid to sexual dimorphism in mouse models and its impact in metabolic phenotypes. We assessed the effect of HFD and the impact of sex on metabolic variables in this strain. Methods: We generated a reference data set encompassing glucose tolerance, body composition and plasma chemistry data from 586 C57BL/6N mice fed a standard chow and 733 fed a HFD collected as part of a high-throughput phenotyping pipeline. Linear mixed model regression analysis was used in a dual analysis to assess the effect of HFD as an absolute change in phenotype, but also as a relative change accounting for the potential confounding effect of body weight. Results: HFD had a significant impact on all variables tested with an average absolute effect size of 29%. For the majority of variables (78%), the treatment effect was modified by sex and this was dominated by male-specific or a male stronger effect. On average, there was a 13.2% difference in the effect size between the male and female mice for sexually dimorphic variables. HFD led to a significant body weight phenotype (24% increase), which acts as a confounding effect on the other analysed variables. For 79% of the variables, body weight was found to be a significant source of variation, but even after accounting for this confounding effect, similar HFD-induced phenotypic changes were found to when not accounting for weight. Conclusion: HFD and sex are powerful modifiers of metabolic parameters in C57BL/6N mice. We also demonstrate the value of considering body size as a covariate to obtain a richer understanding of metabolic phenotypes. PMID:28394359
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Developmental mechanisms underlying variable, invariant and plastic phenotypes
Abley, Katie; Locke, James C. W.; Leyser, H. M. Ottoline
2016-01-01
Background Discussions of phenotypic robustness often consider scenarios where invariant phenotypes are optimal and assume that developmental mechanisms have evolved to buffer the phenotypes of specific traits against stochastic and environmental perturbations. However, plastic plant phenotypes that vary between environments or variable phenotypes that vary stochastically within an environment may also be advantageous in some scenarios. Scope Here the conditions under which invariant, plastic and variable phenotypes of specific traits may confer a selective advantage in plants are examined. Drawing on work from microbes and multicellular organisms, the mechanisms that may give rise to each type of phenotype are discussed. Conclusion In contrast to the view of robustness as being the ability of a genotype to produce a single, invariant phenotype, changes in a phenotype in response to the environment, or phenotypic variability within an environment, may also be delivered consistently (i.e. robustly). Thus, for some plant traits, mechanisms have probably evolved to produce plasticity or variability in a reliable manner. PMID:27072645
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Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases.
Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Banecka-Majkutewicz, Zyta; Banecki, Bogdan; Węgrzyn, Alicja; Węgrzyn, Grzegorz
2014-03-01
Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70%) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.
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Clinical phenotype of ASD-associated DYRK1A haploinsufficiency.
Earl, Rachel K; Turner, Tychele N; Mefford, Heather C; Hudac, Caitlin M; Gerdts, Jennifer; Eichler, Evan E; Bernier, Raphael A
2017-01-01
DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. Phenotypic information from previously published DYRK1A cases ( n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection ( n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender ( n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 ( n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.
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Kulshreshtha, Bindu; Singh, Seerat; Arora, Arpita
2013-12-01
The phenotypic variability among PCOS could be due to differences in insulin patterns. Hyperinsulinemia commonly accompanies Diabetes Mellitus (DM), obesity, hypertension and CAD, though, to a variable degree. We speculate that a family history of these diseases could differentially affect the phenotype of PCOS. To study the effect of DM/CAD/HT and obesity on the phenotype of PCOS. PCOS patients and age matched controls were enquired for a family background of DM, hypertension, CAD and obesity among parents and grandparents. Regression modelling was employed to examine predictors of obesity and first symptom in PCOS patients. There were 88 PCOS women and 77 age-matched controls (46 lean, 31 obese). A high prevalence of DM, CAD, obesity and hypertension was observed among parents and grandparents of women with PCOS compared to controls. Hypertension and CAD manifested more in father's side of family. BMI of PCOS subjects was significantly related to parental DM and obesity after correcting for age. First symptom of weight gain was significantly associated with number of parents with DM (p = 0.02) and first symptom of irregular periods was associated with number of parents with hypertension (p = 0.06). A family background of DM/HT and obesity diseases affects the phenotype of PCOS.
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A platform for high-throughput bioenergy production phenotype characterization in single cells
Kelbauskas, Laimonas; Glenn, Honor; Anderson, Clifford; Messner, Jacob; Lee, Kristen B.; Song, Ganquan; Houkal, Jeff; Su, Fengyu; Zhang, Liqiang; Tian, Yanqing; Wang, Hong; Bussey, Kimberly; Johnson, Roger H.; Meldrum, Deirdre R.
2017-01-01
Driven by an increasing number of studies demonstrating its relevance to a broad variety of disease states, the bioenergy production phenotype has been widely characterized at the bulk sample level. Its cell-to-cell variability, a key player associated with cancer cell survival and recurrence, however, remains poorly understood due to ensemble averaging of the current approaches. We present a technology platform for performing oxygen consumption and extracellular acidification measurements of several hundreds to 1,000 individual cells per assay, while offering simultaneous analysis of cellular communication effects on the energy production phenotype. The platform comprises two major components: a tandem optical sensor for combined oxygen and pH detection, and a microwell device for isolation and analysis of single and few cells in hermetically sealed sub-nanoliter chambers. Our approach revealed subpopulations of cells with aberrant energy production profiles and enables determination of cellular response variability to electron transfer chain inhibitors and ion uncouplers. PMID:28349963
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Recombination and phenotype evolution dynamics of Helicobacter pylori in colonized hosts.
Shafiee, Ahmad; Amini, Massoud; Emamirad, Hassan; Abadi, Amin Talebi Bezmin
2016-07-01
The ample genetic diversity and variability of Helicobater pylori, and therefore its phenotypic evolution, relate not only to frequent mutation and selection but also to intra-specific recombination. Webb and Blaser applied a mathematical model to distinguish the role of selection and mutation for Lewis antigen phenotype evolution during long-term gastric colonization in infected animal hosts (mice and gerbils). To investigate the role of recombination in Lewis antigen phenotype evolution, we have developed a prior population dynamic by adding recombination term to the model. We simulate and interpret the new model simulation's results with a comparative analysis of biological aspects. The main conclusions are as follows: (i) the models and consequently the hosts with higher recombination rate require a longer time for stabilization; and (ii) recombination and mutation have opposite effects on the size of H. pylori populations with phenotypes in the range of the most-fit ones (i.e. those that have a selective advantage) due to natural selection, although both can increase phenotypic diversity.
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Adu-Gyamfi, Raphael; Wetten, Andy; Marcelino Rodríguez López, Carlos
2016-01-01
While cocoa plants regenerated from cryopreserved somatic embryos can demonstrate high levels of phenotypic variability, little is known about the sources of the observed variability. Previous studies have shown that the encapsulation-dehydration cryopreservation methodology imposes no significant extra mutational load since embryos carrying high levels of genetic variability are selected against during protracted culture. Also, the use of secondary rather than primary somatic embryos has been shown to further reduce the incidence of genetic somaclonal variation. Here, the effect of in vitro conservation, cryopreservation and post-cryopreservation generation of somatic embryos on the appearance of epigenetic somaclonal variation were comparatively assessed. To achieve this we compared the epigenetic profiles, generated using Methylation Sensitive Amplified Polymorphisms, of leaves collected from the ortet tree and from cocoa somatic embryos derived from three in vitro conditions: somatic embryos, somatic embryos cryopreserved in liquid nitrogen and somatic embryos generated from cryoproserved somatic embryos. Somatic embryos accumulated epigenetic changes but these were less extensive than in those regenerated after storage in LN. Furthermore, the passage of cryopreserved embryos through another embryogenic stage led to further increase in variation. Interestingly, this detected variability appears to be in some measure reversible. The outcome of this study indicates that the cryopreservation induced phenotypic variability could be, at least partially, due to DNA methylation changes. Phenotypic variability observed in cryostored cocoa somatic-embryos is epigenetic in nature. This variability is partially reversible, not stochastic in nature but a directed response to the in-vitro culture and cryopreservation.
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Adu-Gyamfi, Raphael; Wetten, Andy; Marcelino Rodríguez López, Carlos
2016-01-01
While cocoa plants regenerated from cryopreserved somatic embryos can demonstrate high levels of phenotypic variability, little is known about the sources of the observed variability. Previous studies have shown that the encapsulation-dehydration cryopreservation methodology imposes no significant extra mutational load since embryos carrying high levels of genetic variability are selected against during protracted culture. Also, the use of secondary rather than primary somatic embryos has been shown to further reduce the incidence of genetic somaclonal variation. Here, the effect of in vitro conservation, cryopreservation and post-cryopreservation generation of somatic embryos on the appearance of epigenetic somaclonal variation were comparatively assessed. To achieve this we compared the epigenetic profiles, generated using Methylation Sensitive Amplified Polymorphisms, of leaves collected from the ortet tree and from cocoa somatic embryos derived from three in vitro conditions: somatic embryos, somatic embryos cryopreserved in liquid nitrogen and somatic embryos generated from cryoproserved somatic embryos. Somatic embryos accumulated epigenetic changes but these were less extensive than in those regenerated after storage in LN. Furthermore, the passage of cryopreserved embryos through another embryogenic stage led to further increase in variation. Interestingly, this detected variability appears to be in some measure reversible. The outcome of this study indicates that the cryopreservation induced phenotypic variability could be, at least partially, due to DNA methylation changes. Key message: Phenotypic variability observed in cryostored cocoa somatic-embryos is epigenetic in nature. This variability is partially reversible, not stochastic in nature but a directed response to the in-vitro culture and cryopreservation. PMID:27403857
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Genome-wide association study for feed efficiency traits using SNP and haplotype models
USDA-ARS?s Scientific Manuscript database
Feed costs comprise the majority of variable expenses in beef cattle systems making feed efficiency an important economic consideration within the beef industry. Due to the expense of recording individual feed intake phenotypes, a genomic-enabled approach could be advantageous towards improving this...
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USDA-ARS?s Scientific Manuscript database
The umbilical cord (UC) matrix is a source of multipotent mesenchymal stem cells (MSCs) that have adipogenic potential and thus can be a model to study adipogenesis. However, existing variability in adipocytic differentiation outcomes may be due to discrepancies in methods utilized for adipogenic d...
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Bozzola, E; Savasta, S; Peruzzi, C; Bozzola, M; Bona, G
2007-04-01
In infancy, the autosomal dominant inherited ataxias are severe neurological diseases, due to inherited mutations of ion channels. The main forms are: episodic ataxia type 1 (EA1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6). EA1 is due to a mutation in KCNA1, the gene encoding human Kv1.1 on chromosome 12p13, which contributes as a subunit to the formation of potassium channels in motor nerve terminals and in many central nervous system neurones. To date, there are fifteen different mutations, which affect potassium channel's properties and lead to phenotypic variability and to different responses to therapy. EA2 can result from mutations in the CACNA1A gene, encoding calcium channels on chromosome 19p13.1 and widely distributed throughout the central nervous system. To date, associated with EA2, in the CACNA1A gene thirty different mutations have been described, resulting in altered or truncated protein products and, as a consequence, in nonfunctional calcium channels. There is phenotypic variability, also inside the same family, without correlation genotype-phenotype. SCA6 is a progressive neurodegenerative disease due to mutations of the CACNA1A gene. CACNA1A is responsible for both EA2 and SCA6. Nevertheless, the pathogenesis of the two diseases is different: SCA6 is associated with small expansion of a CAGn repeat, while EA2 is due to point mutations. Clinically, SCA6 is characterized by a slowly progressive development and by an inverse correlation between the number of repeats and the severity of the disease.
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Jamsheer, Aleksander; Sowińska-Seidler, Anna; Olech, Ewelina M; Socha, Magdalena; Kozłowski, Kazimierz; Pyrkosz, Antoni; Trzeciak, Tomasz; Materna-Kiryluk, Anna; Latos-Bieleńska, Anna
2016-05-01
Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.
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Phenotypic variability in familial prion diseases due to the D178N mutation
Zarranz, J; Digon, A; Atares, B; Rodriguez-Martine..., A; Arce, A; Carrera, N; Fernandez-Manchol..., I; Fernandez-Martine..., M; Fernandez-Maizteg..., C; Forcadas, I; Galdos, L; Gomez-Esteban, J; Ibanez, A; Lezcano, E; d Lopez; Marti-Masso, J; Mendibe, M; Urtasun, M; Uterga, J; Saracibar, N; Velasco, F; de Pancorbo, M M
2005-01-01
Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene. PMID:16227536
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Howard, Réka; Carriquiry, Alicia L.; Beavis, William D.
2014-01-01
Parametric and nonparametric methods have been developed for purposes of predicting phenotypes. These methods are based on retrospective analyses of empirical data consisting of genotypic and phenotypic scores. Recent reports have indicated that parametric methods are unable to predict phenotypes of traits with known epistatic genetic architectures. Herein, we review parametric methods including least squares regression, ridge regression, Bayesian ridge regression, least absolute shrinkage and selection operator (LASSO), Bayesian LASSO, best linear unbiased prediction (BLUP), Bayes A, Bayes B, Bayes C, and Bayes Cπ. We also review nonparametric methods including Nadaraya-Watson estimator, reproducing kernel Hilbert space, support vector machine regression, and neural networks. We assess the relative merits of these 14 methods in terms of accuracy and mean squared error (MSE) using simulated genetic architectures consisting of completely additive or two-way epistatic interactions in an F2 population derived from crosses of inbred lines. Each simulated genetic architecture explained either 30% or 70% of the phenotypic variability. The greatest impact on estimates of accuracy and MSE was due to genetic architecture. Parametric methods were unable to predict phenotypic values when the underlying genetic architecture was based entirely on epistasis. Parametric methods were slightly better than nonparametric methods for additive genetic architectures. Distinctions among parametric methods for additive genetic architectures were incremental. Heritability, i.e., proportion of phenotypic variability, had the second greatest impact on estimates of accuracy and MSE. PMID:24727289
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Multivariate Analysis of Genotype-Phenotype Association.
Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela
2016-04-01
With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map has important consequences for gene identification and may shed light on the evolvability of organisms. Copyright © 2016 by the Genetics Society of America.
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López, Rosana; López de Heredia, Unai; Collada, Carmen; Cano, Francisco Javier; Emerson, Brent C; Cochard, Hervé; Gil, Luis
2013-06-01
It is widely accepted that hydraulic failure due to xylem embolism is a key factor contributing to drought-induced mortality in trees. In the present study, an attempt is made to disentangle phenotypic plasticity from genetic variation in hydraulic traits across the entire distribution area of a tree species to detect adaptation to local environments. A series of traits related to hydraulics (vulnerability to cavitation and hydraulic conductivity in branches), growth performance and leaf mass per area were assessed in eight Pinus canariensis populations growing in two common gardens under contrasting environments. In addition, the neutral genetic variability (FST) and the genetic differentiation of phenotypic variation (QST) were compared in order to identify the evolutionary forces acting on these traits. The variability for hydraulic traits was largely due to phenotypic plasticity. Nevertheless, the vulnerability to cavitation displayed a significant genetic variability (approx. 5 % of the explained variation), and a significant genetic × environment interaction (between 5 and 19 % of the explained variation). The strong correlation between vulnerability to cavitation and survival in the xeric common garden (r = -0·81; P < 0·05) suggests a role for the former in the adaptation to xeric environments. Populations from drier sites and higher temperature seasonality were less vulnerable to cavitation than those growing at mesic sites. No trade-off between xylem safety and efficiency was detected. QST of parameters of the vulnerability curve (0·365 for P50 and the slope of the vulnerability curve and 0·452 for P88) differed substantially from FST (0·091), indicating divergent selection. In contrast, genetic drift alone was found to be sufficient to explain patterns of differentiation for xylem efficiency and growth. The ability of P. canariensis to inhabit a wide range of ecosystems seemed to be associated with high phenotypic plasticity and some degree of local adaptations of xylem and leaf traits. Resistance to cavitation conferred adaptive potential for this species to adapt successfully to xeric conditions.
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ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.
Danilov, Sergei M; Tovsky, Stan I; Schwartz, David E; Dull, Randal O
2017-07-01
Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.
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The human clinical phenotypes of altered CHRNA7 copy number.
Gillentine, Madelyn A; Schaaf, Christian P
2015-10-15
Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the α7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed. Copyright © 2015 Elsevier Inc. All rights reserved.
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Differential gene expression patterns in the autogamous plant Hordeum euclaston (Poaceae).
Georg-Kraemer, J E; Ferreira, C A S; Cavalli, S S
2011-02-22
Sib-seedlings of 95 strains of the strictly autogamous grass Hordeum euclaston were analyzed by horizontal polyacrylamide gel electrophoresis for four isoenzyme systems at a specific ontogenetic stage. We found differences in the activity of some genes among individuals of this species. Hence, an ontogenetic analysis was carried out to investigate 12 strains at five ontogenetic stages, to determine the patterns of expression of these genes during development. The differences in the presence versus absence of certain isoenzyme bands may be due to differential regulatory activation in response to environmental differences, as all plants showed the same structural genes, although these genes were active in different tissues and/or times of development. These results indicate the importance of differential gene activation in the metabolic phenotype variability of this strictly autogamous, highly homozygous species. The same structural alleles for isoenzymes showed the active form of the enzymes (phenotypic expression) to be present in different tissues and/or stages of development. Differential isoenzyme gene activation was shown to be directly responsible for the enzymatic variability (metabolic phenotype) presented by the plants, which seem to possess almost no heterozygosis.
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Path analysis of phenotypic traits in young cacao plants under drought conditions.
Santos, Emerson Alves Dos; Almeida, Alex-Alan Furtado de; Branco, Marcia Christina da Silva; Santos, Ivanildes Conceição Dos; Ahnert, Dario; Baligar, Virupax C; Valle, Raúl René
2018-01-01
Drought is worldwide considered one of the most limiting factors of Theobroma cacao production, which can be intensified by global climate changes. In this study, we aimed to investigate the phenotypic correlation among morphological characteristics of cacao progenies submitted to irrigation and drought conditions and their partitions into direct and indirect effects. Path analysis with phenotypic plasticity index was used as criteria for estimation of basic and explanatory variables. The experiment was conducted in a greenhouse at the Cacao Research Center (CEPEC), Ilhéus, Bahia, Brazil, in a randomized block 21 x 2 factorial arrangement [21 cacao progenies obtained from complete diallel crosses and two water regimes (control and drought)] and six replications. In general, drought conditions influenced biomass production in most progenies, causing significant reductions in total leaf area, leaf number, leaf biomass, fine-roots length (diameter <1 mm), root volume and root area for considered drought intolerant. All progenies showed alterations in growth due to drought. Phenotypic plasticity was most strongly pronounced in root volume. Stem and root diameters, as well as stem dry biomass were the growth variables with the greatest direct effects on root volume under drought conditions, these characters being indicated in screening of cacao progenies drought tolerant.
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Path analysis of phenotypic traits in young cacao plants under drought conditions
dos Santos, Emerson Alves; de Almeida, Alex-Alan Furtado; Branco, Marcia Christina da Silva; dos Santos, Ivanildes Conceição; Ahnert, Dario; Baligar, Virupax C.; Valle, Raúl René
2018-01-01
Drought is worldwide considered one of the most limiting factors of Theobroma cacao production, which can be intensified by global climate changes. In this study, we aimed to investigate the phenotypic correlation among morphological characteristics of cacao progenies submitted to irrigation and drought conditions and their partitions into direct and indirect effects. Path analysis with phenotypic plasticity index was used as criteria for estimation of basic and explanatory variables. The experiment was conducted in a greenhouse at the Cacao Research Center (CEPEC), Ilhéus, Bahia, Brazil, in a randomized block 21 x 2 factorial arrangement [21 cacao progenies obtained from complete diallel crosses and two water regimes (control and drought)] and six replications. In general, drought conditions influenced biomass production in most progenies, causing significant reductions in total leaf area, leaf number, leaf biomass, fine-roots length (diameter <1 mm), root volume and root area for considered drought intolerant. All progenies showed alterations in growth due to drought. Phenotypic plasticity was most strongly pronounced in root volume. Stem and root diameters, as well as stem dry biomass were the growth variables with the greatest direct effects on root volume under drought conditions, these characters being indicated in screening of cacao progenies drought tolerant. PMID:29408854
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Genotype-phenotype variability of retinal manifestation in primary hyperoxaluria type 1.
Dulz, S; Bigdon, E; Atiskova, Y; Schuettauf, F; Cerkauskiene, R; Oh, J; Brinkert, F
2018-04-01
Primary hyperoxaluria type 1 (PH1) is a rare congenital metabolic disorder of the glyoxylate pathway, which manifests with nephrocalcinosis, urolithiasis, and end-stage renal failure (ESRD) as well as deposition of oxalate crystals within ocular tissues. This report demonstrates classical ocular features of PH1 of the posterior pole and furthermore highlights the ocular genotype-phenotype variability among siblings with identical compound heterozygous alanine-glyoxylate aminotransferase (AGXT) mutations. Two siblings, an 8-year-old boy and an 18-year-old girl, with genetically confirmed AGXT mutation (c.364C>T (p.R122X) and c.33dupC), but different renal phenotype underwent an ophthalmic examination, including slit-lamp examination and funduscopy as well as optical coherence tomography (OCT), near-infrared autofluorescence (NIA), and microperimetry examination. The 8-year-old boy presented with a best-corrected visual acuity (BCVA) of 20/630. Fundus examination revealed bilateral, whitish oxalate deposits and prominent fibrotic macular scars. OCT imaging illustrated hyperdense deposits in all retinal layers and the choroid and the vitreous body along with a prominent dome-shaped macular fibrosis. NIA imaging outlined macular retinal pigment epithelium (RPE) atrophy with panretinal hyperreflective material. Bilateral symptomatic epiphora was putatively due to bilateral depositions of palpable nodular oxalate deposits at the level of the lacrimal sac. In contrary, the 18-year-old sister presented without any signs of ocular oxalate deposition and a BCVA of 20/20. PH1 is potentially accompanied with a considerable decline in visual acuity due to macular scaring and fibrosis, whereas a profound variability of ocular manifestations can be observed in PH1 patients with identical genotypes.
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de Goede, Christian; Yue, Wyatt W; Yan, Guanhua; Ariyaratnam, Shyamala; Chandler, Kate E; Downes, Laura; Khan, Nasaim; Mohan, Meyyammai; Lowe, Martin; Banka, Siddharth
2016-03-01
Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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Fiévet, Julie B; Nidelet, Thibault; Dillmann, Christine; de Vienne, Dominique
2018-01-01
Heterosis, the superiority of hybrids over their parents for quantitative traits, represents a crucial issue in plant and animal breeding as well as evolutionary biology. Heterosis has given rise to countless genetic, genomic and molecular studies, but has rarely been investigated from the point of view of systems biology. We hypothesized that heterosis is an emergent property of living systems resulting from frequent concave relationships between genotypic variables and phenotypes, or between different phenotypic levels. We chose the enzyme-flux relationship as a model of the concave genotype-phenotype (GP) relationship, and showed that heterosis can be easily created in the laboratory. First, we reconstituted in vitro the upper part of glycolysis. We simulated genetic variability of enzyme activity by varying enzyme concentrations in test tubes. Mixing the content of "parental" tubes resulted in "hybrids," whose fluxes were compared to the parental fluxes. Frequent heterotic fluxes were observed, under conditions that were determined analytically and confirmed by computer simulation. Second, to test this model in a more realistic situation, we modeled the glycolysis/fermentation network in yeast by considering one input flux, glucose, and two output fluxes, glycerol and acetaldehyde. We simulated genetic variability by randomly drawing parental enzyme concentrations under various conditions, and computed the parental and hybrid fluxes using a system of differential equations. Again we found that a majority of hybrids exhibited positive heterosis for metabolic fluxes. Cases of negative heterosis were due to local convexity between certain enzyme concentrations and fluxes. In both approaches, heterosis was maximized when the parents were phenotypically close and when the distributions of parental enzyme concentrations were contrasted and constrained. These conclusions are not restricted to metabolic systems: they only depend on the concavity of the GP relationship, which is commonly observed at various levels of the phenotypic hierarchy, and could account for the pervasiveness of heterosis.
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Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.
Fernández, Raquel M; Núñez-Ramos, Raquel; Enguix-Riego, M Valle; Román-Rodríguez, Francisco José; Galán-Gómez, Enrique; Blesa-Sánchez, Emilio; Antiñolo, Guillermo; Núñez-Núñez, Ramón; Borrego, Salud
2014-02-01
Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. © 2013 Wiley Periodicals, Inc.
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Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.
Van Montfrans, Joris M; Hartman, Esther A R; Braun, Kees P J; Hennekam, Eric A M; Hak, Elisabeth A; Nederkoorn, Paul J; Westendorp, Willeke F; Bredius, Robbert G M; Kollen, Wouter J W; Schölvinck, Elisabeth H; Legger, G Elizabeth; Meyts, Isabelle; Liston, Adrian; Lichtenbelt, Klaske D; Giltay, Jacques C; Van Haaften, Gijs; De Vries Simons, Gaby M; Leavis, Helen; Sanders, Cornelis J G; Bierings, Marc B; Nierkens, Stefan; Van Gijn, Marielle E
2016-05-01
To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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López, Rosana; López de Heredia, Unai; Collada, Carmen; Cano, Francisco Javier; Emerson, Brent C.; Cochard, Hervé; Gil, Luis
2013-01-01
Background and Aims It is widely accepted that hydraulic failure due to xylem embolism is a key factor contributing to drought-induced mortality in trees. In the present study, an attempt is made to disentangle phenotypic plasticity from genetic variation in hydraulic traits across the entire distribution area of a tree species to detect adaptation to local environments. Methods A series of traits related to hydraulics (vulnerability to cavitation and hydraulic conductivity in branches), growth performance and leaf mass per area were assessed in eight Pinus canariensis populations growing in two common gardens under contrasting environments. In addition, the neutral genetic variability (FST) and the genetic differentiation of phenotypic variation (QST) were compared in order to identify the evolutionary forces acting on these traits. Key Results The variability for hydraulic traits was largely due to phenotypic plasticity. Nevertheless, the vulnerability to cavitation displayed a significant genetic variability (approx. 5 % of the explained variation), and a significant genetic × environment interaction (between 5 and 19 % of the explained variation). The strong correlation between vulnerability to cavitation and survival in the xeric common garden (r = –0·81; P < 0·05) suggests a role for the former in the adaptation to xeric environments. Populations from drier sites and higher temperature seasonality were less vulnerable to cavitation than those growing at mesic sites. No trade-off between xylem safety and efficiency was detected. QST of parameters of the vulnerability curve (0·365 for P50 and the slope of the vulnerability curve and 0·452 for P88) differed substantially from FST (0·091), indicating divergent selection. In contrast, genetic drift alone was found to be sufficient to explain patterns of differentiation for xylem efficiency and growth. Conclusions The ability of P. canariensis to inhabit a wide range of ecosystems seemed to be associated with high phenotypic plasticity and some degree of local adaptations of xylem and leaf traits. Resistance to cavitation conferred adaptive potential for this species to adapt successfully to xeric conditions. PMID:23644361
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McParland, D; Phillips, C M; Brennan, L; Roche, H M; Gormley, I C
2017-12-10
The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub-phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub-phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.
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Sinclair, Thomas R; Manandhar, Anju; Shekoofa, Avat; Rosas-Anderson, Pablo; Bagherzadi, Laleh; Schoppach, Remy; Sadok, Walid; Rufty, Thomas W
2017-04-01
Theoretical derivation predicted growth retardation due to pot water limitations, i.e., pot binding. Experimental observations were consistent with these limitations. Combined, these results indicate a need for caution in high-throughput screening and phenotyping. Pot experiments are a mainstay in many plant studies, including the current emphasis on developing high-throughput, phenotyping systems. Pot studies can be vulnerable to decreased physiological activity of the plants particularly when pot volume is small, i.e., "pot binding". It is necessary to understand the conditions under which pot binding may exist to avoid the confounding influence of pot binding in interpreting experimental results. In this paper, a derivation is offered that gives well-defined conditions for the occurrence of pot binding based on restricted water availability. These results showed that not only are pot volume and plant size important variables, but the potting media is critical. Artificial potting mixtures used in many studies, including many high-throughput phenotyping systems, are particularly susceptible to the confounding influences of pot binding. Experimental studies for several crop species are presented that clearly show the existence of thresholds of plant leaf area at which various pot sizes and potting media result in the induction of pot binding even though there may be no immediate, visual plant symptoms. The derivation and experimental results showed that pot binding can readily occur in plant experiments if care is not given to have sufficiently large pots, suitable potting media, and maintenance of pot water status. Clear guidelines are provided for avoiding the confounding effects of water-limited pot binding in studying plant phenotype.
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Blanco, Juan Felipe; Tamayo, Silvana; Scatena, Frederick N
2014-04-01
Gastropods of the Neritinidae family exhibit an amphidromous life cycle and an impressive variability in shell coloration in Puerto Rican streams and rivers. Various nominal species have been described, but Neritina virginea [Linne 1758], N. punctulata [Lamarck 1816] and N. reclivata [Say 1822] are the only broadly reported. However, recent studies have shown that these three species are sympatric at the river scale and that species determination might be difficult due to the presence of intermediate color morphs. Individuals (8 751) were collected from ten rivers across Puerto Rico, and from various segments and habitats in Mameyes River (the most pristine island-wide) during three years (2000-2003), and they were assigned to one of seven phenotypes corresponding to nominal species and morphs (non-nominal species). The "axial lines and dots" morph corresponding to N. reclivata was the most frequent island-wide, while the patelliform N. punctulata was scant, but the only found in headwater reaches. The "yellowish large tongues" phenotype, typical of N. virginea s.s. was the most frequent in the river mouth. The frequency of secondary phenotypes varied broadly among rivers, along the rivers, and among habitats, seemly influenced by salinity and predation gradients. The occurrence of individuals with coloration shifts after predation injuries, suggests phenotypic plasticity in the three nominal species, and urges for the use of molecular markers to unravel the possible occurrence of a species complex, and to understand the genetic basis of polymorphism. The longitudinal distribution of individual sizes, population density and egg capsules suggested the adaptive value of upstream migration, possibly to avoid marine predators.
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Reasor, Eric H; Brosnan, James T; Staton, Margaret E; Lane, Thomas; Trigiano, Robert N; Wadl, Phillip A; Conner, Joann A; Schwartz, Brian M
2018-01-01
Interspecific hybrid bermudagrass [ Cynodon dactylon (L.) Pers. x C. transvaalensis Burtt-Davy] is one of the most widely used grasses on golf courses, with cultivars derived from 'Tifgreen' or 'Tifdwarf' particularly used for putting greens. Many bermudagrass cultivars established for putting greens can be genetically unstable and lead to the occurrence of undesirable off-type grasses that vary in phenotype. The objective of this research was to genetically and phenotypically differentiate off-type grasses and hybrid cultivars. Beginning in 2013, off-type and desirable hybrid bermudagrass samples were collected from golf course putting greens in the southeastern United States and genetically and phenotypically characterized using genotyping-by-sequencing and morphology. Genotyping-by-sequencing determined that 11% (5) of off-type and desirable samples from putting greens were genetically divergent from standard cultivars such as Champion, MiniVerde, Tifdwarf, TifEagle, and Tifgreen. In addition, genotyping-by-sequencing was unable to genetically distinguish all standard cultivars from one another due to their similar origin and clonal propagation; however, over 90,000 potentially informative nucleotide variants were identified among the triploid hybrid cultivars. Although few genetic differences were found in this research, samples harvested from golf course putting greens had variable morphology and were clustered into three distinct phenotypic groups. The majority of off-type grasses in hybrid bermudagrass putting greens were genetically similar with variable morphological traits. Off-type grasses within golf course putting greens have the potential to compromise putting surface functionality and aesthetics.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lopez, M.; Torres, L.; Cervantes, A.
Most individuals with the rare 46,XX male {open_quotes}syndrome{close_quotes} arise due to an unequal interchange between Xp and Yp termini during paternal meiosis. The pattern of Y-sequences in these patients varies considerably, but very few cases have been reported showing only SRY. The phenotype in these patients is also variable ranging from severe impairment of the external genitalia through hypospadias and/or cryptorchidism to occasional normal male phenotype. We report a Mexican 46,XX male patient without genital ambiguities in whom DNA analysis showed the presence of SRY and the absence of ZFY. We conclude that in this case SRY alone was enoughmore » for complete male sexual differentiation. 25 refs., 1 fig.« less
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Outbreeding increases offspring survival in wild greater horseshoe bats (Rhinolophus ferrumequinum).
Rossiter, S. J.; Jones, G.; Ransome, R. D.; Barratt, E. M.
2001-01-01
The factors influencing the survival of greater horseshoe bat (Rhinolophus ferrumequinum) offspring born over seven years at a maternity colony in south-west Britain were studied. The effects of a range of phenotypic and maternal variables were analysed using a historical data set. In addition, the influence of two genetic measures on mortality, individual heterozygosity and a new measure of outbreeding, termed mean d(2), was assessed. Logistic regressions were undertaken with survival modelled as a binary response variable. Survival to two life stages was studied for each variable and all models were developed for both sexes separately and together. Only one variable, mean d(2), was significantly associated with survival. Male offspring with high mean d(2) scores were more likely to survive to their first and second summers. The influence of mean d(2) was not due to a single locus under selection but a wider multilocus effect and probably represents heterosis as opposed to solely inbreeding depression. Therefore, the extent to which an individual is outbred may determine survival more than widely used phenotypic characteristics such as size and mass. Mean d(2) may reflect immunocompetence, which influences mortality. Protection of mating sites in order to facilitate gene flow and, therefore, outbreeding may help to promote population stability and growth. PMID:11375090
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The effect of artificial selection on phenotypic plasticity in maize.
Gage, Joseph L; Jarquin, Diego; Romay, Cinta; Lorenz, Aaron; Buckler, Edward S; Kaeppler, Shawn; Alkhalifah, Naser; Bohn, Martin; Campbell, Darwin A; Edwards, Jode; Ertl, David; Flint-Garcia, Sherry; Gardiner, Jack; Good, Byron; Hirsch, Candice N; Holland, Jim; Hooker, David C; Knoll, Joseph; Kolkman, Judith; Kruger, Greg; Lauter, Nick; Lawrence-Dill, Carolyn J; Lee, Elizabeth; Lynch, Jonathan; Murray, Seth C; Nelson, Rebecca; Petzoldt, Jane; Rocheford, Torbert; Schnable, James; Schnable, Patrick S; Scully, Brian; Smith, Margaret; Springer, Nathan M; Srinivasan, Srikant; Walton, Renee; Weldekidan, Teclemariam; Wisser, Randall J; Xu, Wenwei; Yu, Jianming; de Leon, Natalia
2017-11-07
Remarkable productivity has been achieved in crop species through artificial selection and adaptation to modern agronomic practices. Whether intensive selection has changed the ability of improved cultivars to maintain high productivity across variable environments is unknown. Understanding the genetic control of phenotypic plasticity and genotype by environment (G × E) interaction will enhance crop performance predictions across diverse environments. Here we use data generated from the Genomes to Fields (G2F) Maize G × E project to assess the effect of selection on G × E variation and characterize polymorphisms associated with plasticity. Genomic regions putatively selected during modern temperate maize breeding explain less variability for yield G × E than unselected regions, indicating that improvement by breeding may have reduced G × E of modern temperate cultivars. Trends in genomic position of variants associated with stability reveal fewer genic associations and enrichment of variants 0-5000 base pairs upstream of genes, hypothetically due to control of plasticity by short-range regulatory elements.
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Akimoto, Yuki; Yugi, Katsuyuki; Uda, Shinsuke; Kudo, Takamasa; Komori, Yasunori; Kubota, Hiroyuki; Kuroda, Shinya
2013-01-01
Cells use common signaling molecules for the selective control of downstream gene expression and cell-fate decisions. The relationship between signaling molecules and downstream gene expression and cellular phenotypes is a multiple-input and multiple-output (MIMO) system and is difficult to understand due to its complexity. For example, it has been reported that, in PC12 cells, different types of growth factors activate MAP kinases (MAPKs) including ERK, JNK, and p38, and CREB, for selective protein expression of immediate early genes (IEGs) such as c-FOS, c-JUN, EGR1, JUNB, and FOSB, leading to cell differentiation, proliferation and cell death; however, how multiple-inputs such as MAPKs and CREB regulate multiple-outputs such as expression of the IEGs and cellular phenotypes remains unclear. To address this issue, we employed a statistical method called partial least squares (PLS) regression, which involves a reduction of the dimensionality of the inputs and outputs into latent variables and a linear regression between these latent variables. We measured 1,200 data points for MAPKs and CREB as the inputs and 1,900 data points for IEGs and cellular phenotypes as the outputs, and we constructed the PLS model from these data. The PLS model highlighted the complexity of the MIMO system and growth factor-specific input-output relationships of cell-fate decisions in PC12 cells. Furthermore, to reduce the complexity, we applied a backward elimination method to the PLS regression, in which 60 input variables were reduced to 5 variables, including the phosphorylation of ERK at 10 min, CREB at 5 min and 60 min, AKT at 5 min and JNK at 30 min. The simple PLS model with only 5 input variables demonstrated a predictive ability comparable to that of the full PLS model. The 5 input variables effectively extracted the growth factor-specific simple relationships within the MIMO system in cell-fate decisions in PC12 cells.
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The effects of a skeletal muscle titin mutation on walking in mice.
Pace, Cinnamon M; Mortimer, Sarah; Monroy, Jenna A; Nishikawa, Kiisa C
2017-01-01
Titin contributes to sarcomere assembly, muscle signaling, and mechanical properties of muscle. The mdm mouse exhibits a small deletion in the titin gene resulting in dystrophic mutants and phenotypically normal heterozygotes. We examined the effects of this mutation on locomotion to assess how, and if, changes to muscle phenotype explain observed locomotor differences. Mutant mice are much smaller in size than their siblings and gait abnormalities may be driven by differences in limb proportions and/or by changes to muscle phenotype caused by the titin mutation. We quantified differences in walking gait among mdm genotypes and also determined whether genotypes vary in limb morphometrics. Mice were filmed walking, and kinematic and morphological variables were measured. Mutant mice had a smaller range of motion at the ankle, shorter stride lengths, and shorter stance duration, but walked at the same relative speeds as the other genotypes. Although phenotypically similar to wildtype mice, heterozygous mice frequently exhibited intermediate gait mechanics. Morphological differences among genotypes in hindlimb proportions were small and do not explain the locomotor differences. We suggest that differences in locomotion among mdm genotypes are due to changes in muscle phenotype caused by the titin mutation.
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Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype
Tsuda, Takeshi; Fitzgerald, Kristi K.
2017-01-01
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. PMID:29367543
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Early constraints in sexual dimorphism: survival benefits of feminized phenotypes.
López-Rull, I; Vergara, P; Martínez-Padilla, J; Fargallo, J A
2016-02-01
Sexual dimorphism (SD) has evolved in response to selection pressures that differ between sexes. Since such pressures change across an individual's life, SD may vary within age classes. Yet, little is known about how selection on early phenotypes may drive the final SD observed in adults. In many dimorphic species, juveniles resemble adult females rather than adult males, meaning that out of the selective pressures established by sexual selection feminized phenotypes may be adaptive. If true, fitness benefits of early female-like phenotypes may constrain the expression of male phenotypes in adulthood. Using the common kestrel Falco tinnunculus as a study model, we evaluated the fitness advantages of expressing more feminized phenotypes at youth. Although more similar to adult females than to adult males, common kestrel fledglings are still sexually dimorphic in size and coloration. Integrating morphological and chromatic variables, we analysed the phenotypic divergence between sexes as a measure of how much each individual looks like the sex to which it belongs (phenotypic sexual resemblance, PSR). We then tested the fitness benefits associated with PSR by means of the probability of recruitment in the population. We found a significant interaction between PSR and sex, showing that in both sexes more feminized phenotypes recruited more into the population than less feminized phenotypes. Moreover, males showed lower PSR than females and a higher proportion of incorrect sex classifications. These findings suggest that the mechanisms in males devoted to resembling female phenotypes in youth, due to a trend to increase fitness through more feminized phenotypes, may provide a mechanism to constrain the SD in adulthood. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.
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Alves, Alexandre Alonso; Bhering, Leonardo Lopes; Rosado, Tatiana Barbosa; Laviola, Bruno Galvêas; Formighieri, Eduardo Fernandes; Cruz, Cosme Damião
2013-01-01
The genetic variability of the Brazilian physic nut (Jatropha curcas) germplasm bank (117 accessions) was assessed using a combination of phenotypic and molecular data. The joint dissimilarity matrix showed moderate correlation with the original matrices of phenotypic and molecular data. However, the correlation between the phenotypic dissimilarity matrix and the genotypic dissimilarity matrix was low. This finding indicated that molecular markers (RAPD and SSR) did not adequately sample the genomic regions that were relevant for phenotypic differentiation of the accessions. The dissimilarity values of the joint dissimilarity matrix were used to measure phenotypic + molecular diversity. This diversity varied from 0 to 1.29 among the 117 accessions, with an average dissimilarity among genotypes of 0.51. Joint analysis of phenotypic and molecular diversity indicated that the genetic diversity of the physic nut germplasm was 156% and 64% higher than the diversity estimated from phenotypic and molecular data, respectively. These results show that Jatropha genetic variability in Brazil is not as limited as previously thought. PMID:24130445
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Alves, Alexandre Alonso; Bhering, Leonardo Lopes; Rosado, Tatiana Barbosa; Laviola, Bruno Galvêas; Formighieri, Eduardo Fernandes; Cruz, Cosme Damião
2013-09-01
The genetic variability of the Brazilian physic nut (Jatropha curcas) germplasm bank (117 accessions) was assessed using a combination of phenotypic and molecular data. The joint dissimilarity matrix showed moderate correlation with the original matrices of phenotypic and molecular data. However, the correlation between the phenotypic dissimilarity matrix and the genotypic dissimilarity matrix was low. This finding indicated that molecular markers (RAPD and SSR) did not adequately sample the genomic regions that were relevant for phenotypic differentiation of the accessions. The dissimilarity values of the joint dissimilarity matrix were used to measure phenotypic + molecular diversity. This diversity varied from 0 to 1.29 among the 117 accessions, with an average dissimilarity among genotypes of 0.51. Joint analysis of phenotypic and molecular diversity indicated that the genetic diversity of the physic nut germplasm was 156% and 64% higher than the diversity estimated from phenotypic and molecular data, respectively. These results show that Jatropha genetic variability in Brazil is not as limited as previously thought.
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Genotype and phenotype spectrum of NRAS germline variants.
Altmüller, Franziska; Lissewski, Christina; Bertola, Debora; Flex, Elisabetta; Stark, Zornitza; Spranger, Stephanie; Baynam, Gareth; Buscarilli, Michelle; Dyack, Sarah; Gillis, Jane; Yntema, Helger G; Pantaleoni, Francesca; van Loon, Rosa LE; MacKay, Sara; Mina, Kym; Schanze, Ina; Tan, Tiong Yang; Walsh, Maie; White, Susan M; Niewisch, Marena R; García-Miñaúr, Sixto; Plaza, Diego; Ahmadian, Mohammad Reza; Cavé, Hélène; Tartaglia, Marco; Zenker, Martin
2017-06-01
RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.
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Picinelli, Chiara; Lintas, Carla; Piras, Ignazio Stefano; Gabriele, Stefano; Sacco, Roberto; Brogna, Claudia; Persico, Antonio Maria
2016-12-01
Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg 2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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Phenotypic variability and selection of lipid-producing microalgae in a microfluidic centrifuge
NASA Astrophysics Data System (ADS)
Estévez-Torres, André.; Mestler, Troy; Austin, Robert H.
2010-03-01
Isogenic cells are known to display various expression levels that may result in different phenotypes within a population. Here we focus on the phenotypic variability of a species of unicellular algae that produce neutral lipids. Lipid-producing algae are one of the most promising sources of biofuel. We have implemented a simple microfluidic method to assess lipid-production variability in a population of algae that relays on density differences. We will discuss the reasons of this variability and address the promising avenues of this technique for directing the evolution of algae towards high lipid productivity.
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[Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options].
Martos-Moreno, Gabriel A; Calzada, Joan; Couce, María L; Argente, Jesús
2018-06-01
Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.
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Hoogerheide, E S S; Azevedo Filho, J A; Vencovsky, R; Zucchi, M I; Zago, B W; Pinheiro, J B
2017-05-31
The cultivated garlic (Allium sativum L.) displays a wide phenotypic diversity, which is derived from natural mutations and phenotypic plasticity, due to dependence on soil type, moisture, latitude, altitude and cultural practices, leading to a large number of cultivars. This study aimed to evaluate the genetic variability shown by 63 garlic accessions belonging to Instituto Agronômico de Campinas and the Escola Superior de Agricultura "Luiz de Queiroz" germplasm collections. We evaluated ten quantitative characters in experimental trials conducted under two localities of the State of São Paulo: Monte Alegre do Sul and Piracicaba, during the agricultural year of 2007, in a randomized blocks design with five replications. The Mahalanobis distance was used to measure genetic dissimilarities. The UPGMA method and Tocher's method were used as clustering procedures. Results indicated significant variation among accessions (P < 0.01) for all evaluated characters, except for the percentage of secondary bulb growth in MAS, indicating the existence of genetic variation for bulb production, and germplasm evaluation considering different environments is more reliable for the characterization of the genotypic variability among garlic accessions, since it diminishes the environmental effects in the clustering of genotypes.
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Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.
Pollitt, Rebecca C; Saraff, Vrinda; Dalton, Ann; Webb, Emma A; Shaw, Nick J; Sobey, Glenda J; Mughal, M Zulf; Hobson, Emma; Ali, Farhan; Bishop, Nicholas J; Arundel, Paul; Högler, Wolfgang; Balasubramanian, Meena
2016-12-01
Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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Chan, Daisy K L
2008-12-01
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common genetic enzyme defect present in many people from African, Middle Eastern, Mediterranean and Asian countries. Individuals with the enzyme deficiency may remain asymptomatic, develop an acute haemolytic crises to infections or Fava beans, neonatal jaundice or chronic non-spherocytic haemolytic anaemia. Electrophoretic mobility may be fast, slow or normal. Over 160 mutations have been described, mostly due to single amino acid substitution. Although correlation of the genotype and biochemistry with the clinical phenotype of G6PD deficient individuals remains somewhat variable, there is better correlation among individuals presenting with chronic non-spherocytic haemolytic anaemia, which is related to the NADP structure of the enzyme.
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Shafie, Suraiya M.; Barria von-Bischhoffshausen, Fernando R.; Bateman, J. Bronwyn
2006-01-01
PURPOSE To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). DESIGN Prospective observational case series. METHODS We performed ophthalmologic examination in four Chilean ADC families. RESULTS The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. CONCLUSIONS The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation. PMID:16564818
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Twin studies advance the understanding of gene-environment interplay in human nutrigenomics.
Pallister, Tess; Spector, Tim D; Menni, Cristina
2014-12-01
Investigations into the genetic architecture of diet-disease relationships are particularly relevant today with the global epidemic of obesity and chronic disease. Twin studies have demonstrated that genetic makeup plays a significant role in a multitude of dietary phenotypes such as energy and macronutrient intakes, dietary patterns, and specific food group intakes. Besides estimating heritability of dietary assessment, twins provide a naturally unique, case-control experiment. Due to their shared upbringing, matched genes and sex (in the case of monozygotic (MZ) twin pairs), and age, twins provide many advantages over classic epidemiological approaches. Future genetic epidemiological studies could benefit from the twin approach particularly where defining what is 'normal' is problematic due to the high inter-individual variability underlying metabolism. Here, we discuss the use of twins to generate heritability estimates of food intake phenotypes. We then highlight the value of discordant MZ pairs to further nutrition research through discovery and validation of biomarkers of intake and health status in collaboration with cutting-edge omics technologies.
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Adaptations to Climate in Candidate Genes for Common Metabolic Disorders
Hancock, Angela M; Witonsky, David B; Gordon, Adam S; Eshel, Gidon; Pritchard, Jonathan K; Coop, Graham; Di Rienzo, Anna
2008-01-01
Evolutionary pressures due to variation in climate play an important role in shaping phenotypic variation among and within species and have been shown to influence variation in phenotypes such as body shape and size among humans. Genes involved in energy metabolism are likely to be central to heat and cold tolerance. To test the hypothesis that climate shaped variation in metabolism genes in humans, we used a bioinformatics approach based on network theory to select 82 candidate genes for common metabolic disorders. We genotyped 873 tag SNPs in these genes in 54 worldwide populations (including the 52 in the Human Genome Diversity Project panel) and found correlations with climate variables using rank correlation analysis and a newly developed method termed Bayesian geographic analysis. In addition, we genotyped 210 carefully matched control SNPs to provide an empirical null distribution for spatial patterns of allele frequency due to population history alone. For nearly all climate variables, we found an excess of genic SNPs in the tail of the distributions of the test statistics compared to the control SNPs, implying that metabolic genes as a group show signals of spatially varying selection. Among our strongest signals were several SNPs (e.g., LEPR R109K, FABP2 A54T) that had previously been associated with phenotypes directly related to cold tolerance. Since variation in climate may be correlated with other aspects of environmental variation, it is possible that some of the signals that we detected reflect selective pressures other than climate. Nevertheless, our results are consistent with the idea that climate has been an important selective pressure acting on candidate genes for common metabolic disorders. PMID:18282109
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Robinow syndrome: phenotypic variability in a family with a novel intragenic ROR2 mutation.
Brunetti-Pierri, Nicola; Del Gaudio, Daniela; Peters, Hartmut; Justino, Henri; Ott, Claus-Eric; Mundlos, Stefan; Bacino, Carlos A
2008-11-01
Robinow syndrome comprises dysmorphic facial features, short stature, brachymesomelia, segmental spine defects, and genital hypoplasia. The range of severity in this disorder is broad. We report on the clinical and molecular findings of two sib pairs from the same extended family with Robinow syndrome due to a novel intragenic ROR2 deletion involving exons 6 and 7 that could not be detected by sequencing. The affected individuals exhibited variability with respect to the cleft lip, cleft palate, and cardiac findings and for the presence in one of the patients of syringomyelia, which has not been previously reported in Robinow syndrome. Copyright 2008 Wiley-Liss, Inc.
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Phenotypic Variability in the Coccolithophore Emiliania huxleyi.
Blanco-Ameijeiras, Sonia; Lebrato, Mario; Stoll, Heather M; Iglesias-Rodriguez, Debora; Müller, Marius N; Méndez-Vicente, Ana; Oschlies, Andreas
2016-01-01
Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean.
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Coverdale, Tyler C; Goheen, Jacob R; Palmer, Todd M; Pringle, Robert M
2018-06-25
Intraspecific variation in plant defense phenotype is common and has wide-ranging ecological consequences. Yet prevailing theories of plant defense allocation, which primarily account for interspecific differences in defense phenotype, often fail to predict intraspecific patterns. Furthermore, although individual variation in defense phenotype is often attributed to ecological interactions, few general mechanisms have been proposed to explain the ubiquity of variable defense phenotype within species. Here, we show experimentally that associational refuges and induced resistance interact to create predictable intraspecific variation in defense phenotype in African savanna plants. Physically defended species from four families (Acanthaceae, Asparagaceae, Cactaceae, and Solanaceae) growing in close association with spinescent Acacia trees had 39-78% fewer spines and thorns than did isolated conspecifics. For a subset of these species, we used a series of manipulative experiments to show that this variability is maintained primarily by a reduction in induced responses among individuals that seldom experience mammalian herbivory, whether due to association with Acacia trees or to experimental herbivore exclusion. Unassociated plants incurred 4- to 16-fold more browsing damage than did associated individuals and increased spine density by 16-38% within one month following simulated browsing. In contrast, experimental clipping induced no net change in spine density among plants growing beneath Acacia canopies or inside long-term herbivore exclosures. Associated and unassociated individuals produced similar numbers of flowers and seeds, but seedling recruitment and survival were vastly greater in refuge habitats, suggesting a net fitness benefit of association. We conclude that plant-plant associations consistently decrease defense investment in this system by reducing both the frequency of herbivory and the intensity of induced responses, and that inducible responses enable plants to capitalize on such associations in heterogeneous environments. Given the prevalence of associational and induced defenses in plant communities worldwide, our results suggest a potentially general mechanism by which biotic interactions might predictably shape intraspecific variation in plant defense phenotype. © 2018 by the Ecological Society of America.
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Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10.
Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie
2014-09-01
Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. © 2014 Wiley Periodicals, Inc.
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Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10
Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie
2014-01-01
Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. PMID:24845202
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Cadle-Davidson, Lance; Gadoury, David; Fresnedo-Ramírez, Jonathan; Yang, Shanshan; Barba, Paola; Sun, Qi; Demmings, Elizabeth M; Seem, Robert; Schaub, Michelle; Nowogrodzki, Anna; Kasinathan, Hema; Ledbetter, Craig; Reisch, Bruce I
2016-10-01
The genomics era brought unprecedented opportunities for genetic analysis of host resistance, but it came with the challenge that accurate and reproducible phenotypes are needed so that genomic results appropriately reflect biology. Phenotyping host resistance by natural infection in the field can produce variable results due to the uncontrolled environment, uneven distribution and genetics of the pathogen, and developmentally regulated resistance among other factors. To address these challenges, we developed highly controlled, standardized methodologies for phenotyping powdery mildew resistance in the context of a phenotyping center, receiving samples of up to 140 grapevine progeny per F 1 family. We applied these methodologies to F 1 families segregating for REN1- or REN2-mediated resistance and validated that some but not all bioassays identified the REN1 or REN2 locus. A point-intercept method (hyphal transects) to quantify colony density objectively at 8 or 9 days postinoculation proved to be the phenotypic response most reproducibly predicted by these resistance loci. Quantitative trait locus (QTL) mapping with genotyping-by-sequencing maps defined the REN1 and REN2 loci at relatively high resolution. In the reference PN40024 genome under each QTL, nucleotide-binding site-leucine-rich repeat candidate resistance genes were identified-one gene for REN1 and two genes for REN2. The methods described here for centralized resistance phenotyping and high-resolution genetic mapping can inform strategies for breeding resistance to powdery mildews and other pathogens on diverse, highly heterozygous hosts.
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Segel, Reeval; Levy-Lahad, Ephrat; Pasutto, Francesca; Picard, Elie; Rauch, Anita; Alterescu, Gheona; Schimmel, Michael S
2009-11-01
Microphthalmic syndrome 9 (OMIM601186) is a genetically and phenotypically variable condition, comprising anophthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac malformations (PDAC syndrome). Reported cases have all been associated with fetal/neonatal death or developmental delay. Recessive stimulated by retinoic acid gene 6 homolog (STRA6) mutations have recently been identified as the cause of cases of PDAC in which distinct, "bushy" eyebrows have been observed. We describe a patient with clinical anophthalmia, bushy eyebrows, patent ductus arteriosus, and normal development at age 30 months, who is a compound heterozygote for two novel STRA6 missense mutations. This patient's phenotype is consistent with the multisystemic malformations of PDAC syndrome, but is somewhat milder. This is the first living patient with compound heterozygous STRA6 mutations, which may explain her milder phenotype. We conclude that STRA6 analysis should be considered in all patients with clinical anophthalmia. Genetic counseling should be cautious with respect to long-term developmental outcomes. Copyright 2009 Wiley-Liss, Inc.
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Lee, Seungyeoun; Kim, Yongkang; Kwon, Min-Seok; Park, Taesung
2015-01-01
Genome-wide association studies (GWAS) have extensively analyzed single SNP effects on a wide variety of common and complex diseases and found many genetic variants associated with diseases. However, there is still a large portion of the genetic variants left unexplained. This missing heritability problem might be due to the analytical strategy that limits analyses to only single SNPs. One of possible approaches to the missing heritability problem is to consider identifying multi-SNP effects or gene-gene interactions. The multifactor dimensionality reduction method has been widely used to detect gene-gene interactions based on the constructive induction by classifying high-dimensional genotype combinations into one-dimensional variable with two attributes of high risk and low risk for the case-control study. Many modifications of MDR have been proposed and also extended to the survival phenotype. In this study, we propose several extensions of MDR for the survival phenotype and compare the proposed extensions with earlier MDR through comprehensive simulation studies. PMID:26339630
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Adaptive potential of genomic structural variation in human and mammalian evolution.
Radke, David W; Lee, Charles
2015-09-01
Because phenotypic innovations must be genetically heritable for biological evolution to proceed, it is natural to consider new mutation events as well as standing genetic variation as sources for their birth. Previous research has identified a number of single-nucleotide polymorphisms that underlie a subset of adaptive traits in organisms. However, another well-known class of variation, genomic structural variation, could have even greater potential to produce adaptive phenotypes, due to the variety of possible types of alterations (deletions, insertions, duplications, among others) at different genomic positions and with variable lengths. It is from these dramatic genomic alterations, and selection on their phenotypic consequences, that adaptations leading to biological diversification could be derived. In this review, using studies in humans and other mammals, we highlight examples of how phenotypic variation from structural variants might become adaptive in populations and potentially enable biological diversification. Phenotypic change arising from structural variants will be described according to their immediate effect on organismal metabolic processes, immunological response and physical features. Study of population dynamics of segregating structural variation can therefore provide a window into understanding current and historical biological diversification. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Kumar, Shivendra; Ambreen, Heena; Variath, Murali T.; Rao, Atmakuri R.; Agarwal, Manu; Kumar, Amar; Goel, Shailendra; Jagannath, Arun
2016-01-01
Safflower (Carthamus tinctorius L.) is a dryland oilseed crop yielding high quality edible oil. Previous studies have described significant phenotypic variability in the crop and used geographical distribution and phenotypic trait values to develop core collections. However, the molecular diversity component was lacking in the earlier collections thereby limiting their utility in breeding programs. The present study evaluated the phenotypic variability for 12 agronomically important traits during two growing seasons (2011–12 and 2012–13) in a global reference collection of 531 safflower accessions, assessed earlier by our group for genetic diversity and population structure using AFLP markers. Significant phenotypic variation was observed for all the agronomic traits in the representative collection. Cluster analysis of phenotypic data grouped the accessions into five major clusters. Accessions from the Indian Subcontinent and America harbored maximal phenotypic variability with unique characters for a few traits. MANOVA analysis indicated significant interaction between genotypes and environment for both the seasons. Initially, six independent core collections (CC1–CC6) were developed using molecular marker and phenotypic data for two seasons through POWERCORE and MSTRAT. These collections captured the entire range of trait variability but failed to include complete genetic diversity represented in 19 clusters reported earlier through Bayesian analysis of population structure (BAPS). Therefore, we merged the three POWERCORE core collections (CC1–CC3) to generate a composite core collection, CartC1 and three MSTRAT core collections (CC4–CC6) to generate another composite core collection, CartC2. The mean difference percentage, variance difference percentage, variable rate of coefficient of variance percentage, coincidence rate of range percentage, Shannon's diversity index, and Nei's gene diversity for CartC1 were 11.2, 43.7, 132.4, 93.4, 0.47, and 0.306, respectively while the corresponding values for CartC2 were 9.3, 58.8, 124.6, 95.8, 0.46, and 0.301. Each composite core collection represented the complete range of phenotypic and genetic variability of the crop including 19 BAPS clusters. This is the first report describing development of core collections in safflower using molecular marker data with phenotypic values and geographical distribution. These core collections will facilitate identification of genetic determinants of trait variability and effective utilization of the prevalent diversity in crop improvement programs. PMID:27807441
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Brummett, Chad M.; Goesling, Jenna; Tsodikov, Alex; Meraj, Taha S.; Wasserman, Ronald A.; Clauw, Daniel J.; Hassett, Afton L.
2014-01-01
Objective Injections for spinal pain have high failure rates, emphasizing the importance of patient selection. It is possible that detecting the presence of a fibromyalgia-like phenotype could aid in prediction, because in these individuals a peripheral injection would not address pain due to alterations in central neurotransmission. We hypothesized that spine pain patients meeting survey criteria for fibromyalgia would be phenotypically distinct from those who do not meet criteria. Methods 548 patients with a primary spine pain diagnosis were studied. All patients completed validated self-report questionnaires, including the Brief Pain Inventory, PainDETECT, Hospital Anxiety and Depression Scale, measures of physical function, and the American College of Rheumatology survey criteria for fibromyalgia. Results 42% met survey criteria for fibromyalgia (FM+). When compared with criteria negative patients, FM+ patients were more likely to be younger, unemployed, receiving compensation, have greater pain intensity, pain interference and neuropathic pain descriptors, as well as higher levels of depression and anxiety, and lower level of physical function (p < 0.0001 for each comparison). Gender, neuropathic pain, pain interference, physical function, and anxiety were independently predictive of fibromyalgia status in a multivariate analysis (p < 0.01, all variables). ROC analysis showed the strength of association of 0.81 as measured by the cross-validated C-statistic. Conclusion Using the survey criteria for fibromyalgia, we demonstrated profound phenotypic differences in a spine pain population. Although centralized pain cannot be confirmed with a survey alone, the pathophysiology of fibromyalgia may help explain a portion of the variability of responses to spine interventions. PMID:24022710
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A patient with 22q11.2 deletion syndrome: case report.
Eryılmaz, Sema Kabataş; Baş, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin
2009-01-01
22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia.
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A Patient with 22q11.2 Deletion Syndrome: Case Report
Baş, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin
2009-01-01
22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia. Conflict of interest:None declared. PMID:21274400
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Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sibille, A.; Eng, C.M.; Kim, S.J.
1993-06-01
Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, andmore » severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.« less
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Synchrotron microCT imaging of soft tissue in juvenile zebrafish reveals retinotectal projections
NASA Astrophysics Data System (ADS)
Xin, Xuying; Clark, Darin; Ang, Khai Chung; van Rossum, Damian B.; Copper, Jean; Xiao, Xianghui; La Riviere, Patrick J.; Cheng, Keith C.
2017-02-01
Biomedical research and clinical diagnosis would benefit greatly from full volume determinations of anatomical phenotype. Comprehensive tools for morphological phenotyping are central for the emerging field of phenomics, which requires high-throughput, systematic, accurate, and reproducible data collection from organisms affected by genetic, disease, or environmental variables. Theoretically, complete anatomical phenotyping requires the assessment of every cell type in the whole organism, but this ideal is presently untenable due to the lack of an unbiased 3D imaging method that allows histopathological assessment of any cell type despite optical opacity. Histopathology, the current clinical standard for diagnostic phenotyping, involves the microscopic study of tissue sections to assess qualitative aspects of tissue architecture, disease mechanisms, and physiological state. However, quantitative features of tissue architecture such as cellular composition and cell counting in tissue volumes can only be approximated due to characteristics of tissue sectioning, including incomplete sampling and the constraints of 2D imaging of 5 micron thick tissue slabs. We have used a small, vertebrate organism, the zebrafish, to test the potential of microCT for systematic macroscopic and microscopic morphological phenotyping. While cell resolution is routinely achieved using methods such as light sheet fluorescence microscopy and optical tomography, these methods do not provide the pancellular perspective characteristic of histology, and are constrained by the limited penetration of visible light through pigmented and opaque specimens, as characterizes zebrafish juveniles. Here, we provide an example of neuroanatomy that can be studied by microCT of stained soft tissue at 1.43 micron isotropic voxel resolution. We conclude that synchrotron microCT is a form of 3D imaging that may potentially be adopted towards more reproducible, large-scale, morphological phenotyping of optically opaque tissues. Further development of soft tissue microCT, visualization and quantitative tool development will enhance its utility.
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Phenotypic Variability in the Coccolithophore Emiliania huxleyi
Lebrato, Mario; Stoll, Heather M.; Iglesias-Rodriguez, Debora; Müller, Marius N.; Méndez-Vicente, Ana; Oschlies, Andreas
2016-01-01
Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean. PMID:27348427
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Phenotypic variability of Cat-Eye syndrome.
Berends, M J; Tan-Sindhunata, G; Leegte, B; van Essen, A J
2001-01-01
Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.
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Potter, Huntington
2017-01-01
Phenotypic variability is a fundamental feature of the human population and is particularly evident among people with Down syndrome and/or Alzheimer’s disease. Herein, we review current theories of the potential origins of this phenotypic variability and propose a novel mechanism based on our finding that the Alzheimer’s disease-associated Aβ peptide, encoded on chromosome 21, disrupts the mitotic spindle, induces abnormal chromosome segregation, and produces mosaic populations of aneuploid cells in all tissues of people with Alzheimer’s disease and in mouse and cell models thereof. Thus, individuals exposed to increased levels of the Aβ peptide should accumulate mosaic populations of aneuploid cells, with different chromosomes affected in different tissues and in different individuals. Specifically, people with Down syndrome, who express elevated levels of Aβ peptide throughout their lifetimes, would be predicted to accumulate additional types of aneuploidy, beyond trisomy 21 and including changes in their trisomy 21 status, in mosaic cell populations. Such mosaic aneuploidy would introduce a novel form of genetic variability that could potentially underlie much of the observed phenotypic variability among people with Down syndrome, and possibly also among people with Alzheimer’s disease. This mosaic aneuploidy theory of phenotypic variability in Down syndrome is supported by several observations, makes several testable predictions, and identifies a potential approach to reducing the frequency of some of the most debilitating features of Down syndrome, including Alzheimer’s disease. PMID:29516054
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Feltri, M. Laura; Wrabetz, Lawrence
2016-01-01
Globoid cell leukodystrophy (GLD, Krabbe disease) is due to autosomal recessive mutations in the lysosomal enzyme galactosylceramidase (GALC). Many GLD patients develop infantile-onset of progressive neurologic deterioration and death by 2 years of age, whereas others have a later-onset, milder disease. Cord blood transplant slows disease progression much more effectively when performed presymptomatically, highlighting the importance of early diagnosis. Current diagnosis is based on reduced GALC activity, DNA sequence, and clinical examination. However, presymptomatic diagnosis is hampered by imperfect genotype-GALC activity-phenotype correlations. In addition, three polymorphisms in the GALC gene are variably associated with disease mutations and have unknown effects on GALC activity and disease outcome. Here, we study mutations that cause infantile or later-onset GLD, and show that GALC activity is significantly lower in infantile versus later-onset mutants when measured in the lysosomal fraction, but not in whole-cell lysates. In parallel, infantile-onset mutant GALCs showed reduced trafficking to lysosomes and processing than later-onset mutant GALCs. Finally, the cis-polymorphisms also affected trafficking to the lysosome and processing of GALC. These differences potentially explain why the activity of different mutations appears similar in whole-cell extracts from lymphocytes, and suggest that measure of GALC activity in lysosomes may better predict the onset and severity of disease for a given GLD genotype. SIGNIFICANCE STATEMENT Globoid cell leukodystrophy (GLD, Krabbe disease) is diagnosed by measuring galactosylceramidase (GALC) activity and DNA analysis. However, genotype and phenotype often do not correlate due to considerable clinical variability, even for the same mutation, for unknown reasons. We find that altered trafficking to the lysosome and processing of GALC correlates with GLD severity and is modulated by cis-polymorphisms. Current diagnosis of GLD is based on GALC activity of total cell lysates from blood, which does not discriminate whether the activity comes from the lysosome or other subcellular organelles. Measurement of GALC activity in lysosomes may predict which infants are at high risk for the infantile phenotype while distinguishing other children who will develop later-onset phenotypes without onset of symptoms for years. PMID:26865610
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RBBP8 syndrome with microcephaly, intellectual disability, short stature and brachydactyly.
Mumtaz, Sara; Yıldız, Esra; Jabeen, Saliha; Khan, Amjad; Tolun, Aslıhan; Malik, Sajid
2015-12-01
Primary microcephaly is clinically variable and genetically heterogeneous. Four phenotypically distinct types of autosomal recessive microcephaly syndromes are due to different RBBP8 mutations. We report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (p.Ile603Lysfs*7) manifesting microcephaly and a distinct combination of skeletal, limb and ectodermal defects, mild intellectual disability, minor facial anomalies, anonychia, disproportionate short stature and brachydactyly, and additionally talipes in one patient. © 2015 Wiley Periodicals, Inc.
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Combining Genotype, Phenotype, and Environment to Infer Potential Candidate Genes.
Talbot, Benoit; Chen, Ting-Wen; Zimmerman, Shawna; Joost, Stéphane; Eckert, Andrew J; Crow, Taylor M; Semizer-Cuming, Devrim; Seshadri, Chitra; Manel, Stéphanie
2017-03-01
Population genomic analysis can be an important tool in understanding local adaptation. Identification of potential adaptive loci in such analyses is usually based on the survey of a large genomic dataset in combination with environmental variables. Phenotypic data are less commonly incorporated into such studies, although combining a genome scan analysis with a phenotypic trait analysis can greatly improve the insights obtained from each analysis individually. Here, we aimed to identify loci potentially involved in adaptation to climate in 283 Loblolly pine (Pinus taeda) samples from throughout the species' range in the southeastern United States. We analyzed associations between phenotypic, molecular, and environmental variables from datasets of 3082 single nucleotide polymorphism (SNP) loci and 3 categories of phenotypic traits (gene expression, metabolites, and whole-plant traits). We found only 6 SNP loci that displayed potential signals of local adaptation. Five of the 6 identified SNPs are linked to gene expression traits for lignin development, and 1 is linked with whole-plant traits. We subsequently compared the 6 candidate genes with environmental variables and found a high correlation in only 3 of them (R2 > 0.2). Our study highlights the need for a combination of genotypes, phenotypes, and environmental variables, and for an appropriate sampling scheme and study design, to improve confidence in the identification of potential candidate genes. © The American Genetic Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Liccardo, Raffaella; De Rosa, Marina; Duraturo, Francesca
2018-01-01
Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair ( MMR ) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.
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Addressing phenoconversion: the Achilles' heel of personalized medicine
Shah, Rashmi R; Smith, Robert L
2015-01-01
Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype–phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype–phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype–phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. PMID:24913012
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Tang, Weijuan; Hazebroek, Jan; Zhong, Cathy; Harp, Teresa; Vlahakis, Chris; Baumhover, Brian; Asiago, Vincent
2017-06-28
We evaluated the variability of metabolites in various maize hybrids due to the effect of environment, genotype, phenotype as well as the interaction of the first two factors. We analyzed 480 forage and the same number of grain samples from 21 genetically diverse non-GM Pioneer brand maize hybrids, including some with drought tolerance and viral resistance phenotypes, grown at eight North American locations. As complementary platforms, both GC/MS and LC/MS were utilized to detect a wide diversity of metabolites. GC/MS revealed 166 and 137 metabolites in forage and grain samples, respectively, while LC/MS captured 1341 and 635 metabolites in forage and grain samples, respectively. Univariate and multivariate analyses were utilized to investigate the response of the maize metabolome to the environment, genotype, phenotype, and their interaction. Based on combined percentages from GC/MS and LC/MS datasets, the environment affected 36% to 84% of forage metabolites, while less than 7% were affected by genotype. The environment affected 12% to 90% of grain metabolites, whereas less than 27% were affected by genotype. Less than 10% and 11% of the metabolites were affected by phenotype in forage and grain, respectively. Unsupervised PCA and HCA analyses revealed similar trends, i.e., environmental effect was much stronger than genotype or phenotype effects. On the basis of comparisons of disease tolerant and disease susceptible hybrids, neither forage nor grain samples originating from different locations showed obvious phenotype effects. Our findings demonstrate that the combination of GC/MS and LC/MS based metabolite profiling followed by broad statistical analysis is an effective approach to identify the relative impact of environmental, genetic and phenotypic effects on the forage and grain composition of maize hybrids.
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2011-01-01
Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity. PMID:21699693
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Bunyan, David J; Baker, Kevin R; Harvey, John F; Thomas, N Simon
2013-06-01
Léri-Weill dyschondrosteosis (LWD) results from heterozygous mutations of the SHOX gene, with homozygosity or compound heterozygosity resulting in the more severe form, Langer mesomelic dysplasia (LMD). These mutations typically take the form of whole or partial gene deletions, point mutations within the coding sequence, or large (>100 kb) 3' deletions of downstream regulatory elements. We have analyzed the coding sequence of the SHOX gene and its downstream regulatory regions in a cohort of 377 individuals referred with symptoms of LWD, LMD or short stature. A causative mutation was identified in 68% of the probands with LWD or LMD (91/134). In addition, a 47.5 kb deletion was found 160 kb downstream of the SHOX gene in 17 of the 377 patients (12% of the LWD referrals, 4.5% of all referrals). In 14 of these 17 patients, this was the only potentially causative abnormality detected (13 had symptoms consistent with LWD and one had short stature only), but the other three 47.5 kb deletions were found in patients with an additional causative SHOX mutation (with symptoms of LWD rather than LMD). Parental samples were available on 14/17 of these families, and analysis of these showed a more variable phenotype ranging from apparently unaffected to LWD. Breakpoint sequence analysis has shown that the 47.5 kb deletion is identical in all 17 patients, most likely due to an ancient founder mutation rather than recurrence. This deletion was not seen in 471 normal controls (P<0.0001), providing further evidence for a phenotypic effect, albeit one with variable penetration. Copyright © 2013 Wiley Periodicals, Inc.
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Feinberg, Andrew P; Irizarry, Rafael A
2010-01-26
Neo-Darwinian evolutionary theory is based on exquisite selection of phenotypes caused by small genetic variations, which is the basis of quantitative trait contribution to phenotype and disease. Epigenetics is the study of nonsequence-based changes, such as DNA methylation, heritable during cell division. Previous attempts to incorporate epigenetics into evolutionary thinking have focused on Lamarckian inheritance, that is, environmentally directed epigenetic changes. Here, we propose a new non-Lamarckian theory for a role of epigenetics in evolution. We suggest that genetic variants that do not change the mean phenotype could change the variability of phenotype; and this could be mediated epigenetically. This inherited stochastic variation model would provide a mechanism to explain an epigenetic role of developmental biology in selectable phenotypic variation, as well as the largely unexplained heritable genetic variation underlying common complex disease. We provide two experimental results as proof of principle. The first result is direct evidence for stochastic epigenetic variation, identifying highly variably DNA-methylated regions in mouse and human liver and mouse brain, associated with development and morphogenesis. The second is a heritable genetic mechanism for variable methylation, namely the loss or gain of CpG dinucleotides over evolutionary time. Finally, we model genetically inherited stochastic variation in evolution, showing that it provides a powerful mechanism for evolutionary adaptation in changing environments that can be mediated epigenetically. These data suggest that genetically inherited propensity to phenotypic variability, even with no change in the mean phenotype, substantially increases fitness while increasing the disease susceptibility of a population with a changing environment.
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Mallick, Himel; Tiwari, Hemant K.
2016-01-01
Count data are increasingly ubiquitous in genetic association studies, where it is possible to observe excess zero counts as compared to what is expected based on standard assumptions. For instance, in rheumatology, data are usually collected in multiple joints within a person or multiple sub-regions of a joint, and it is not uncommon that the phenotypes contain enormous number of zeroes due to the presence of excessive zero counts in majority of patients. Most existing statistical methods assume that the count phenotypes follow one of these four distributions with appropriate dispersion-handling mechanisms: Poisson, Zero-inflated Poisson (ZIP), Negative Binomial, and Zero-inflated Negative Binomial (ZINB). However, little is known about their implications in genetic association studies. Also, there is a relative paucity of literature on their usefulness with respect to model misspecification and variable selection. In this article, we have investigated the performance of several state-of-the-art approaches for handling zero-inflated count data along with a novel penalized regression approach with an adaptive LASSO penalty, by simulating data under a variety of disease models and linkage disequilibrium patterns. By taking into account data-adaptive weights in the estimation procedure, the proposed method provides greater flexibility in multi-SNP modeling of zero-inflated count phenotypes. A fast coordinate descent algorithm nested within an EM (expectation-maximization) algorithm is implemented for estimating the model parameters and conducting variable selection simultaneously. Results show that the proposed method has optimal performance in the presence of multicollinearity, as measured by both prediction accuracy and empirical power, which is especially apparent as the sample size increases. Moreover, the Type I error rates become more or less uncontrollable for the competing methods when a model is misspecified, a phenomenon routinely encountered in practice. PMID:27066062
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Mallick, Himel; Tiwari, Hemant K
2016-01-01
Count data are increasingly ubiquitous in genetic association studies, where it is possible to observe excess zero counts as compared to what is expected based on standard assumptions. For instance, in rheumatology, data are usually collected in multiple joints within a person or multiple sub-regions of a joint, and it is not uncommon that the phenotypes contain enormous number of zeroes due to the presence of excessive zero counts in majority of patients. Most existing statistical methods assume that the count phenotypes follow one of these four distributions with appropriate dispersion-handling mechanisms: Poisson, Zero-inflated Poisson (ZIP), Negative Binomial, and Zero-inflated Negative Binomial (ZINB). However, little is known about their implications in genetic association studies. Also, there is a relative paucity of literature on their usefulness with respect to model misspecification and variable selection. In this article, we have investigated the performance of several state-of-the-art approaches for handling zero-inflated count data along with a novel penalized regression approach with an adaptive LASSO penalty, by simulating data under a variety of disease models and linkage disequilibrium patterns. By taking into account data-adaptive weights in the estimation procedure, the proposed method provides greater flexibility in multi-SNP modeling of zero-inflated count phenotypes. A fast coordinate descent algorithm nested within an EM (expectation-maximization) algorithm is implemented for estimating the model parameters and conducting variable selection simultaneously. Results show that the proposed method has optimal performance in the presence of multicollinearity, as measured by both prediction accuracy and empirical power, which is especially apparent as the sample size increases. Moreover, the Type I error rates become more or less uncontrollable for the competing methods when a model is misspecified, a phenomenon routinely encountered in practice.
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Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.
Rice, Gillian I; Kitabayashi, Naoki; Barth, Magalie; Briggs, Tracy A; Burton, Annabel C E; Carpanelli, Maria Luisa; Cerisola, Alfredo M; Colson, Cindy; Dale, Russell C; Danti, Federica Rachele; Darin, Niklas; De Azua, Begoña; De Giorgis, Valentina; De Goede, Christian G L; Desguerre, Isabelle; De Laet, Corinne; Eslahi, Atieh; Fahey, Michael C; Fallon, Penny; Fay, Alex; Fazzi, Elisa; Gorman, Mark P; Gowrinathan, Nirmala Rani; Hully, Marie; Kurian, Manju A; Leboucq, Nicolas; Lin, Jean-Pierre S-M; Lines, Matthew A; Mar, Soe S; Maroofian, Reza; Martí-Sanchez, Laura; McCullagh, Gary; Mojarrad, Majid; Narayanan, Vinodh; Orcesi, Simona; Ortigoza-Escobar, Juan Dario; Pérez-Dueñas, Belén; Petit, Florence; Ramsey, Keri M; Rasmussen, Magnhild; Rivier, François; Rodríguez-Pombo, Pilar; Roubertie, Agathe; Stödberg, Tommy I; Toosi, Mehran Beiraghi; Toutain, Annick; Uettwiller, Florence; Ulrick, Nicole; Vanderver, Adeline; Waldman, Amy; Livingston, John H; Crow, Yanick J
2017-06-01
We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1 . The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context. Georg Thieme Verlag KG Stuttgart · New York.
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Mutants of the Paf1 Complex Alter Phenotypic Expression of the Yeast Prion [PSI+
Strawn, Lisa A.; Lin, Changyi A.; Tank, Elizabeth M.H.; Osman, Morwan M.; Simpson, Sarah A.
2009-01-01
The yeast [PSI+] prion is an epigenetic modifier of translation termination fidelity that causes nonsense suppression. The prion [PSI+] forms when the translation termination factor Sup35p adopts a self-propagating conformation. The presence of the [PSI+] prion modulates survivability in a variety of growth conditions. Nonsense suppression is essential for many [PSI+]-mediated phenotypes, but many do not appear to be due to read-through of a single stop codon, but instead are multigenic traits. We hypothesized that other global mechanisms act in concert with [PSI+] to influence [PSI+]-mediated phenotypes. We have identified one such global regulator, the Paf1 complex (Paf1C). Paf1C is conserved in eukaryotes and has been implicated in several aspects of transcriptional and posttranscriptional regulation. Mutations in Ctr9p and other Paf1C components reduced [PSI+]-mediated nonsense suppression. The CTR9 deletion also alters nonsense suppression afforded by other genetic mutations but not always to the same extent as the effects on [PSI+]-mediated read-through. Our data suggest that the Paf1 complex influences mRNA translatability but not solely through changes in transcript stability or abundance. Finally, we demonstrate that the CTR9 deletion alters several [PSI+]-dependent phenotypes. This provides one example of how [PSI+] and genetic modifiers can interact to uncover and regulate phenotypic variability. PMID:19225160
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Phenotypic variability in unicellular organisms: from calcium signalling to social behaviour
Vogel, David; Nicolis, Stamatios C.; Perez-Escudero, Alfonso; Nanjundiah, Vidyanand; Sumpter, David J. T.; Dussutour, Audrey
2015-01-01
Historically, research has focused on the mean and often neglected the variance. However, variability in nature is observable at all scales: among cells within an individual, among individuals within a population and among populations within a species. A fundamental quest in biology now is to find the mechanisms that underlie variability. Here, we investigated behavioural variability in a unique unicellular organism, Physarum polycephalum. We combined experiments and models to show that variability in cell signalling contributes to major differences in behaviour underpinning some aspects of social interactions. First, following thousands of cells under various contexts, we identified distinct behavioural phenotypes: ‘slow–regular–social’, ‘fast–regular–social’ and ‘fast–irregular–asocial’. Second, coupling chemical analysis and behavioural assays we found that calcium signalling is responsible for these behavioural phenotypes. Finally, we show that differences in signalling and behaviour led to alternative social strategies. Our results have considerable implications for our understanding of the emergence of variability in living organisms. PMID:26609088
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Phenotypic variability in unicellular organisms: from calcium signalling to social behaviour.
Vogel, David; Nicolis, Stamatios C; Perez-Escudero, Alfonso; Nanjundiah, Vidyanand; Sumpter, David J T; Dussutour, Audrey
2015-11-22
Historically, research has focused on the mean and often neglected the variance. However, variability in nature is observable at all scales: among cells within an individual, among individuals within a population and among populations within a species. A fundamental quest in biology now is to find the mechanisms that underlie variability. Here, we investigated behavioural variability in a unique unicellular organism, Physarum polycephalum. We combined experiments and models to show that variability in cell signalling contributes to major differences in behaviour underpinning some aspects of social interactions. First, following thousands of cells under various contexts, we identified distinct behavioural phenotypes: 'slow-regular-social', 'fast-regular-social' and 'fast-irregular-asocial'. Second, coupling chemical analysis and behavioural assays we found that calcium signalling is responsible for these behavioural phenotypes. Finally, we show that differences in signalling and behaviour led to alternative social strategies. Our results have considerable implications for our understanding of the emergence of variability in living organisms. © 2015 The Author(s).
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Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15.
Olander, E; Stamberg, J; Steinberg, L; Wulfsberg, E A
2000-07-31
We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.
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Assessment of metabolic phenotypic variability in children’s urine using 1H NMR spectroscopy
NASA Astrophysics Data System (ADS)
Maitre, Léa; Lau, Chung-Ho E.; Vizcaino, Esther; Robinson, Oliver; Casas, Maribel; Siskos, Alexandros P.; Want, Elizabeth J.; Athersuch, Toby; Slama, Remy; Vrijheid, Martine; Keun, Hector C.; Coen, Muireann
2017-04-01
The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8-9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life.
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Phenotype-genotype correlations in congenital isolated growth hormone deficiency (IGHD).
Alatzoglou, Kyriaki S; Dattani, Mehul T
2012-01-01
Isolated growth hormone deficiency (IGHD) may be congenital, often due to genetic mutations, or acquired as a result of other factors such as cranial irradiation. The commonest genes implicated in its genetic etiology are those encoding growth hormone (GH1) and the receptor for GH-releasing hormone (GHRHR). Rarely, IGHD may be caused by mutations in transcription factors (HESX1, SOX3, OTX2) or be the first presentation before the development of other pituitary hormone deficiencies. IGHD has been classified in four genetic forms (type IA, IB, II and III). Despite the increasing number of genes implicated in the etiology of IGHD, mutations in known genes account only for a small percentage of cases; therefore, other as yet unidentified factors may be implicated in its etiology. Although there is no strict genotype/phenotype correlation in patients with IGHD, there are some emerging patterns that may guide us towards a genetic diagnosis of the condition. There is increasing understanding that the phenotype of patients with IGHD is highly variable and sometimes even evolving, dictating the need for long term follow-up in these cases.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Helali, A.N.; Jafolla, A.K.; Oumsiych, M.B.
1994-09-01
A 10-year-old white male presented with mild microcephaly, slight growth and psychomotor retardation, soft fleshy ears, and normal facial features except for thin lips. No other significant anomalies were reported except for tethered cord discovered at age 8 years. The karyotype was found to be 46,XY,der(18)t(13;18)(q32;p11.32)pat. The mild phenotype appears to be primarily due to the duplication of 13q32{yields}qter. None of the cardinal features of trisomy 13 are found in cases of duplication of bands 13q22 to qter. This case shows that Patau syndrome phenotype does not originate by duplication of 13q32{yields}qter and may thus be restricted to 13q22 tomore » 13q32. The variability in phenotypes points to an alternative explanation to the classical one of additive and interactive gene effects. This model involves effects of changes in chromosome position in the interphase nucleus on gene expression.« less
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Phenotype-genotype correlations in a series of wolfram syndrome families.
Smith, Casey J A; Crock, Patricia A; King, Bruce R; Meldrum, Cliff J; Scott, Rodney J
2004-08-01
Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes in association with progressive optic atrophy. The genetic basis of this disease has been shown to be due to mutations in the WFS1 gene. The WFS1 gene encodes a novel transmembrane protein called wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. Genotype-phenotype correlations in this syndrome are becoming apparent and may help in explaining some of the variable characteristics observed in this disease. In this report, we have studied 13 patients with Wolfram syndrome from nine families to further define the relationship between mutation site and type with specific disease characteristics. A severe phenotype was seen in patients with mutations in exon 4 and with a large deletion encompassing most of exon 8. In total, nine novel mutations were identified as well as three new silent polymorphisms. Similar to all other mutation reports, most causative changes identified in the WFS1 gene occurred in exon 8, and only one was identified outside this region in exon 4.
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Nghiem, Peter P.; Bello, Luca; Stoughton, William B.; López, Sara Mata; Vidal, Alexander H.; Hernandez, Briana V.; Hulbert, Katherine N.; Gourley, Taylor R.; Bettis, Amanda K.; Balog-Alvarez, Cynthia J.; Heath-Barnett, Heather; Kornegay, Joe N.
2017-01-01
Duchenne muscular dystrophy (DMD) is an X-chromosome-linked disorder and the most common monogenic disease in people. Affected boys are diagnosed at a young age, become non-ambulatory by their early teens, and succumb to cardiorespiratory failure by their thirties. Despite being a monogenic condition resulting from mutations in the DMD gene, affected boys have noteworthy phenotypic variability. Efforts have identified genetic modifiers that could modify disease progression and be pharmacologic targets. Dogs affected with golden retriever muscular dystrophy (GRMD) have absent dystrophin and demonstrate phenotypic variability at the functional, histopathological, and molecular level. Our laboratory is particularly interested in muscle metabolism changes in dystrophin-deficient muscle. We identified several metabolic alterations, including myofiber type switching from fast (type II) to slow (type I), reduced glycolytic enzyme expression, reduced and morphologically abnormal mitochondria, and differential AMP-kinase phosphorylation (activation) between hypertrophied and wasted muscle. We hypothesize that muscle metabolism changes are, in part, responsible for phenotypic variability in GRMD. Pharmacological therapies aimed at modulating muscle metabolism can be tested in GRMD dogs for efficacy. PMID:28955176
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Crean, Angela J.; Dwyer, John M.; Marshall, Dustin J.
2012-01-01
Sperm are the most diverse cell type known: varying not only among- and within- species, but also among- and within-ejaculates of a single male. Recently, the causes and consequences of variability in sperm phenotypes have received much attention, but the importance of within-ejaculate variability remains largely unknown. Correlative evidence suggests that reduced within-ejaculate variation in sperm phenotype increases a male’s fertilization success in competitive conditions; but the transgenerational consequences of within-ejaculate variation in sperm phenotype remain relatively unexplored. Here we examine the relationship between sperm longevity and offspring performance in a marine invertebrate with external fertilization, Styela plicata. Offspring sired by longer-lived sperm had higher performance compared to offspring sired by freshly-extracted sperm of the same ejaculate, both in the laboratory and the field. This indicates that within-ejaculate differences in sperm longevity can influence offspring fitness – a source of variability in offspring phenotypes that has not previously been considered. Links between sperm phenotype and offspring performance may constrain responses to selection on either sperm or offspring traits, with broad ecological and evolutionary implications. PMID:23155458
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Genotypic and phenotypic diversity of Alicyclobacillus acidocaldarius isolates.
Félix-Valenzuela, L; Guardiola-Avila, I; Burgara-Estrella, A; Ibarra-Zavala, M; Mata-Haro, V
2015-10-01
The fruit juice industry recognizes Alicyclobacillus as a major quality control target micro-organism. In this study, we analysed 19 bacterial isolates to identify Alicyclobacillus species by polymerase chain reaction (PCR) and sequencing analyses. Phenotypic and genomic diversity among isolates were investigated by API 50CHB system and ERIC-PCR (enterobacterial repetitive intergenic consensus-PCR) respectively. All bacterial isolates were identified as Alicyclobacillus acidocaldarius, and almost all showed identical DNA sequences according to their 16S rRNA (rDNA) gene partial sequences. Only few carbohydrates were fermented by A. acidocaldarius isolates, and there was little variability in the biochemical profile. Genotypic fingerprinting of the A. acidocaldarius isolates showed high diversity, and clusters by ERIC-PCR were distinct to those obtained from the 16S rRNA gene phylogenetic tree. There was no correlation between phenotypic and genotypic variability in the A. acidocaldarius isolates analysed in this study. Detection of Alicyclobacillus strains is imperative in fruit concentrates and juices due to the production of guaiacol. Identification of the genera originates rejection of the product by processing industry. However, not all the Alicyclobacillus species are deteriorative and hence the importance to differentiate among them. In this study, partial 16S ribosomal RNA sequence alignment allowed the differentiation of species. In addition, ERIC-PCR was introduced for the genotypic characterization of Alicyclobacillus, as an alternative for differentiation among isolates from the same species. © 2015 The Society for Applied Microbiology.
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Masotti, Cibele; Armelin-Correa, Lucia M; Splendore, Alessandra; Lin, Chin J; Barbosa, Angela; Sogayar, Mari C; Passos-Bueno, Maria Rita
2005-10-10
Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.
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Børud, Bente; Bårnes, Guro K; Brynildsrud, Ola Brønstad; Fritzsønn, Elisabeth; Caugant, Dominique A
2018-03-19
Species within the genus Neisseria display significant glycan diversity associated with the O -linked protein glycosylation ( pgl ) systems due to phase variation, polymorphic genes and gene content. The aim of this study was to examine in detail the pgl genotype and glycosylation phenotype in meningococcal isolates and the changes occurring during short-term asymptomatic carriage. Paired meningococcal isolates derived from 50 asymptomatic meningococcal carriers, taken about two months apart, were analyzed with whole genome sequencing. The O -linked protein glycosylation genes were characterized in detail using the Genome Comparator tool at the PubMLST.org database. Immunoblotting with glycan specific antibodies were used to investigate the protein glycosylation phenotype. All major pgl locus polymorphisms identified in N. meningitidis to date were present in our isolate collection, with the variable presence of pglG-pglH, both in combination with either pglB or pglB2. We identified significant changes and diversity in the pgl genotype and/or glycan phenotype in 96% of the paired isolates. There was also a high degree of glycan microheterogeneity, in which different variants of glycan structures were found at a given glycoprotein. The main mechanism responsible for the observed differences was phase variable expression of the involved glycosyltransferases and the O-acetyltransferase. To our knowledge, this is the first characterization of the pgl genotype and glycosylation phenotype in a larger strain collection. This study thus provides important insight into glycan diversity in N. meningitidis and phase variability changes that influence the expressed glycoform repertoire during meningococcal carriage. Importance Bacterial meningitis is a serious global health problem and one of the major causative organisms is Neisseria meningitidis , which is also a common commensal in the upper respiratory tract of healthy humans. In bacteria, numerous loci involved in biosynthesis of surface exposed antigenic structures that are involved in the interaction between bacteria and host, are frequently subjected to homologous recombination and phase variation. These mechanisms are well described in Neisseria, and phase variation provides the ability to change these structures reversibly in response to the environment. Protein glycosylation systems are becoming widely identified in bacteria, yet little is known about the mechanisms and evolutionary forces influencing glycan composition during carriage and disease. Copyright © 2018 American Society for Microbiology.
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Alsultan, Abdulrahman; Alabdulaali, Mohammed K.; Griffin, Paula J.; AlSuliman, Ahmed M.; Ghabbour, Hazem A.; Sebastiani, Paola; Albuali, Waleed H.; Al-Ali, Amein K.; Chui, David H.K.; Steinberg, Martin H.
2014-01-01
Summary Sickle cell disease (SCD) in Saudi patients from the Eastern Province is associated with the Arab-Indian (AI) HBB (β-globin gene) haplotype. The phenotype of AI SCD in children was described as benign and was attributed to their high fetal haemoglobin (HbF). We conducted a hospital-based study to assess the pattern of SCD complications in adults. A total of 104 patients with average age of 27 years were enrolled. Ninety-six percent of these patients reported history of painful crisis; 47% had at least one episode of acute chest syndrome, however, only 15% had two or more episodes; symptomatic osteonecrosis was reported in 18%; priapism in 17%; overt stroke in 6%; none had leg ulcers. The majority of patients had persistent splenomegaly and 66% had gallstones. Half of the patients co-inherited α-thalassaemia and about one third had glucose-6-phosphate dehydrogenase deficiency. Higher HbF correlated with higher rate of splenic sequestration but not with other phenotypes. The phenotype of adult patients with AI SCD is not benign despite their relatively high HbF level. This is probably due to the continued decline in HbF level in adults and the heterocellular and variable distribution of HbF amongst F-cells. PMID:24224700
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The finite state projection approach to analyze dynamics of heterogeneous populations
NASA Astrophysics Data System (ADS)
Johnson, Rob; Munsky, Brian
2017-06-01
Population modeling aims to capture and predict the dynamics of cell populations in constant or fluctuating environments. At the elementary level, population growth proceeds through sequential divisions of individual cells. Due to stochastic effects, populations of cells are inherently heterogeneous in phenotype, and some phenotypic variables have an effect on division or survival rates, as can be seen in partial drug resistance. Therefore, when modeling population dynamics where the control of growth and division is phenotype dependent, the corresponding model must take account of the underlying cellular heterogeneity. The finite state projection (FSP) approach has often been used to analyze the statistics of independent cells. Here, we extend the FSP analysis to explore the coupling of cell dynamics and biomolecule dynamics within a population. This extension allows a general framework with which to model the state occupations of a heterogeneous, isogenic population of dividing and expiring cells. The method is demonstrated with a simple model of cell-cycle progression, which we use to explore possible dynamics of drug resistance phenotypes in dividing cells. We use this method to show how stochastic single-cell behaviors affect population level efficacy of drug treatments, and we illustrate how slight modifications to treatment regimens may have dramatic effects on drug efficacy.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lindsay, E.A.; Grillo, A.; Ferrero, G.B.
The microphthalmia with linear skin defects (MLS) syndrome (MIM309801) is a severe developmental disorder observed in XX individuals with distal Xp segmental monosomy. The phenotype of this syndrome overlaps with that of both Aicardi (MIM 305050) and Goltz (MIM 305600) syndromes, two X-linked dominant, male-lethal disorders. Here the authors report the clinical, cytogenetic, and molecular characterization of 3 patients with this syndrome. Two of these patients are females with a terminal Xpter-p22.2 deletion. One of these 2 patients had an aborted fetus with anencephaly and the same chromosome abnormality. The third patient is an XX male with Xp/Yp exchange spanningmore » the SRY gene which results in distal Xp monosomy. The extensive clinical variability observed in these patients and the results of the molecular analysis suggest that X-inactivation plays an important role in determining the phenotype of the MLS syndrome. The authors propose that the MLS, Aicardi, and Goltz syndromes are due to the involvement of the same gene(s), and that different patterns of X-inactivation are responsible for the phenotypic differences observed in these 3 disorders. However, they cannot rule out that each component of the MLS phenotype is caused by deletion of a different gene (a contiguous gene syndrome). 24 refs., 4 figs., 1 tab.« less
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Fischer, A; Delagarde, R; Faverdin, P
2018-05-01
Residual feed intake, which is usually used to estimate individual variation of feed efficiency, requires frequent and accurate measurements of individual feed intake to be carried out. Developing a breeding scheme based on residual feed intake in dairy cows is therefore complicated, especially because feed intake is not measurable for a large population. Another solution could be to focus on biological determinants of feed efficiency, which could potentially be directly and broadband measurable on farm. Several phenotypes have been identified in literature as being associated with differences in feed efficiency. The present study therefore aims to identify which biological mechanisms are associated with residual energy intake (REI) differences among dairy cows. Several candidate phenotypes were recorded frequently and simultaneously throughout the first 238 d in milk for 60 Holstein cows fed on a constant diet based on maize silage. A multiple linear regression of the 238 d in milk average of net energy intake was fitted on the 238 d in milk averages for milk energy output, metabolic body weight, the sum over the 238 d in milk of both, body condition score loss and gain, and the residuals were defined as REI. A partial least square regression was fitted over all biological traits to explain REI variability. Linear multiple regression explained 93.6% of net energy intake phenotypic variation, with 65.5% associated with lactation requirement, 23.2% with maintenance, and 4.9% with body reserves change; the 6.4% residuals represented REI. Overall, measured biological traits contributed to 58.9% of REI phenotypic variability, which were mainly explained by activity (26.5%) and feeding behavior (21.3%). However, apparent confounding was observed between behavior, activity, digestibility, and rumen-temperature variables. Drawing a conclusion on biological traits that explain feed efficiency differences among dairy cows was not possible due to this apparent confounding between the measured variables. Further investigation is needed to validate these results and to characterize the causal relationship of feed efficiency with feeding behavior, digestibility, body reserves change, activity, and rumen temperature. The Authors. Published by FASS Inc. and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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Sharma, Abhay
2015-01-01
Transgenerational epigenetic inheritance in mammals has been controversial due to inherent difficulties in its experimental demonstration. A recent report has, however, opened a new front in the ongoing debate by claiming that endocrine disrupting chemicals, contrary to previous findings, do not cause effects across generations. This claim is based on the observation that gene expression changes induced by these chemicals in the exposed and unexposed generations are mainly in the opposite direction. This analysis shows that the pattern of gene expression reported in the two generations is not expected by chance and is suggestive of transmission across generations. A meta-analysis of diverse data sets related to endocrine disruptor-induced transgenerational gene expression alterations, including the data provided in the said report, further suggests that effects of endocrine disrupting chemicals persist in unexposed generations. Based on the prior evidence of phenotypic variability and gene expression alterations in opposite direction between generations, it is argued here that calling evidence of mismatched directionality in gene expression in experiments testing potential of environmental agents in inducing epigenetic inheritance of phenotypic traits as negative is untenable. This is expected to settle the newly raised doubts over epigenetic inheritance in mammals.
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Bergamo, Pedro Joaquim; Wolowski, Marina; Maruyama, Pietro Kiyoshi; Vizentin-Bugoni, Jeferson; Carvalheiro, Luísa G; Sazima, Marlies
2017-07-01
Plant species within communities may overlap in pollinators' use and influence visitation patterns of shared pollinators, potentially engaging in indirect interactions (e.g., facilitation or competition). While several studies have explored the mechanisms regulating insect-pollination networks, there is a lack of studies on bird-pollination systems, particularly in species-rich tropical areas. Here, we evaluated if phenotypic similarity, resource availability (floral abundance), evolutionary relatedness and flowering phenology affect the potential for indirect effects via shared pollinators in hummingbird-pollinated plant species within four communities in the Brazilian Atlantic forest. Among the evaluated factors, phenotypic similarity (corolla length and anther height) was the most important variable, while resource availability (floral abundance) had a secondary importance. On the other hand, evolutionary relatedness and flowering phenology were less important, which altogether highlights the relevance of convergent evolution and that the contribution of a plant to the diet of the pollinators of another plant is independent of the level of temporal overlap in flowering in this tropical system. Interestingly, our findings contrast with results from multiple insect-pollinated plant communities, mostly from temperate regions, in which floral abundance was the most important driver, followed by evolutionary relatedness and phenotypic similarity. We propose that these contrasting results are due to high level of specialization inherent to tropical hummingbird-pollination systems. Moreover, our results demonstrated that factors defining linkage rules of plant-hummingbird networks also determinate plant-plant potential indirect effects. Future studies are needed to test if these findings can be generalized to other highly specialized systems. Overall, our results have important implications for the understanding of ecological processes due resource sharing in mutualistic systems. © 2017 by the Ecological Society of America.
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2016-10-01
this is due, at least in part, to an additional acquired GOTF defect caused by the mutant protein that interferes with the secretion of WT C1INH. Our...overall hypothesis is that mutant C1INH proteins exert a variable GOTF phenotype that inhibit secretion of WT C1INH protein and worsen disease...will assess the mechanisms of the GOTF with a hypothesis that misfolding of mutant C1INH protein in the ER causes impairment of WT C1INH secretion
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Survival strategies of Bacillus spores in food.
Stecchini, Mara Lucia; Del Torre, Manuela; Polese, Pierluigi
2013-11-01
Control of bacterial spores is one of the major problem in the food preservation. Spores of Bacillus genus are commonly present in different environments, including soil and the gut of insects and animals and, as a result, they can be spread to all kind of foods. Due to their high resistance properties, their complete inactivation in food is often impossible without changing the product characteristics. Surviving spores can germinate and grow out to vegetative cells, with the consequent great risk of food spoilage and food poisoning after consumption. Spores have evolved various mechanisms, including phenotypic variability, to protect themselves from a wide range of damage resulting from food preservation treatments. Even if the phenotypic heterogeneity contributes to increase the chances of survival of Bacillus spore to conventional preservation treatments, in some specific instances, an homogeneous response could be the result of a strategy adopted by the spores to increase resistance to those treatments.
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Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies
Jordanova, Albena
2014-01-01
Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098
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Multidisciplinary treatment approach in Treacher Collins syndrome.
Hylton, Joseph B; Leon-Salazar, Vladimir; Anderson, Gary C; De Felippe, Nanci L O
2012-01-01
Treacher Collins syndrome (TCS) is a common genetic disorder with high penetrance and phenotypic variability. First and second branchial arches are affected in TCS, resulting in craniofacial and intraoral anomalies such as: severe convex facial profile; mid-face hypoplasia; microtia; eyelid colobomas; mandibular retrognathism; cleft palate; dental hypoplasia; heterotopic teeth; maxillary transverse hypoplasia; anterior open bite; and Angle Class II molar relationship. A high incidence of caries is also a typical finding in TCS patients. Nonetheless, even simple dental restorative procedures can be challenging in this patient population due to other associated medical conditions, such as: congenital heart defects; decreased oropharyngeal airways; hearing loss; and anxiety toward treatment. These patients often require a multidisciplinary treatment approach, including: audiology; speech and language pathology; otorhinolaryngology; general dentistry; orthodontics; oral and maxillofacial surgery; and plastic and reconstructive surgeries to improve facial appearance. This paper's purpose was to present a current understanding of Treacher Collins syndrome etiology, phenotype, and current treatment approaches.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Rinchik, E.M.; Carpenter, D.A.; Handel, M.A.
1995-07-03
Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p{sup 6H} deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p{sup 6H} deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profoundmore » abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p{sup 6H} deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p{sup 6H} deletion homozygotes. Because etNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p{sup 6H} deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans. 29 refs., 3 figs., 1 tab.« less
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Alport syndrome: impact of digenic inheritance in patients management.
Fallerini, C; Baldassarri, M; Trevisson, E; Morbidoni, V; La Manna, A; Lazzarin, R; Pasini, A; Barbano, G; Pinciaroli, A R; Garosi, G; Frullanti, E; Pinto, A M; Mencarelli, M A; Mari, F; Renieri, A; Ariani, F
2017-07-01
Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Some Like It Hot, Some Like It Warm: Phenotyping to Explore Thermotolerance Diversity
Yeh, Ching-Hui; Kaplinsky, Nicholas J.; Hu, Catherine; Charng, Yee-yung
2012-01-01
Plants have evolved overlapping but distinct cellular responses to different aspects of high temperature stress. These responses include basal thermotolerance, short- and long-term acquired thermotolerance, and thermotolerance to moderately high temperatures. This thermotolerance diversity’ means that multiple phenotypic assays are essential for fully describing the functions of genes involved in heat stress responses. A large number of genes with potential roles in heat stress responses have been identified using genetic screens and genome wide expression studies. We examine the range of phenotypic assays that have been used to characterize thermotolerance phenotypes in both Arabidopsis and crop plants. Three major variables differentiate thermotolerance assays: 1) the heat stress regime used, 2) the developmental stage of the plants being studied, and 3) the actual phenotype which is scored. Consideration of these variables will be essential for deepening our understanding of the molecular genetics of plant thermotolerance. PMID:22920995
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Maintenance of Genetic Variability under Strong Stabilizing Selection: A Two-Locus Model
Gavrilets, S.; Hastings, A.
1993-01-01
We study a two locus model with additive contributions to the phenotype to explore the relationship between stabilizing selection and recombination. We show that if the double heterozygote has the optimum phenotype and the contributions of the loci to the trait are different, then any symmetric stabilizing selection fitness function can maintain genetic variability provided selection is sufficiently strong relative to linkage. We present results of a detailed analysis of the quadratic fitness function which show that selection need not be extremely strong relative to recombination for the polymorphic equilibria to be stable. At these polymorphic equilibria the mean value of the trait, in general, is not equal to the optimum phenotype, there exists a large level of negative linkage disequilibrium which ``hides'' additive genetic variance, and different equilibria can be stable simultaneously. We analyze dependence of different characteristics of these equilibria on the location of optimum phenotype, on the difference in allelic effect, and on the strength of selection relative to recombination. Our overall result that stabilizing selection does not necessarily eliminate genetic variability is compatible with some experimental results where the lines subject to strong stabilizing selection did not have significant reductions in genetic variability. PMID:8514145
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Identification of quantitative trait loci for fibrin clot phenotypes: The EuroCLOT study
Williams, Frances MK; Carter, Angela M; Kato, Bernet; Falchi, Mario; Bathum, Lise; Surdulescu, Gabriela; Kyvik, Kirsten Ohm; Palotie, Aarno; Spector, Tim D; Grant, Peter J
2012-01-01
Objectives Fibrin makes up the structural basis of an occlusive arterial thrombus and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to 1) determine the heritability of fibrin phenotypes and 2) identify QTLs associated with fibrin phenotypes. Methods 447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK Caucasian female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology and lysis were determined by turbidimetric assays. Heritability estimates and genome-wide linkage analysis were performed. Results Estimates of heritability for d-dimer and turbidometric variables were in the range 17 - 46%, with highest levels for maximal absorbance which provides an estimate of clot density. Genome-wide linkage analysis revealed 6 significant regions with LOD>3 on 5 chromosomes (5, 6, 9, 16 and 17). Conclusions The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischaemic cardiovascular disorders and their therapy. PMID:19150881
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Drought tolerance in cacao is mediated by root phenotypic plasticity
USDA-ARS?s Scientific Manuscript database
This study aimed to evaluate phenotypic relationships and their direct and indirect effects through path analysis, and evaluate the use of the phenotypic plasticity index as criteria for the estimation of the basic and explanatory variables used to analysis several cacao progenies subjected to soil ...
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Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations.
Tryon, Rebecca; Zierhut, Heather; MacMillan, Margaret L; Wagner, John E
2017-01-01
Fanconi anemia is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital anomalies, and markedly increased risk for malignancies. Mutations in the FANCF (FA-F) gene represent approximately 2% of affected patients. Currently, information on the phenotypic findings of patients with Fanconi anemia from biallelic mutations in FANCF is limited. Here, we report three patients who illustrate the clinical variability within the FA-F group. This analysis suggests a more severe phenotype for those with the common c.484_485delCT mutation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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USDA-ARS?s Scientific Manuscript database
Species can respond to environmental pressures through genetic and epigenetic changes and through phenotypic plasticity, but few studies have evaluated the relationships between genetic differentiation and phenotypic plasticity of plant species along changing environmental conditions such as through...
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Chillon, M.; Casals, T.; Nunes, V.
1994-09-01
About 65% or the individuals with congenital bilateral absence of the vas deferens (CBAVD) have mutations in at least one of the CFTR alleles. We have studied the phenotypic effects of the CFTR gene intron 8 polyT tract 5T allele in 90 CBAVD subjects and in parents of CF patients. This group was compared with normal individuals, and with fathers and mothers of CF patients. Allele 5T was significantly associated with CBAVD (19.6%) when compared to the general population (5.2%) ({chi}{sup 2} = 33.3%; p<<0.0001). It was represented poorly in fathers of CF patients (1.3%). Mutations were identified in onemore » (60%) or both CFTR alleles (8.9%) of CBAVD patients. Heterozygosity for the 5T allele was strongly associated with heterozygosity for CF mutations ({chi}{sup 2} = 10.9; p<0.0004). The strong correlation between allele 5T and CBAVD, together with the low frequency of this allele in fathers of CF patients, demonstrates that variable {Delta}exon 9 produces infertility in males if associated with a CF mutation on the other chromosome. The 30% of CBAVD cases with only one CFTR mutation and without a 5T-allele may be due to other molecular mechanisms involving CFTR, distinct from {Delta}exon 9. Since there is a relatively high proportion of CBAVD without CF mutations (25%), other gene(s), distinct from CFTR, may have a role in the CBAVD phenotype.« less
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Biondi, Emanuele G.; Tatti, Enrico; Comparini, Diego; Giuntini, Elisa; Mocali, Stefano; Giovannetti, Luciana; Bazzicalupo, Marco; Mengoni, Alessio; Viti, Carlo
2009-01-01
Sinorhizobium meliloti is a soil bacterium that fixes atmospheric nitrogen in plant roots. The high genetic diversity of its natural populations has been the subject of extensive analysis. Recent genomic studies of several isolates revealed a high content of variable genes, suggesting a correspondingly large phenotypic differentiation among strains of S. meliloti. Here, using the Phenotype MicroArray (PM) system, hundreds of different growth conditions were tested in order to compare the metabolic capabilities of the laboratory reference strain Rm1021 with those of four natural S. meliloti isolates previously analyzed by comparative genomic hybridization (CGH). The results of PM analysis showed that most phenotypic differences involved carbon source utilization and tolerance to osmolytes and pH, while fewer differences were scored for nitrogen, phosphorus, and sulfur source utilization. Only the variability of the tested strain in tolerance to sodium nitrite and ammonium sulfate of pH 8 was hypothesized to be associated with the genetic polymorphisms detected by CGH analysis. Colony and cell morphologies and the ability to nodulate Medicago truncatula plants were also compared, revealing further phenotypic diversity. Overall, our results suggest that the study of functional (phenotypic) variability of S. meliloti populations is an important and complementary step in the investigation of genetic polymorphism of rhizobia and may help to elucidate rhizobial evolutionary dynamics, including adaptation to diverse environments. PMID:19561177
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[Phenotypic variability in 47, XXX patients: Clinical report of four new cases].
Goldschmidt, Ernesto; Márquez, Marisa; Solari, Andrea; Ziembar, María I; Laudicina, Alejandro
2010-08-01
The 47, XXX karyotype has a frequency of 1 in 1000 female newborns. However, this karyotype is not usually suspected at birth or childhood. These patients are usually diagnosed during adulthood when they develop premature ovarian failure or infertility, because the early phenotype doesn t have any specific features. The study describes four cases and the clinical variability of the 47, XXX karyotype.
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Sugars in peach fruit: a breeding perspective
Cirilli, Marco; Bassi, Daniele; Ciacciulli, Angelo
2016-01-01
The last decade has been characterized by a decrease in peach (Prunus persica) fruit consumption in many countries, foremost due to unsatisfactory quality. The sugar content is one of the most important quality traits perceived by consumers, and the development of novel peach cultivars with sugar-enhanced content is a primary objective of breeding programs to revert the market inertia. Nevertheless, the progress reachable through classical phenotypic selection is limited by the narrow genetic bases of peach breeding material and by the complex quantitative nature of the trait, which is deeply affected by environmental conditions and agronomical management. The development of molecular markers applicable in MAS or MAB has become an essential strategy to boost the selection efficiency. Despite the enormous advances in ‘omics’ sciences, providing powerful tools for plant genotyping, the identification of the genetic bases of sugar-related traits is hindered by the lack of adequate phenotyping methods that are able to address strong within-plant variability. This review provides an overview of the current knowledge of the metabolic pathways and physiological mechanisms regulating sugar accumulation in peach fruit, the main advances in phenotyping approaches and genetic background, and finally addressing new research priorities and prospective for breeders. PMID:26816618
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Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.
Fergelot, Patricia; Van Belzen, Martine; Van Gils, Julien; Afenjar, Alexandra; Armour, Christine M; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany; Collet, Marie; Deforges, Julie; de Vries, Bert B A; Dominguez Garrido, Elena; Dorison, Nathalie; Dupont, Juliette; Francannet, Christine; Garciá-Minaúr, Sixto; Gabau Vila, Elisabeth; Gebre-Medhin, Samuel; Gener Querol, Blanca; Geneviève, David; Gérard, Marion; Gervasini, Cristina Giovanna; Goldenberg, Alice; Josifova, Dragana; Lachlan, Katherine; Maas, Saskia; Maranda, Bruno; Moilanen, Jukka S; Nordgren, Ann; Parent, Philippe; Rankin, Julia; Reardon, Willie; Rio, Marlène; Roume, Joëlle; Shaw, Adam; Smigiel, Robert; Sojo, Amaia; Solomon, Benjamin; Stembalska, Agnieszka; Stumpel, Constance; Suarez, Francisco; Terhal, Paulien; Thomas, Simon; Touraine, Renaud; Verloes, Alain; Vincent-Delorme, Catherine; Wincent, Josephine; Peters, Dorien J M; Bartsch, Oliver; Larizza, Lidia; Lacombe, Didier; Hennekam, Raoul C
2016-12-01
Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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Fitzgerald, Jamie; Holden, Paul; Wright, Hollis; Wilmot, Beth; Hata, Abigail; Steiner, Robert D.; Basel, Don
2016-01-01
Background Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the IFITM5 gene was found to be responsible for OI type V. This mutation, a C to T transition 14 nucleotides upstream from the endogenous start codon, creates a new start methionine that appears to be preferentially used by the translational machinery. However, the mechanism by which the lengthened protein results in a dominant type of OI is unknown. Methods and Results We report 7 ethnically diverse (African-American, Caucasian, Hispanic, and African) individuals with OI type V from 2 families and 2 sporadic cases. Exome sequencing failed to identify a causative mutation. Using Sanger sequencing, we found that all affected individuals in our cohort possess the c.−14 IFITM5 variant, further supporting the notion that OI type V is caused by a single, discrete mutation. Our patient cohort demonstrated inter-and intrafamilial phenotypic variability, including a father with classic OI type V whose daughter had a phenotype similar to OI type I. This clinical variability suggests that modifier genes influence the OI type V phenotype. We also confirm that the mutation creates an aberrant IFITM5 protein containing an additional 5 amino acids at the N-terminus. Conclusions The variable clinical signs in these cases illustrate the significant variability of the OI type V phenotype caused by the c.−14 IFITM5 mutation. The affected individuals are more ethnically diverse than previously reported. PMID:28824928
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Hoppmann, Julia; Gesing, Julia; Silve, Caroline; Leroy, Chrystel; Bertsche, Astrid; Hirsch, Franz Wolfgang; Kiess, Wieland; Pfäffle, Roland; Schuster, Volker
2017-01-01
Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders. PMID:28515031
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GUSTAFSON, D.R.; SHI, Q.; THURN, M.; HOLMAN, S.A.; MINKOFF, H.; COHEN, M.; PLANKEY, M.W.; HAVLIK, R.; SHARMA, A.; GANGE, S.; GANDHI, M.; MILAM, J.; HOOVER, D.
2016-01-01
Background Biological similarities are noted between aging and HIV infection. Middle-aged adults with HIV infection may present as elderly due to accelerated aging or having more severe aging phenotypes occurring at younger ages. Objectives We explored age-adjusted prevalence of frailty, a geriatric condition, among HIV+ and at risk HIV− women. Design Cross-sectional. Setting The Women's Interagency HIV Study (WIHS). Participants 2028 middle-aged (average age 39 years) female participants (1449 HIV+; 579 HIV−). Measurements The Fried Frailty Index (FFI), HIV status variables, and constellations of variables representing Demographic/health behaviors and Aging-related chronic diseases. Associations between the FFI and other variables were estimated, followed by stepwise regression models. Results Overall frailty prevalence was 15.2% (HIV+, 17%; HIV−, 10%). A multivariable model suggested that HIV infection with CD4 count<200; age>40 years; current or former smoking; income ≤$12,000; moderate vs low fibrinogen-4 (FIB-4) levels; and moderate vs high estimated glomerular filtration rate (eGFR) were positively associated with frailty. Low or moderate drinking was protective. Conclusions Frailty is a multidimensional aging phenotype observed in mid-life among women with HIV infection. Prevalence of frailty in this sample of HIV-infected women exceeds that for usual elderly populations. This highlights the need for geriatricians and gerontologists to interact with younger `at risk' populations, and assists in the formulation of best recommendations for frailty interventions to prevent early aging, excess morbidities and early death. PMID:26980368
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Valle, Benoît; Simonneau, Thierry; Boulord, Romain; Sourd, Francis; Frisson, Thibault; Ryckewaert, Maxime; Hamard, Philippe; Brichet, Nicolas; Dauzat, Myriam; Christophe, Angélique
2017-01-01
Plant science uses increasing amounts of phenotypic data to unravel the complex interactions between biological systems and their variable environments. Originally, phenotyping approaches were limited by manual, often destructive operations, causing large errors. Plant imaging emerged as a viable alternative allowing non-invasive and automated data acquisition. Several procedures based on image analysis were developed to monitor leaf growth as a major phenotyping target. However, in most proposals, a time-consuming parameterization of the analysis pipeline is required to handle variable conditions between images, particularly in the field due to unstable light and interferences with soil surface or weeds. To cope with these difficulties, we developed a low-cost, 2D imaging method, hereafter called PYM. The method is based on plant leaf ability to absorb blue light while reflecting infrared wavelengths. PYM consists of a Raspberry Pi computer equipped with an infrared camera and a blue filter and is associated with scripts that compute projected leaf area. This new method was tested on diverse species placed in contrasting conditions. Application to field conditions was evaluated on lettuces grown under photovoltaic panels. The objective was to look for possible acclimation of leaf expansion under photovoltaic panels to optimise the use of solar radiation per unit soil area. The new PYM device proved to be efficient and accurate for screening leaf area of various species in wide ranges of environments. In the most challenging conditions that we tested, error on plant leaf area was reduced to 5% using PYM compared to 100% when using a recently published method. A high-throughput phenotyping cart, holding 6 chained PYM devices, was designed to capture up to 2000 pictures of field-grown lettuce plants in less than 2 h. Automated analysis of image stacks of individual plants over their growth cycles revealed unexpected differences in leaf expansion rate between lettuces rows depending on their position below or between the photovoltaic panels. The imaging device described here has several benefits, such as affordability, low cost, reliability and flexibility for online analysis and storage. It should be easily appropriated and customized to meet the needs of various users.
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Granell, Raquel; Sterne, Jonathan A C; Henderson, John
2012-01-01
Asthma is a complex heterogeneous disease that has increased in prevalence in many industrialised countries. However, the causes of asthma inception remain elusive. Consideration of sub-phenotypes of wheezing may reveal important clues to aetiological risk factors. Longitudinal phenotypes capturing population heterogeneity in wheezing reports from birth to 7 years were derived using latent class analysis in the Avon Longitudinal Study of Parents and Children (ALSPAC). Probability of class membership was used to examine the association between five wheezing phenotypes (transient early, prolonged early, intermediate-onset, late-onset, persistent) and early life risk factors for asthma. Phenotypes had similar patterns and strengths of associations with early environmental factors. Comparing transient early with prolonged early wheezing showed a similar pattern of association with most exposure variables considered in terms of the direction of the effect estimates but with prolonged early wheezing tending to have stronger associations than transient early wheezing except for parity and day care attendance. Associations with early life risk factors suggested that prolonged early wheeze might be a severe form of transient early wheezing. Although differences were found in the associations of early life risk factors with individual phenotypes, these did not point to novel aetiological pathways. Persistent wheezing phenotype has features suggesting overlap of early and late-onset phenotypes.
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Adaptation to local ultraviolet radiation conditions among neighbouring Daphnia populations
Miner, Brooks E.; Kerr, Benjamin
2011-01-01
Understanding the historical processes that generated current patterns of phenotypic diversity in nature is particularly challenging in subdivided populations. Populations often exhibit heritable genetic differences that correlate with environmental variables, but the non-independence among neighbouring populations complicates statistical inference of adaptation. To understand the relative influence of adaptive and non-adaptive processes in generating phenotypes requires joint evaluation of genetic and phenotypic divergence in an integrated and statistically appropriate analysis. We investigated phenotypic divergence, population-genetic structure and potential fitness trade-offs in populations of Daphnia melanica inhabiting neighbouring subalpine ponds of widely differing transparency to ultraviolet radiation (UVR). Using a combination of experimental, population-genetic and statistical techniques, we separated the effects of shared population ancestry and environmental variables in predicting phenotypic divergence among populations. We found that native water transparency significantly predicted divergence in phenotypes among populations even after accounting for significant population structure. This result demonstrates that environmental factors such as UVR can at least partially account for phenotypic divergence. However, a lack of evidence for a hypothesized trade-off between UVR tolerance and growth rates in the absence of UVR prevents us from ruling out the possibility that non-adaptive processes are partially responsible for phenotypic differentiation in this system. PMID:20943691
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Galán, Maria; García-Herrero, Carmen-Maria; Azriel, Sharona; Gargallo, Manuel; Durán, Maria; Gorgojo, Juan-Jose; Andía, Victor-Manuel; Navas, Maria-Angeles
2011-01-01
Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype. PMID:21170474
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The Neurocognitive Phenotype in Velo-Cardio-Facial Syndrome: A Developmental Perspective
ERIC Educational Resources Information Center
Antshel, Kevin M.; Fremont, Wanda; Kates, Wendy R.
2008-01-01
Although research has focused primarily on the wide range of variability in the cognitive phenotype between individuals with velo-cardio-facial syndrome (VCFS), we know relatively little about the extent to which within-individual expressions of the cognitive phenotype remain stable throughout development. General cognitive functioning in the low…
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Erkizia, Itziar; Pino, Maria; Pou, Christian; Paredes, Roger; Clotet, Bonaventura; Martinez-Picado, Javier; Prado, Julia G.
2012-01-01
Background The use of in vitro models to unravel the phenotypic characteristics of circulating viral variants is key to understanding HIV-1 pathogenesis but limited by the availability of primary viral isolates from biological samples. However, overall in vivo genetic variability of HIV-1 within a subject may not be reflected in the viable viral population obtained after isolation. Although several studies have tried to determine whether viral populations expanded in vitro are representative of in vivo findings, the answer remains unclear due to the reduced number of clonal sequences analyzed or samples compared. In order to overcome previous experimental limitations, here we applied Deep Pyrosequencing (DPS) technology in combination with phenotypic experiments to analyze and compare with unprecedented detail the composition of viral isolates and in vivo quasispecies. Methodology/Principal Findings We amplified by DPS HIV-1 genomic regions covering gag, protease, integrase and env-V3 to characterize paired isolates from plasma and peripheral blood mononuclear cells and compare them with total plasma viral RNA in four recently HIV-1 infected subjects. Our study demonstrated the presence of unique haplotypes scattered between sample types with conservation of major variants. In addition, no differences in intra- and inter-population encoded protein variability were found between the different types of isolates or when these were compared to plasma viral RNA within subjects. Additionally, in vitro experiments demonstrated phenotypic similarities in terms of replicative capacity and co-receptor usage between viral isolates and plasma viral RNA. Conclusion This study is the first in-depth comparison and characterization of viral isolates from different sources and plasma circulating quasispecies using DPS in recently HIV-1 infected subjects. Our data supports the use of primary isolates regardless of their plasma or cellular origin to define genetic variability and biological traits of circulating HIV-1 quasispecies. PMID:22393441
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de Luis, Martin; Čufar, Katarina; Di Filippo, Alfredo; Novak, Klemen; Papadopoulos, Andreas; Piovesan, Gianluca; Rathgeber, Cyrille B. K.; Raventós, José; Saz, Miguel Angel; Smith, Kevin T.
2013-01-01
We investigated the variability of the climate-growth relationship of Aleppo pine across its distribution range in the Mediterranean Basin. We constructed a network of tree-ring index chronologies from 63 sites across the region. Correlation function analysis identified the relationships of tree-ring index to climate factors for each site. We also estimated the dominant climatic gradients of the region using principal component analysis of monthly, seasonal, and annual mean temperature and total precipitation from 1,068 climatic gridpoints. Variation in ring width index was primarily related to precipitation and secondarily to temperature. However, we found that the dendroclimatic relationship depended on the position of the site along the climatic gradient. In the southern part of the distribution range, where temperature was generally higher and precipitation lower than the regional average, reduced growth was also associated with warm and dry conditions. In the northern part, where the average temperature was lower and the precipitation more abundant than the regional average, reduced growth was associated with cool conditions. Thus, our study highlights the substantial plasticity of Aleppo pine in response to different climatic conditions. These results do not resolve the source of response variability as being due to either genetic variation in provenance, to phenotypic plasticity, or a combination of factors. However, as current growth responses to inter-annual climate variability vary spatially across existing climate gradients, future climate-growth relationships will also likely be determined by differential adaptation and/or acclimation responses to spatial climatic variation. The contribution of local adaptation and/or phenotypic plasticity across populations to the persistence of species under global warming could be decisive for prediction of climate change impacts across populations. In this sense, a more complex forest dynamics modeling approach that includes the contribution of genetic variation and phenotypic plasticity can improve the reliability of the ecological inferences derived from the climate-growth relationships. PMID:24391786
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Iyadurai, Stanley; Arnold, W David; Kissel, John T; Ruhno, Corey; Mcgovern, Vicki L; Snyder, Pamela J; Prior, Thomas W; Roggenbuck, Jennifer; Burghes, Arthur H; Kolb, Stephen J
2017-08-01
Distal hereditary motor neuropathy (dHMN) causes distal-predominant weakness without prominent sensory loss. Myosin heavy chain disorders most commonly result in distal myopathy and cardiomyopathy with or without hearing loss, but a complex phenotype with dHMN, myopathy, hoarseness, and hearing loss was reported in a Korean family with a c.2822G>T mutation in MYH14. In this study we report phenotypic features in a North American family with the c.2822G>T in MYH14. Clinical and molecular characterization was performed in a large, 6-generation, Caucasian family with MYH14 dHMN. A total of 11 affected and 7 unaffected individuals were evaluated and showed varying age of onset and severity of weakness. Genotypic concordance was confirmed with molecular analysis. Electrophysiological studies demonstrated distal motor axonal degeneration without myopathy in all affected subjects tested. Mutation of MYH14 can result in a range of neuromuscular phenotypes that includes a dHMN and hearing loss phenotype with variable age of onset. Muscle Nerve 56: 341-345, 2017. © 2016 Wiley Periodicals, Inc.
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ERIC Educational Resources Information Center
Schwartzman, Benjamin C.; Wood, Jeffrey J.; Kapp, Steven K.
2016-01-01
The present study aimed to: determine the extent to which the five factor model of personality (FFM) accounts for variability in autism spectrum disorder (ASD) symptomatology in adults, examine differences in average FFM personality traits of adults with and without ASD and identify distinct behavioral phenotypes within ASD. Adults (N = 828;…
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Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016
Huvenne, Hélène; Dubern, Béatrice; Clément, Karine; Poitou, Christine
2016-01-01
Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed. PMID:27241181
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Phipps, Julie; Skirton, Heather
2017-10-01
Muenke syndrome constitutes the most common syndromic form of craniosynostosis, occurring in 1 in 30,000 live births. The phenotype is variable, ranging from no clinical findings to complex presentation. Facilitating reproductive decision making for couples at genetic risk of having a child with Muenke syndrome is an important aspect of genetic counselling. Prenatal genetic testing for Muenke syndrome is accurate; however the value of testing is uncertain with a variable phenotype. The purpose of this study was to explore attitudes towards prenatal testing in couples where one partner had tested positive for the Muenke mutation. We used a qualitative approach based on thematic analysis and collected data using individual semi-structured interviews with eight parents. Five key themes were: The Muenke journey; Impact and knowledge of diagnosis; Knowledge and attitude to prenatal testing; Stigma and sharing of information; and Information retention. Knowledge of Muenke syndrome and prenatal testing was poor. Genetic information was provided when treatment of their affected child was their paramount concern. Couples reported not sharing genetic information with family due to fear of stigmatisation. Couples cannot make reproductive decisions if lacking appropriate understanding of the choices: timely genetic counselling regarding prenatal testing is needed when relevant to them.
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Ma, Yuntao; Li, Baoguo; Zhan, Zhigang; Guo, Yan; Luquet, Delphine; de Reffye, Philippe; Dingkuhn, Michael
2007-01-01
Background and Aims It is increasingly accepted that crop models, if they are to simulate genotype-specific behaviour accurately, should simulate the morphogenetic process generating plant architecture. A functional–structural plant model, GREENLAB, was previously presented and validated for maize. The model is based on a recursive mathematical process, with parameters whose values cannot be measured directly and need to be optimized statistically. This study aims at evaluating the stability of GREENLAB parameters in response to three types of phenotype variability: (1) among individuals from a common population; (2) among populations subjected to different environments (seasons); and (3) among different development stages of the same plants. Methods Five field experiments were conducted in the course of 4 years on irrigated fields near Beijing, China. Detailed observations were conducted throughout the seasons on the dimensions and fresh biomass of all above-ground plant organs for each metamer. Growth stage-specific target files were assembled from the data for GREENLAB parameter optimization. Optimization was conducted for specific developmental stages or the entire growth cycle, for individual plants (replicates), and for different seasons. Parameter stability was evaluated by comparing their CV with that of phenotype observation for the different sources of variability. A reduced data set was developed for easier model parameterization using one season, and validated for the four other seasons. Key Results and Conclusions The analysis of parameter stability among plants sharing the same environment and among populations grown in different environments indicated that the model explains some of the inter-seasonal variability of phenotype (parameters varied less than the phenotype itself), but not inter-plant variability (parameter and phenotype variability were similar). Parameter variability among developmental stages was small, indicating that parameter values were largely development-stage independent. The authors suggest that the high level of parameter stability observed in GREENLAB can be used to conduct comparisons among genotypes and, ultimately, genetic analyses. PMID:17158141
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Helm, Benjamin M; Willer, Jason R; Sadeghpour, Azita; Golzio, Christelle; Crouch, Eric; Vergano, Samantha Schrier; Katsanis, Nicholas; Davis, Erica E
2017-07-19
The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings. Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete. Using clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.
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Phenotypic Stability of Zea mays Grain Yield and Its Attributing Traits under Drought Stress
Ali, Fawad; Ahsan, Muhammad; Ali, Qurban; Kanwal, Naila
2017-01-01
Phenotypic stability under stress environment facilitate the fitness of genotype and opens new horizons to explore the cryptic genetic variation. Variation in tolerance to drought stress, a major grain yield constraint to global maize production, was identified, at the phenotypic and genotypic level. Here we found a prominent hybrid H9 that showed fitness over four growing seasons for grain yield under water stress conditions. Genotypic and phenotypic correlation of yield attributing traits over four seasons demonstrated that cobs per plant, 100 seed weight, number of grains rows per cob, total dry matter, cob diameter had positive association (r2 = 0.3–0.9) to grain yield. The perturbation was found for chlorophyll content as it showed moderate to strong association (P < 0.01) over four seasons, might be due to environment or genotype dependent. Highest heritability (95%) and genetic advance (79%) for grain yield was found in H9 over four consecutive crop growing seasons. Combined analysis over four seasons showed that studied variables together explained 85% of total variation in dependent structure (grain yield) obtained by Principal component analysis. This significant finding is the best example of phenotypic stability of grain yield in H9 and made it best fitted for grain yield under drought stress scenario. Detailed genetic analysis of H9 will help us to identify significant loci and alleles that made H9 the best fitted and it could serve as a potential source to generate novel transgressive levels of tolerance for drought stress in arid/semiarid regions. PMID:28878785
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Phenotypic Stability of Zea mays Grain Yield and Its Attributing Traits under Drought Stress.
Ali, Fawad; Ahsan, Muhammad; Ali, Qurban; Kanwal, Naila
2017-01-01
Phenotypic stability under stress environment facilitate the fitness of genotype and opens new horizons to explore the cryptic genetic variation. Variation in tolerance to drought stress, a major grain yield constraint to global maize production, was identified, at the phenotypic and genotypic level. Here we found a prominent hybrid H 9 that showed fitness over four growing seasons for grain yield under water stress conditions. Genotypic and phenotypic correlation of yield attributing traits over four seasons demonstrated that cobs per plant, 100 seed weight, number of grains rows per cob, total dry matter, cob diameter had positive association ( r 2 = 0.3-0.9) to grain yield. The perturbation was found for chlorophyll content as it showed moderate to strong association ( P < 0.01) over four seasons, might be due to environment or genotype dependent. Highest heritability (95%) and genetic advance (79%) for grain yield was found in H 9 over four consecutive crop growing seasons. Combined analysis over four seasons showed that studied variables together explained 85% of total variation in dependent structure (grain yield) obtained by Principal component analysis. This significant finding is the best example of phenotypic stability of grain yield in H 9 and made it best fitted for grain yield under drought stress scenario. Detailed genetic analysis of H 9 will help us to identify significant loci and alleles that made H 9 the best fitted and it could serve as a potential source to generate novel transgressive levels of tolerance for drought stress in arid/semiarid regions.
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Phenotypic analysis of a novel chordin mutant in medaka.
Takashima, Shigeo; Shimada, Atsuko; Kobayashi, Daisuke; Yokoi, Hayato; Narita, Takanori; Jindo, Tomoko; Kage, Takahiro; Kitagawa, Tadao; Kimura, Tetsuaki; Sekimizu, Koshin; Miyake, Akimitsu; Setiamarga, Davin H E; Murakami, Ryohei; Tsuda, Sachiko; Ooki, Shinya; Kakihara, Ken; Hojo, Motoki; Naruse, Kiyoshi; Mitani, Hiroshi; Shima, Akihiro; Ishikawa, Yuji; Araki, Kazuo; Saga, Yumiko; Takeda, Hiroyuki
2007-08-01
We have isolated and characterized a ventralized mutant in medaka (the Japanese killifish; Oryzias latipes), which turned out to have a mutation in the chordin gene. The mutant exhibits ventralization of the body axis, malformation of axial bones, over-bifurcation of yolk sac blood vessels, and laterality defects in internal organs. The mutant exhibits variability of phenotypes, depending on the culture temperature, from embryos with a slightly ventralized phenotype to those without any head and trunk structures. Taking advantages of these variable and severe phenotypes, we analyzed the role of Chordin-dependent tissues such as the notochord and Kupffer's vesicle (KV) in the establishment of left-right axis in fish. The results demonstrate that, in the absence of the notochord and KV, the medaka lateral plate mesoderm autonomously and bilaterally expresses spaw gene in a default state. (c) 2007 Wiley-Liss, Inc.
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Bonamichi, Beatriz D S F; Santiago, Stella L M; Bertola, Débora R; Kim, Chong A; Alonso, Nivaldo; Mendonca, Berenice B; Bachega, Tania A S S; Gomes, Larissa G
2016-10-01
P450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient.
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Variability in dentofacial phenotypes in four families with WNT10A mutations
Vink, Christian P; Ockeloen, Charlotte W; ten Kate, Sietske; Koolen, David A; Ploos van Amstel, Johannes Kristian; Kuijpers-Jagtman, Anne-Marie; van Heumen, Celeste C; Kleefstra, Tjitske; Carels, Carine E L
2014-01-01
This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. PMID:24398796
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Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas O.; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.
2015-01-01
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. PMID:26257172
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Riordan, Erin C; Gugger, Paul F; Ortego, Joaquín; Smith, Carrie; Gaddis, Keith; Thompson, Pam; Sork, Victoria L
2016-01-01
Geography and climate shape the distribution of organisms, their genotypes, and their phenotypes. To understand historical and future evolutionary and ecological responses to climate, we compared the association of geography and climate of three oak species (Quercus engelmannii, Quercus berberidifolia, and Quercus cornelius-mulleri) in an environmentally heterogeneous region of southern California at three organizational levels: regional species distributions, genetic variation, and phenotypic variation. We identified climatic variables influencing regional distribution patterns using species distribution models (SDMs), and then tested whether those individual variables are important in shaping genetic (microsatellite) and phenotypic (leaf morphology) variation. We estimated the relative contributions of geography and climate using multivariate redundancy analyses (RDA) with variance partitioning. The modeled distribution of each species was influenced by climate differently. Our analysis of genetic variation using RDA identified small but significant associations between genetic variation with climate and geography in Q. engelmannii and Q. cornelius-mulleri, but not in Q. berberidifolia, and climate explained more of the variation. Our analysis of phenotypic variation in Q. engelmannii indicated that climate had more impact than geography, but not in Q. berberidifolia. Throughout our analyses, we did not find a consistent pattern in effects of individual climatic variables. Our comparative analysis illustrates that climate influences tree response at all organizational levels, but the important climate factors vary depending on the level and on the species. Because of these species-specific and level-specific responses, today's sympatric species are unlikely to have similar distributions in the future. © 2016 Botanical Society of America.
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Ruggiero, Maria Valeria; Procaccini, Gabriele
2004-01-01
Halophila stipulacea is a dioecious marine angiosperm, widely distributed along the western coasts of the Indian Ocean and the Red Sea. This species is thought to be a Lessepsian immigrant that entered the Mediterranean Sea from the Red Sea after the opening of the Suez Canal (1869). Previous studies have revealed both high phenotypic and genetic variability in Halophila stipulacea populations from the western Mediterranean basin. In order to test the hypothesis of a Lessepsian introduction, we compare genetic polymorphism between putative native (Red Sea) and introduced (Mediterranean) populations through rDNA ITS region (ITS1-5.8S-ITS2) sequence analysis. A high degree of intraindividual variability of ITS sequences was found. Most of the intragenomic polymorphism was due to pseudogenic sequences, present in almost all individuals. Features of ITS functional sequences and pseudogenes are described. Possible causes for the lack of homogenization of ITS paralogues within individuals are discussed.
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Scheid, Adam D; Van Keulen, Virginia P; Felts, Sara J; Neier, Steven C; Middha, Sumit; Nair, Asha A; Techentin, Robert W; Gilbert, Barry K; Jen, Jin; Neuhauser, Claudia; Zhang, Yuji; Pease, Larry R
2018-03-01
Human immunity exhibits remarkable heterogeneity among individuals, which engenders variable responses to immune perturbations in human populations. Population studies reveal that, in addition to interindividual heterogeneity, systemic immune signatures display longitudinal stability within individuals, and these signatures may reliably dictate how given individuals respond to immune perturbations. We hypothesize that analyzing relationships among these signatures at the population level may uncover baseline immune phenotypes that correspond with response outcomes to immune stimuli. To test this, we quantified global gene expression in peripheral blood CD4 + cells from healthy individuals at baseline and following CD3/CD28 stimulation at two time points 1 mo apart. Systemic CD4 + cell baseline and poststimulation molecular immune response signatures (MIRS) were defined by identifying genes expressed at levels that were stable between time points within individuals and differential among individuals in each state. Iterative differential gene expression analyses between all possible phenotypic groupings of at least three individuals using the baseline and stimulated MIRS gene sets revealed shared baseline and response phenotypic groupings, indicating the baseline MIRS contained determinants of immune responsiveness. Furthermore, significant numbers of shared phenotype-defining sets of determinants were identified in baseline data across independent healthy cohorts. Combining the cohorts and repeating the analyses resulted in identification of over 6000 baseline immune phenotypic groups, implying that the MIRS concept may be useful in many immune perturbation contexts. These findings demonstrate that patterns in complex gene expression variability can be used to define immune phenotypes and discover determinants of immune responsiveness. Copyright © 2018 by The American Association of Immunologists, Inc.
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The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes.
Lameiras, Ana Rita; Gonçalves, Ana Cláudia; Santos, Ricardo; O'Neill, Assunção; Reis, Luís Roque Dos; Matos, Tiago Daniel; Fialho, Graça; Caria, Helena; Escada, Pedro
2015-08-01
Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance. The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL. The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing. The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants. The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Canafoglia, Laura; Gennaro, Elena; Capovilla, Giuseppe; Gobbi, Giuseppe; Boni, Antonella; Beccaria, Francesca; Viri, Maurizio; Michelucci, Roberto; Agazzi, Pamela; Assereto, Stefania; Coviello, Domenico A; Di Stefano, Maria; Rossi Sebastiano, Davide; Franceschetti, Silvana; Zara, Federico
2012-12-01
Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy. The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron. The protein dose (cystatin B/β-actin) in our heterozygous patients was 0.24 ± 0.02, which is not different from that assessed in patients bearing the homozygous dodecamer expansion. The compound heterozygous patients had a significantly earlier disease onset (7.4 ± 1.7 years) than the homozygous patients, and their disease presentations included frequent myoclonic seizures and absences, often occurring in clusters throughout the course of the disease. The seizures were resistant to the pharmacologic treatments that usually lead to complete seizure control in homozygous patients. EEG-polygraphy allowed repeated seizures to be recorded. Action myoclonus progressively worsened and all of the heterozygous patients older than 30 years were in wheelchairs. Most of the patients showed moderate to severe cognitive impairment, and six had psychiatric symptoms. EPM1A due to compound heterozygous CSTB mutations presents with variable but often markedly severe and particular phenotypes. Most of our patients presented with the electroclinical features of severe epilepsy, which is unexpected in homozygous patients, and showed frequent seizures resistant to pharmacologic treatment. The presence of variable phenotypes (even in siblings) suggests interactions with other genetic factors influencing the final disease presentation. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.
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Titheradge, Hannah; Togneri, Fiona; McMullan, Dominic; Brueton, Louise; Lim, Derek; Williams, Denise
2014-07-01
Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder with variable expressivity. It is characterized by dysgenesis of the anterior segment of the eye together with dental, cardiac, and umbilical anomalies. There is a high incidence of secondary high tension glaucoma. It is a genetically heterogeneous condition due to deletion or mutations of FOXC1 (6p25) or PITX2 (4q25). We report on four unrelated patients with overlapping microdeletions encompassing PITX2 at 4q25. We compare the genotypes and phenotypes of these newly described ARS patients and discuss the involvement of contiguous genes. Patients 1, 2, and 3 had mild learning difficulties, not typically seen in patients with ARS. We implicate the adjacent neuronally expressed genes; NEUROG2, UGT8, NDST3, and PRSS12 as potentially causal. Our findings support the use of microarray analysis in ARS patients for full prognostic information in infants presenting with ARS-like phenotypes. © 2014 Wiley Periodicals, Inc.
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Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lindsay, E.A.; Goldberg, R.; Jurecic, V.
Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). Inmore » 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.« less
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[Waardenburg syndrome. A heterogenic disorder with variable penetrance].
Apaydin, F; Bereketoglu, M; Turan, O; Hribar, K; Maassen, M M; Günhan, O; Zenner, H-P; Pfister, M
2004-06-01
Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary anomalies of the skin, hairs, eyes and various defects of other neural crest derived tissues. It accounts for over 2% of congenital hearing impairment. At least four types are recognized on the basis of clinical and genetic criteria. Based on a screening of congenitally hearing impaired children, 12 families with WS type II were detected. Of special interest was the phenotype of these families, in particular the reduced penetrance of hearing impairment within the families. In all cases a high variability of the disease phenotype was detected and the penetrance of the clinical traits varied accordingly. Therefore, it is not possible to predict the clinical phenotype even in a single family. Based on these studies, we plan to identify the pathogenetic cause of the disease in order to perform a detailed genotype/phenotype analysis.
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Alexandrou, Angelos; Papaevripidou, Ioannis; Tsangaras, Kyriakos; Alexandrou, Ioanna; Tryfonidis, Marios; Christophidou-Anastasiadou, Violetta; Zamba-Papanicolaou, Eleni; Koumbaris, George; Neocleous, Vassos; Phylactou, Leonidas A; Skordis, Nicos; Tanteles, George A; Sismani, Carolina
2016-12-01
Haploinsufficiency of the short stature homeobox contaning SHOX gene has been shown to result in a spectrum of phenotypes ranging from Leri-Weill dyschondrosteosis (LWD) at the more severe end to SHOX-related short stature at the milder end of the spectrum. Most alterations are whole gene deletions, point mutations within the coding region, or microdeletions in its flanking sequences. Here, we present the clinical and molecular data as well as the potential molecular mechanism underlying a novel microdeletion, causing a variable SHOX-related haploinsufficiency disorder in a three-generation family. The phenotype resembles that of LWD in females, in males, however, the phenotypic expression is milder. The 15523-bp SHOX intragenic deletion, encompassing exons 3-6, was initially detected by array-CGH, followed by MLPA analysis. Sequencing of the breakpoints indicated an Alu recombination-mediated deletion (ARMD) as the potential causative mechanism.
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LRH-1 May Rescue SF-1 Deficiency for Steroidogenesis: An in vitro and in vivo Study.
Camats, Núria; Audí, Laura; Fernández-Cancio, Mónica; Andaluz, Pilar; Mullis, Primus E; Carrascosa, Antonio; Flück, Christa E
2015-01-01
Steroidogenic factor 1 (NR5A1/SF-1) mutations usually manifest in 46,XY individuals with variable degrees of disordered sex development and in 46,XX women with ovarian insufficiency. So far, there is no genotype-phenotype correlation. The broad spectrum of phenotype with NR5A1 mutations may be due to a second hit in a gene with similar function to NR5A1/SF-1. Liver receptor homologue-1 (LRH-1/NR5A2) might be a good candidate. We performed in vitro studies for the interplay between SF-1, LRH-1 and DAX-1, expression profiles in human steroidogenic tissues, and NR5A2 genetic studies in a cohort (11 patients, 8 relatives, 11 families) harboring heterozygote NR5A1/SF-1 mutations. LRH-1 isoforms transactivate the CYP17A1 and HSD3B2 promoters similarly to SF-1 and compensate for SF-1 deficiency. DAX-1 inhibits SF-1- and LRH-1-mediated transactivation. LRH-1 is found expressed in human adult and fetal adrenals and testes. However, no NR5A2/LRH-1 mutations were detected in 14 individuals with heterozygote NR5A1/SF-1 mutations. These findings demonstrate that in vitro LRH-1 can act like SF-1 and compensate for its deficiency. Expression of LRH-1 in fetal testis suggests a role in male gonadal development. However, as we found no NR5A2/LRH-1 mutations, the 'second genetic hit' in SF-1 patients explaining the broad phenotypic variability remains elusive. © 2015 S. Karger AG, Basel.
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Friedmann, David; Keller, Baerbel; Harder, Ina; Schupp, Jonas; Tanriver, Yakup; Unger, Susanne; Warnatz, Klaus
2017-11-01
Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc). We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype. Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21 low B cells, but we could not detect an association of the altered ILC phenotype with a T H 1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients. We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21 low B cells, but not overtly with the relative expansion of T H 1-like T cells. Given the relative abundance of T H 1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.
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Genetic and phenotypic characterization of Saccharomyces spp. strains isolated in distillery plants.
Úbeda, Juan F; Chacón-Ocaña, Maria; Díaz-Hellín, Patricia; Ramírez-Pérez, Hector; Briones, Ana
2016-06-01
In this study, the biodiversity and some interesting phenotypic properties of Saccharomyces wild yeasts isolated in distilleries, at least 100 years old, located in La Mancha (Spain), were determined. Strains were genetically characterized by RFLP-mtDNA, which confirmed a great genetic biodiversity with 73% of strains with different mtDNA profiles, highlighting the large variability found in sweet and fermented piquette substrata. The predominant species identified was S. cerevisiae, followed by S. paradoxus and S. bayanus Due to the residual sugar-alcohol extraction process using warm water, a great number of thermophilic Saccharomyces strains with a great cell vitality were found to have potential use as starters in distillery plants. Interesting technological properties such as cell vitality and growth rate at different temperatures were studied. The thermal washing process for the extraction of alcohol and reducing sugars of some raw materials contributes to the presence of Saccharomyces strains with technologically interesting properties, especially in terms of vitality and resistance to high temperatures. Due to the fact that fermentation is spontaneous, the yeast biota of these environments, Saccharomyces and non-Saccharomyces, is very varied so these ecological niches are microbial reserves of undoubted biotechnological interest. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.
Martinelli, Simone; Krumbach, Oliver H F; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Buchholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G; Larsen, Douglas; Farwell, Kelly D; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Di Schiavi, Elia; Della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A; Chong, Jessica X; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D; Bamshad, Michael J; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C; Tartaglia, Marco; Mirzaa, Ghayda M
2018-01-17
Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation
Shapiro, Jay R; Lietman, Caressa; Grover, Monica; Lu, James T; Nagamani, Sandesh CS; Dawson, Brian C; Baldridge, Dustin M; Bainbridge, Matthew N; Cohn, Dan H; Blazo, Maria; Roberts, Timothy T; Brennen, Feng-Shu; Wu, Yimei; Gibbs, Richard A; Melvin, Pamela; Campeau, Philippe M; Lee, Brendan H
2013-01-01
In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation. PMID:23408678
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Gregory, Michael D; Kolachana, Bhaskar; Yao, Yin; Nash, Tiffany; Dickinson, Dwight; Eisenberg, Daniel P; Mervis, Carolyn B; Berman, Karen F
2018-04-04
Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations. Blood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina-HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles. Haploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7. Commonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms.
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Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
Briggs, Tracy A; Rice, Gillian I; Adib, Navid; Ades, Lesley; Barete, Stephane; Baskar, Kannan; Baudouin, Veronique; Cebeci, Ayse N; Clapuyt, Philippe; Coman, David; De Somer, Lien; Finezilber, Yael; Frydman, Moshe; Guven, Ayla; Heritier, Sébastien; Karall, Daniela; Kulkarni, Muralidhar L; Lebon, Pierre; Levitt, David; Le Merrer, Martine; Linglart, Agnes; Livingston, John H; Navarro, Vincent; Okenfuss, Ericka; Puel, Anne; Revencu, Nicole; Scholl-Bürgi, Sabine; Vivarelli, Marina; Wouters, Carine; Bader-Meunier, Brigitte; Crow, Yanick J
2016-04-01
Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.
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Jorge, Alexander A L; Souza, Silvia C; Nishi, Miriam Y; Billerbeck, Ana E; Libório, Débora C C; Kim, Chong A; Arnhold, Ivo J P; Mendonca, Berenice B
2007-01-01
The frequency of SHOX mutations in children with idiopathic short stature (ISS) has been found to be variable. We analysed the SHOX gene in children with ISS and Leri-Weill dyschondrosteosis (LWD) and evaluated the phenotypic variability in patients harbouring SHOX mutations. Sixty-three ISS, nine LWD children and 21 affected relatives. SHOX gene deletion was evaluated by fluorescence in situ hybridization (FISH), Southern blotting and segregation study of polymorphic marker. Point mutations were assessed by direct DNA sequencing. None of the ISS patients presented SHOX deletions, but two (3.2%) presented heterozygous point mutations, including the novel R147H mutation. However, when ISS patients were selected by sitting height : height ratio (SH/H) for age > 2 SD, mutation frequency detection increased to 22%. Eight (89%) LWD patients had SHOX deletions, but none had point mutations. Analysis of the other relatives in the families carrying SHOX mutations identified 14 children and 17 adult patients. A broad phenotypic variability was observed in all families regarding short stature severity and Madelung deformities. However, the presence of disproportional height, assessed by SH/H, was observed in all children and 82% of adult patients, being the most common feature in our patients with SHOX mutations. Patients with SHOX mutations present a broad phenotypic variability. SHOX mutations are very frequent in LWD (89%), in opposition to ISS (3.2%) in our cohort. The use of SH/H SDS as a selection criterion increases the frequency of SHOX mutation detection to 22% and should be used for selecting ISS children to undergo SHOX mutation molecular studies.
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Mendoza, Fernando A; Cichy, Karen A; Sprague, Christy; Goffnett, Amanda; Lu, Renfu; Kelly, James D
2018-01-01
Texture is a major quality parameter for the acceptability of canned whole beans. Prior knowledge of this quality trait before processing would be useful to guide variety development by bean breeders and optimize handling protocols by processors. The objective of this study was to evaluate and compare the predictive power of visible and near infrared reflectance spectroscopy (visible/NIRS, 400-2498 nm) and hyperspectral imaging (HYPERS, 400-1000 nm) techniques for predicting texture of canned black beans from intact dry seeds. Black beans were grown in Michigan (USA) over three field seasons. The samples exhibited phenotypic variability for canned bean texture due to genetic variability and processing practice. Spectral preprocessing methods (i.e. smoothing, first and second derivatives, continuous wavelet transform, and two-band ratios), coupled with a feature selection method, were tested for optimizing the prediction accuracy in both techniques based on partial least squares regression (PLSR) models. Visible/NIRS and HYPERS were effective in predicting texture of canned beans using intact dry seeds, as indicated by their correlation coefficients for prediction (R pred ) and standard errors of prediction (SEP). Visible/NIRS was superior (R pred = 0.546-0.923, SEP = 7.5-1.9 kg 100 g -1 ) to HYPERS (R pred = 0.401-0.883, SEP = 7.6-2.4 kg 100 g -1 ), which is likely due to the wider wavelength range collected in visible/NIRS. However, a significant improvement was reached in both techniques when the two-band ratios preprocessing method was applied to the data, reducing SEP by at least 10.4% and 16.2% for visible/NIRS and HYPERS, respectively. Moreover, results from using the combination of the three-season data sets based on the two-band ratios showed that visible/NIRS (R pred = 0.886, SEP = 4.0 kg 100 g -1 ) and HYPERS (R pred = 0.844, SEP = 4.6 kg 100 g -1 ) models were consistently successful in predicting texture over a wide range of measurements. Visible/NIRS and HYPERS have great potential for predicting the texture of canned beans; the robustness of the models is impacted by genotypic diversity, planting year and phenotypic variability for canned bean texture used for model building, and hence, robust models can be built based on data sets with high phenotypic diversity in textural properties, and periodically maintained and updated with new data. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.
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Burggren, Warren
2018-05-10
The slow, inexorable rise in annual average global temperatures and acidification of the oceans are often advanced as consequences of global change. However, many environmental changes, especially those involving weather (as opposed to climate), are often stochastic, variable and extreme, particularly in temperate terrestrial or freshwater habitats. Moreover, few studies of animal and plant phenotypic plasticity employ realistic (i.e. short-term, stochastic) environmental change in their protocols. Here, I posit that the frequently abrupt environmental changes (days, weeks, months) accompanying much longer-term general climate change (e.g. global warming over decades or centuries) require consideration of the true nature of environmental change (as opposed to statistical means) coupled with an expansion of focus to consider developmental phenotypic plasticity. Such plasticity can be in multiple forms - obligatory/facultative, beneficial/deleterious - depending upon the degree and rate of environmental variability at specific points in organismal development. Essentially, adult phenotypic plasticity, as important as it is, will be irrelevant if developing offspring lack sufficient plasticity to create modified phenotypes necessary for survival. © 2018. Published by The Company of Biologists Ltd.
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Bretscher, P A
2014-01-01
It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the ‘decision criterion’ controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers. PMID:24684592
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Martín-Martín, Lourdes; López, Antonio; Vidriales, Belén; Caballero, María Dolores; Rodrigues, António Silva; Ferreira, Silvia Inês; Lima, Margarida; Almeida, Sérgio; Valverde, Berta; Martínez, Pilar; Ferrer, Ana; Candeias, Jorge; Ruíz-Cabello, Francisco; Buadesa, Josefa Marco; Sempere, Amparo; Villamor, Neus
2015-01-01
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56− phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment. PMID:26056082
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ERIC Educational Resources Information Center
Wulffaert, J.; van Berckelaer-Onnes, I.; Kroonenberg, P.; Scholte, E.; Bhuiyan, Z.; Hennekam, R.
2009-01-01
Background: Studies into the phenotype of rare genetic syndromes largely rely on bivariate analysis. The aim of this study was to describe the phenotype of Cornelia de Lange syndrome (CdLS) in depth by examining a large number of variables with varying measurement levels. Virtually the only suitable multivariate technique for this is categorical…
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Aldridge, Kristina; Boyadjiev, Simeon A.; Capone, George T.; DeLeon, Valerie B.; Richtsmeier, Joan T.
2015-01-01
The genetic basis for complex phenotypes is currently of great interest for both clinical investigators and basic scientists. In order to acquire a thorough understanding of the translation from genotype to phenotype, highly precise measures of phenotypic variation are required. New technologies, such as 3D photogrammetry are being implemented in phenotypic studies due to their ability to collect data rapidly and non-invasively. Before these systems can be broadly implemented the error associated with data collected from images acquired using these technologies must be assessed. This study investigates the precision, error, and repeatability associated with anthropometric landmark coordinate data collected from 3D digital photogrammetric images acquired with the 3dMDface System. Precision, error due to the imaging system, error due to digitization of the images, and repeatability are assessed in a sample of children and adults (N=15). Results show that data collected from images with the 3dMDface System are highly repeatable and precise. The average error associated with the placement of landmarks is sub-millimeter; both the error due to digitization and to the imaging system are very low. The few measures showing a higher degree of error include those crossing the labial fissure, which are influenced by even subtle movement of the mandible. These results suggest that 3D anthropometric data collected using the 3dMDface System are highly reliable and therefore useful for evaluation of clinical dysmorphology and surgery, analyses of genotype-phenotype correlations, and inheritance of complex phenotypes. PMID:16158436
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Hahntow, Ines N; Mairuhu, Gideon; van Valkengoed, Irene Gm; Koopmans, Richard P; Michel, Martin C
2010-06-02
Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates. Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations. We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sinnecker, G.H.G; Hiort, O.; Kruse, K.
Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5{alpha}-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5{alpha}-reductase 2 deficiency (SRD). T/DHT-ratios were highly increased in the classical syndrome, butmore » variable in the less severe affected patients. Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5{alpha}-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5{alpha}-reductase 2 deficiency. 22 refs., 2 figs., 2 tabs.« less
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Samaco, Rodney C.; McGraw, Christopher M.; Ward, Christopher S.; Sun, Yaling; Neul, Jeffrey L.; Zoghbi, Huda Y.
2013-01-01
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2+/− mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2+/− mice, we analyzed Mecp2+/− mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2+/− mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2+/− mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT. PMID:23026749
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Fernandez, Bridget A; Green, Jane S; Bursey, Ford; Barrett, Brendan; MacMillan, Andrée; McColl, Sarah; Fernandez, Sara; Rahman, Proton; Mahoney, Krista; Pereira, Sergio L; Scherer, Stephen W; Boycott, Kym M; Woods, Michael O
2012-11-21
Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with "partial OCA" in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.
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Wightman, Patrick J.; Jackson, George R.; Dipple, Katrina M.
2012-01-01
Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency. PMID:22427807
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Igbokwe, Nanacha Afifi; Igbokwe, Ikechukwu Onyebuchi
2016-11-01
Erythrocyte swelling in non-ionic sucrose media and the subsequent osmotic lysis are influenced by mechanisms of regulatory volume adjustment and osmotic water permeability. Kinetics of transmembrane water and ion fluxes in varied physiologic states may determine the phenotype of erythrocyte osmotic fragility (EOF) and affect estimates of EOF. Effects of sex, age, late pregnancy (third trimester) and lactation on the haemolysis of Sahel goat erythrocytes incubated in a series of hyposmotic non-ionic sucrose media were investigated. The fragiligram was sigmoidal in 72 (97%) out of 74 goats. Two male (3%) goats with low and high extreme median erythrocyte fragilities (MEF), had non-sigmoidal curves. The mean fragilities at osmolarities of 30-300 mosmol/L of sucrose and the mean osmolarities responsible for 10%-90% haemolysis (CH10-CH90) were not significantly different between males and non-pregnant dry (NPD) females, amongst the age groups and between pregnant or lactating and NPD female goats. The MEF (CH50) of the goats were at osmolarities of 126-252 mosmol/L (median of data: 171 mosmol/L) with a mean of 175.24±16.20 mosmol/L. Therefore, phenotypic homogeneity of EOF occurred with minor deviance, since EOF variables were not differentiated by sex, age, late pregnancy or lactation. Physiologic states of the goat did not affect EOF phenotype in non-ionic sucrose media. Sigmoidal fragility phenotype seemed to be homogeneously conserved by osmoregulatory mechanisms not partitioned by sex, age, late pregnancy or lactation, but a minor non-sigmoidal curve might have occurred due to altered erythrocyte osmotic behaviour that would require further investigation.
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Gidaro, Teresa; Modoni, Anna; Sabatelli, Mario; Tasca, Giorgio; Broccolini, Aldobrando; Mirabella, Massimiliano
2008-01-01
Mutations of the valosin-containing protein gene (VCP) are responsible for autosomal-dominant hereditary inclusion-body myopathy associated with frontotemporal dementia and Paget's disease of bone. We identified the p.R155C missense mutation in the VCP gene segregating in an Italian family with three affected siblings, two of whom had a progressive myopathy associated with dementia, whereas one exhibited a progressive myopathy and preclinical signs of Paget's disease of bone. Our study demonstrates that VCP mutations are found in patients of Italian background and may lead to a variable clinical phenotype even within the same kinship.
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Forno, Erick; Gogna, Mudita; Cepeda, Alfonso; Yañez, Anahi; Solé, Dirceu; Cooper, Philip; Avila, Lydiana; Soto-Quiros, Manuel; Castro-Rodriguez, Jose A.; Celedón, Juan C.
2015-01-01
Consistent with the diversity of Latin America, there is profound variability in asthma burden among and within countries in this region. Regional variation in asthma prevalence is likely multifactorial and due to genetics, perinatal exposures, diet, obesity, tobacco use, indoor and outdoor pollutants, psychosocial stress, and microbial or parasitic infections. Similarly, nonuniform progress in asthma management leads to regional variability in disease morbidity. Future studies of distinct asthma phenotypes should follow up well-characterized Latin American subgroups and examine risk factors that are unique or common in Latin America (e.g. stress and violence, parasitic infections and use of biomass fuels for cooking). Because most Latin American countries share the same barriers to asthma management, concerted and multifaceted public health and research efforts are needed, including approaches to curtail tobacco use, campaigns to improve asthma treatment, broadening access to care and clinical trials of non-pharmacologic interventions (e.g. replacing biomass fuels with gas or electric stoves). PMID:26103996
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Pediatric patients with common variable immunodeficiency: long-term follow-up.
Mohammadinejad, P; Aghamohammadi, A; Abolhassani, H; Sadaghiani, M S; Abdollahzade, S; Sadeghi, B; Soheili, H; Tavassoli, M; Fathi, S M; Tavakol, M; Behniafard, N; Darabi, B; Pourhamdi, S; Rezaei, N
2012-01-01
Common variable immunodeficiency (CVID) is the most common form of symptomatic primary immunodeficiency disease. It is characterized by hypogammaglobulinemia, increased predisposition to infections, autoimmunity, and cancer. This study was performed to evaluate the clinical and immunological features of a group of pediatric patients with CVID. The study population comprised 69 individuals with CVID diagnosed during childhood. The patients were followed up for a mean (SD) period of 5.2 (4.3) years. The mean diagnostic delay was 4.4 (3.6) years, which was significantly lower in patients who were diagnosed recently. Children were classified according to 5 clinical phenotypes: infections only (n=39), polyclonal lymphocytic infiltration (n=17), autoimmunity (n=12), malignancy (n=7), and enteropathy (n=3). Postdiagnosis survival (10-year) was 71%. The high percentages of pediatric patients with CVID in Iran may be due to the considerable prevalence of parental consanguinity in the region and an underlying genetic background.
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Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.; ...
2017-11-26
Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography. Our derivation, which is based on the rate summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills maturemore » pine trees. This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.
Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography. Our derivation, which is based on the rate summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills maturemore » pine trees. This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less
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Mikobi, Tite M; Lukusa Tshilobo, Prosper; Aloni, Michel N; Akilimali, Pierre Z; Mvumbi-Lelo, Georges; Mbuyi-Muamba, Jean Marie
2017-11-01
The influence of phenotype on the clinical course and laboratory features of sickle cell anemia (SCA) is rarely described in sub-Saharan Africa. A cross-sectional study was conducted in Kinshasa. A clinical phenotype score was built up. The following definitions were applied: asymptomatic clinical phenotype (ACP; score≤5), moderate clinical phenotype (MCP; score between 6 and 15), and severe clinical phenotype (SCP; score≥16). ANOVA test were used to compare differences among categorical variables. We have studied 140 patients. The mean body mass index (BMI) value of three groups was lower (<25 kg/m 2 ) than the limit defining overweight. BMI of the subjects with ACP was significantly higher than those of other phenotypes (P<.05). Sickle cell patients with ACP have a high mean steady-state hemoglobin concentration compared to those with MCP and SCP (P<.001). A significant elevated baseline leukocyte count is associated with SCP (P<.001). Fetal Hemoglobin (HbF) was significantly higher in ACP. Significant elevation of alpha 1 and alpha 2 globulins in SCP were observed. In our study, fetal hemoglobin has an influence on the clinical severity and the biological parameters of SCA. The study provides data concerning the sickle cell anemia clinical and biological variability in our midst. © 2017 Wiley Periodicals, Inc.
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Garcia-Vicente, Ana María; Pérez-Beteta, Julián; Pérez-García, Víctor Manuel; Molina, David; Jiménez-Londoño, German Andrés; Soriano-Castrejón, Angel; Martínez-González, Alicia
2017-08-01
The aim of the study was to investigate the influence of dual time point 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) on the standard uptake value (SUV) and volume-based metabolic variables of breast lesions and their relation with biological characteristics and molecular phenotypes. Retrospective analysis including 67 patients with locally advanced breast cancer (LABC). All patients underwent a dual time point [ 18 F]FDG PET/CT, 1 h (PET-1) and 3 h (PET-2) after [ 18 F]FDG administration. Tumors were segmented following a three-dimensional methodology. Semiquantitative metabolic variables (SUV max , SUV mean , and SUV peak ) and volume-based variables (metabolic tumor volume, MTV, and total lesion glycolysis, TLG) were obtained. Biologic prognostic parameters, such as the hormone receptors status, p53, HER2 expression, proliferation rate (Ki-67), and grading were obtained. Molecular phenotypes and risk-classification [low: luminal A, intermediate: luminal B HER2 (-) or luminal B HER2 (+), and high: HER2 pure or triple negative] were established. Relations between clinical and biological variables with the metabolic parameters were studied. The relevance of each metabolic variable in the prediction of phenotype risk was assessed using a multivariate analysis. SUV-based variables and TLG obtained in the PET-1 and PET-2 showed high and significant correlations between them. MTV and SUV variables (SUV max , SUV mean , and SUV peak ) where only marginally correlated. Significant differences were found between mean SUV variables and TLG obtained in PET-1 and PET-2. High and significant associations were found between metabolic variables obtained in PET-1 and their homonymous in PET-2. Based on that, only relations of PET-1 variables with biological tumor characteristics were explored. SUV variables showed associations with hormone receptors status (p < 0.001 and p = 0.001 for estrogen and progesterone receptor, respectively) and risk-classification according to phenotype (SUV max , p = 0.003; SUV mean , p = 0.004; SUV peak , p = 0.003). As to volume-based variables, only TLG showed association with hormone receptors status (estrogen, p < 0.001; progesterone, p = 0.031), risk-classification (p = 0.007), and grade (p = 0.036). Hormone receptor negative tumors, high-grade tumors, and high-risk phenotypes showed higher TLG values. No association was found between the metabolic variables and Ki-67, HER2, or p53 expression. Statistical differences were found between mean SUV-based variables and TLG obtained in the dual time point PET/CT. Most of PET-derived parameters showed high association with molecular factors of breast cancer. However, dual time point PET/CT did not offer any added value to the single PET acquisition with respect to the relations with biological variables, based on PET-1 SUV, and volume-based variables were predictors of those obtained in PET-2.
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Interactive effects of genotype and food quality on consumer growth rate and elemental content.
Prater, Clay; Wagner, Nicole D; Frost, Paul C
2017-05-01
Consumer body stoichiometry is a key trait that links organismal physiology to population and ecosystem-level dynamics. However, as elemental composition has traditionally been considered to be constrained within a species, the ecological and evolutionary factors shaping consumer elemental composition have not been clearly resolved. To this end, we examined the causes and extent of variation in the body phosphorus (P) content and the expression of P-linked traits, mass specific growth rate (MSGR), and P use efficiency (PUE) of the keystone aquatic consumer Daphnia using lake surveys and common garden experiments. While daphnid body %P was relatively constrained in field assemblages sampled across an environmental P gradient, unique genotypes isolated from these lakes showed highly variable phenotypic responses when raised across dietary P gradients in the laboratory. Specifically, we observed substantial inter- and intra-specific variation and differences in daphnid responses within and among our study lakes. While variation in Daphnia body %P was mostly due to plastic phenotypic changes, we documented considerable genetic differences in daphnid MSGR and PUE, and relationships between MSGR and body P content were highly variable among genotypes. Overall, our study found that consumer responses to food quality may differ considerably among genotypes and that relationships between organismal life-history traits and body stoichiometry may be strongly influenced by genetic and environmental variation in natural assemblages. © 2017 by the Ecological Society of America.
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Implication of LRRC4C and DPP6 in neurodevelopmental disorders
Maussion, Gilles; Cruceanu, Cristiana; Rosenfeld, Jill A.; Bell, Scott C.; Jollant, Fabrice; Szatkiewicz, Jin; Collins, Ryan L.; Hanscom, Carrie; Kolobova, Ilaria; de Champfleur, Nicolas Menjot; Blumenthal, Ian; Chiang, Colby; Ota, Vanessa; Hultman, Christina; O’Dushlaine, Colm; McCarroll, Steve; Alda, Martin; Jacquemont, Sebastien; Ordulu, Zehra; Marshall, Christian R.; Carter, Melissa T.; Shaffer, Lisa G.; Sklar, Pamela; Girirajan, Santhosh; Morton, Cynthia C.; Gusella, James F.; Turecki, Gustavo; Stavropoulos, D. J.; Sullivan, Patrick F.; Scherer, Stephen W.; Talkowski, Michael E.; Ernst, Carl
2018-01-01
We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband’s autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. PMID:27759917
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Concolino, Daniela; Sestito, Simona; Falvo, Francesca; Romano, Giusy; Ceravolo, Miriam; Anastasio, Elisa; Pensabene, Licia; Colombo, Elisa A; Larizza, Lidia
2018-05-23
Clericuzio-type poikiloderma with neutropenia is a well-defined nosological entity, but despite a remarkable number of clinical reports, no long term follow-up data has been presented to date regarding patients with this rare condition. Here we describe the results of clinical follow-up of three siblings, one male (Patient 1) and two females (Patients 2 and 3), subsequent to their first clinical and then molecular diagnosis of Clericuzio-type poikiloderma with neutropenia syndrome due to mutation of USB1gene. Patient 1 always expressed the most severe phenotype, while patients 2 and 3 showed an intermediate and mild phenotype, respectively, as observed since their first clinical evaluation. None of the patients developed skin cancer and/or myelodysplastic disorders considering the peripheral haematological findings. Lens opacity, never reported before, was found in two of the three patients. The long term follow-up observations confirm the stability over time of the pronounced intra-familial heterogeneity of clinical manifestations observed prior to and upon molecular diagnosis. We conclude that prolonged follow-up is an adjunct tool to monitor intra-familial variability of PN clinical spectrum which may favour surveillance of more serious complications of the disease among siblings, when a patient-specific clinical expressivity is present. Copyright © 2018. Published by Elsevier Masson SAS.
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Lalucque, Hervé; Silar, Philippe
2004-01-01
We describe an example of incomplete penetrance and variable expressivity in the filamentous fungus Podospora anserina, two genetic properties classically associated with mutations in more complex organisms, such as green plants and animals. We show that the knockouts of two TRK-related K(+) transporters of this ascomycete present variability in their phenotype that cannot be attributed to fluctuations of the genetic background or the environment. Thalli of the knockout strains derived from independent monokaryotic ascospores or from a single monokaryotic ascospore and cultivated under standard growth conditions may or may not present impaired growth. When impaired, thalli exhibit a range of phenotypes. Environmental conditions control expressivity to a large extent and penetrance to a low extent. Restoration of functional potassium transport by heterologous expression of K(+) transporters from Neurospora crassa abolishes or strongly diminishes the growth impairment. These data show that incomplete penetrance and variable expressivity can be an intrinsic property of a single Mendelian loss-of-function mutation. They also show that such variability in the expression of a mutant phenotype can be promoted by a phenomenon not obviously related to the well-known chromatin structure modifications, i.e., potassium transport. They provide a framework to understand human channelopathies with similar properties. PMID:15020412
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Lalucque, Hervé; Silar, Philippe
2004-01-01
We describe an example of incomplete penetrance and variable expressivity in the filamentous fungus Podospora anserina, two genetic properties classically associated with mutations in more complex organisms, such as green plants and animals. We show that the knockouts of two TRK-related K(+) transporters of this ascomycete present variability in their phenotype that cannot be attributed to fluctuations of the genetic background or the environment. Thalli of the knockout strains derived from independent monokaryotic ascospores or from a single monokaryotic ascospore and cultivated under standard growth conditions may or may not present impaired growth. When impaired, thalli exhibit a range of phenotypes. Environmental conditions control expressivity to a large extent and penetrance to a low extent. Restoration of functional potassium transport by heterologous expression of K(+) transporters from Neurospora crassa abolishes or strongly diminishes the growth impairment. These data show that incomplete penetrance and variable expressivity can be an intrinsic property of a single Mendelian loss-of-function mutation. They also show that such variability in the expression of a mutant phenotype can be promoted by a phenomenon not obviously related to the well-known chromatin structure modifications, i.e., potassium transport. They provide a framework to understand human channelopathies with similar properties.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Gillessen-Kaesbach, G.; Passarge, E.; Horsthemke, B.
1995-04-10
This {open_quotes}Letter to the Editor{close_quotes} decribes a patient with Angelman syndrome due to paternal uniparental disomy of chromosome 15 and a milder phenotype compared to Angelman syndrome patients with a 15q deletion. 10 refs., 1 fig.
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High phenotypic variability in Gerstmann-Sträussler-Scheinker disease.
Smid, Jerusa; Studart, Adalberto; Landemberger, Michele Christine; Machado, Cleiton Fagundes; Nóbrega, Paulo Ribeiro; Canedo, Nathalie Henriques Silva; Schultz, Rodrigo Rizek; Naslavsky, Michel Satya; Rosemberg, Sérgio; Kok, Fernando; Chimelli, Leila; Martins, Vilma Regina; Nitrini, Ricardo
2017-06-01
Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.
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From Local Adaptation to Ecological Speciation in Copepod Populations from Neighboring Lakes
Barrera-Moreno, Omar Alfredo; Ciros-Pérez, Jorge; Ortega-Mayagoitia, Elizabeth; Alcántara-Rodríguez, José Arturo; Piedra-Ibarra, Elías
2015-01-01
Continental copepods have been derived from several independent invasive events from the sea, but the subsequent evolutionary processes that account for the current diversity in lacustrine environments are virtually unknown. Salinity is highly variable among lakes and constitutes a source of divergent selection driving potential reproductive isolation. We studied four populations of the calanoid copepod Leptodiaptomus cf. sicilis inhabiting four neighboring lakes with a common history (since the Late Pleistocene) located in the Oriental Basin, Mexico; one lake is shallow and varies in salinity periodically (1.4–10 g L-1), while three are deep and permanent, with constant salinity (0.5, 1.1 and 6.5 g L-1, respectively). We hypothesized that (1) these populations belong to a different species than L. sicilis sensu stricto and (2) are experiencing ecologically based divergence due to salinity differences. We assessed morphological and molecular (mtDNA) COI variation, as well as fitness differences and tests of reproductive isolation. Although relationships of the Mexican populations with L. sicilis s.s. could not be elucidated, we identified a clear pattern of divergent selection driven by salinity conditions. The four populations can still be considered a single biological species (sexual recognition and hybridization are still possible in laboratory conditions), but they have diverged into at least three different phenotypes: two locally adapted, specialized in the lakes of constant salinity (saline vs. freshwater), and an intermediate generalist phenotype inhabiting the temporary lake with fluctuating salinity. The specialized phenotypes are poorly suited as migrants, so prezygotic isolation due to immigrant inviability is highly probable. This implication was supported by molecular evidence that showed restricted gene flow, persistence of founder events, and a pattern of allopatric fragmentation. This study showed how ecologically based divergent selection may explain diversification patterns in lacustrine copepods. PMID:25915059
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Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life.
Lehmann-Horn, Frank; D'Amico, Adele; Bertini, Enrico; Lomonaco, Mauro; Merlini, Luciano; Nelson, Kevin R; Philippi, Heike; Siciliano, Gabriele; Spaans, Frank; Jurkat-Rott, Karin
2017-09-01
Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.
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Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life
LEHMANN-HORN, FRANK; D’AMICO, ADELE; BERTINI, ENRICO; LOMONACO, MAURO; MERLINI, LUCIANO; NELSON, KEVIN R.; PHILIPPI, HEIKE; SICILIANO, GABRIELE; SPAANS, FRANK; JURKAT-ROTT, KARIN
2017-01-01
Introduction Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Methods Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. Results In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Discussion Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling. PMID:29774303
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X-linked juvenile retinoschisis (XLRS): a review of genotype-phenotype relationships.
Kim, David Y; Mukai, Shizuo
2013-01-01
X-linked juvenile retinoschisis (XLRS) is one of the most common genetic causes of juvenile progressive retinal-vitreal degeneration in males. To date, more than 196 different mutations of the RS1 gene have been associated with XLRS. The mutation spectrum is large and the phenotype variable. This review will focus on the clinical features of XLRS and examine the relationship between phenotype and genotype.
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Gemenetzi, M; Lotery, A J
2013-11-01
To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and confirmed ABCA4 mutations. Entire coding region analysis of the ABCA4 gene by direct sequencing of seven patients with clinical findings of STGD seen in the Retina Clinics of Southampton Eye Unit between 2002 and 2011.Phenotypic variables recorded were BCVA, fluorescein angiographic appearance, electrophysiology, and visual fields. All patients had heterozygous amino acid-changing variants (missense mutations) in the ABCA4 gene. A splice sequence change was found in a 30-year-old patient with severly affected vision. Two novel sequence changes were identified: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient. The identified ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA. Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype. This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information may prove useful in selection of candidates for clinical trials in ABCA4 disease.
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Tufto, Jarle
2015-08-01
Adaptive responses to autocorrelated environmental fluctuations through evolution in mean reaction norm elevation and slope and an independent component of the phenotypic variance are analyzed using a quantitative genetic model. Analytic approximations expressing the mutual dependencies between all three response modes are derived and solved for the joint evolutionary outcome. Both genetic evolution in reaction norm elevation and plasticity are favored by slow temporal fluctuations, with plasticity, in the absence of microenvironmental variability, being the dominant evolutionary outcome for reasonable parameter values. For fast fluctuations, tracking of the optimal phenotype through genetic evolution and plasticity is limited. If residual fluctuations in the optimal phenotype are large and stabilizing selection is strong, selection then acts to increase the phenotypic variance (bet-hedging adaptive). Otherwise, canalizing selection occurs. If the phenotypic variance increases with plasticity through the effect of microenvironmental variability, this shifts the joint evolutionary balance away from plasticity in favor of genetic evolution. If microenvironmental deviations experienced by each individual at the time of development and selection are correlated, however, more plasticity evolves. The adaptive significance of evolutionary fluctuations in plasticity and the phenotypic variance, transient evolution, and the validity of the analytic approximations are investigated using simulations. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.
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Cervera-Acedo, C; Coloma, A; Huarte-Loza, E; Sierra-Carpio, M; Domínguez-Garrido, E
2017-10-31
Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely COL4A3 and COL4A4 in chromosome 2 and COL4A5 in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis. Mutational analysis of COL4A3 and COL4A4 genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the COL4A3 gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional COL4A3 mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone. Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.
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Variable Bone Fragility Associated With an Amish COL1A2 Variant and a Knock-in Mouse Model
Daley, Ethan; Streeten, Elizabeth A; Sorkin, John D; Kuznetsova, Natalia; Shapses, Sue A; Carleton, Stephanie M; Shuldiner, Alan R; Marini, Joan C; Phillips, Charlotte L; Goldstein, Steven A; Leikin, Sergey; McBride, Daniel J
2010-01-01
Osteogenesis imperfecta (OI) is a heritable form of bone fragility typically associated with a dominant COL1A1 or COL1A2 mutation. Variable phenotype for OI patients with identical collagen mutations is well established, but phenotype variability is described using the qualitative Sillence classification. Patterning a new OI mouse model on a specific collagen mutation therefore has been hindered by the absence of an appropriate kindred with extensive quantitative phenotype data. We benefited from the large sibships of the Old Order Amish (OOA) to define a wide range of OI phenotypes in 64 individuals with the identical COL1A2 mutation. Stratification of carrier spine (L1–4) areal bone mineral density (aBMD) Z-scores demonstrated that 73% had moderate to severe disease (less than −2), 23% had mild disease (−1 to −2), and 4% were in the unaffected range (greater than −1). A line of knock-in mice was patterned on the OOA mutation. Bone phenotype was evaluated in four F1 lines of knock-in mice that each shared approximately 50% of their genetic background. Consistent with the human pedigree, these mice had reduced body mass, aBMD, and bone strength. Whole-bone fracture susceptibility was influenced by individual genomic factors that were reflected in size, shape, and possibly bone metabolic regulation. The results indicate that the G610C OI (Amish) knock-in mouse is a novel translational model to identify modifying genes that influence phenotype and for testing potential therapies for OI. © 2010 American Society for Bone and Mineral Research PMID:19594296
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Autosomal dominant frontonasal dysplasia (atypical Greig syndrome): Lessons from the Xt mutant mouse
DOE Office of Scientific and Technical Information (OSTI.GOV)
Cunningham, M.L.; Nunes, M.E.
1994-09-01
Greig syndrome is the autosomal dominant association of mild hypertelorism, variable polysyndactyly, and normal intelligence. Several families have been found to have translocations or deletions of 7p13 interrupting the normal expression of GLI3 (a zinc finger, DNA binding, transcription repressor). Recently, a mutation in the mouse homologue of GLI3 was found in the extra-toes mutant mouse (Xt). The phenotypic features of this mouse model include mild hypertelorism, postaxial polydactyly of the forelimbs, preaxial polydactyly of the hindlimbs, and variable tibial hemimelia. The homozygous mutant Xt/Xt have severe frontonasal dysplasia (FND), polysyndactyly of fore-and hindlimbs and invariable tibial hemimelia. We havemore » recently evaluated a child with severe (type D) frontonasal dysplasia, fifth finger camptodactyly, preaxial polydactyly of one foot, and ispilateral tibial hemimelia. His father was born with a bifid nose, broad columnella, broad feet, and a two centimeter leg length discrepancy. The paternal grandmother of the proband is phenotypically normal; however, her fraternal twin died at birth with severe facial anomalies. The paternal great-grandmother of the proband is phenotypically normal however her niece was born with moderate ocular hypertelorism. This pedigree is suggestive of an autosomal dominant form of frontonasal dysplasia with variable expressivity. The phenotypic features of our case more closely resemble the Xt mouse than the previously defined features of Greig syndrome in humans. This suggests that a mutation in GLI3 may be responsible for FND in this family. We are currently using polymorphic dinucleotide repeat markers flanking GLI3 in a attempt to demonstrate linkage in this pedigree. Demonstration of a GLI3 mutation in this family would broaden our view of the spectrum of phenotypes possible in Greig syndrome and could provide insight into genotype/phenotype correlation in FND.« less
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Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype.
Tyler, Andrea D; Kirsch, Richard; Milgrom, Raquel; Stempak, Joanne M; Kabakchiev, Boyko; Silverberg, Mark S
2016-04-01
Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes.
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Schelly, Robert C.; Smith, W. Leo; Davis, Matthew P.; Tchernov, Dan; Pieribone, Vincent A.
2014-01-01
The discovery of fluorescent proteins has revolutionized experimental biology. Whereas the majority of fluorescent proteins have been identified from cnidarians, recently several fluorescent proteins have been isolated across the animal tree of life. Here we show that biofluorescence is not only phylogenetically widespread, but is also phenotypically variable across both cartilaginous and bony fishes, highlighting its evolutionary history and the possibility for discovery of numerous novel fluorescent proteins. Fish biofluorescence is especially common and morphologically variable in cryptically patterned coral-reef lineages. We identified 16 orders, 50 families, 105 genera, and more than 180 species of biofluorescent fishes. We have also reconstructed our current understanding of the phylogenetic distribution of biofluorescence for ray-finned fishes. The presence of yellow long-pass intraocular filters in many biofluorescent fish lineages and the substantive color vision capabilities of coral-reef fishes suggest that they are capable of detecting fluoresced light. We present species-specific emission patterns among closely related species, indicating that biofluorescence potentially functions in intraspecific communication and evidence that fluorescence can be used for camouflage. This research provides insight into the distribution, evolution, and phenotypic variability of biofluorescence in marine lineages and examines the role this variation may play. PMID:24421880
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Maternal source of variability in the embryo development of an annual killifish.
Polačik, M; Smith, C; Reichard, M
2017-04-01
Organisms inhabiting unpredictable environments often evolve diversified reproductive bet-hedging strategies, expressed as production of multiple offspring phenotypes, thereby avoiding complete reproductive failure. To cope with unpredictable rainfall, African annual killifish from temporary savannah pools lay drought-resistant eggs that vary widely in the duration of embryo development. We examined the sources of variability in the duration of individual embryo development, egg production and fertilization rate in Nothobranchius furzeri. Using a quantitative genetics approach (North Carolina type II design), we found support for maternal effects rather than polyandrous mating as the primary source of the variability in the duration of embryo development. The number of previously laid eggs appeared to serve as an internal physiological cue initiating a shift from rapid-to-slow embryo developmental mode. In annual killifish, extensive phenotypic variability in progeny traits is adaptive, as the conditions experienced by parents have limited relevance to the offspring generation. In contrast to genetic control, with high phenotypic expression and heritability, maternal control of traits under natural selection prevents standing genetic diversity from potentially detrimental effects of selection in fluctuating environments. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.
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Sparks, John S; Schelly, Robert C; Smith, W Leo; Davis, Matthew P; Tchernov, Dan; Pieribone, Vincent A; Gruber, David F
2014-01-01
The discovery of fluorescent proteins has revolutionized experimental biology. Whereas the majority of fluorescent proteins have been identified from cnidarians, recently several fluorescent proteins have been isolated across the animal tree of life. Here we show that biofluorescence is not only phylogenetically widespread, but is also phenotypically variable across both cartilaginous and bony fishes, highlighting its evolutionary history and the possibility for discovery of numerous novel fluorescent proteins. Fish biofluorescence is especially common and morphologically variable in cryptically patterned coral-reef lineages. We identified 16 orders, 50 families, 105 genera, and more than 180 species of biofluorescent fishes. We have also reconstructed our current understanding of the phylogenetic distribution of biofluorescence for ray-finned fishes. The presence of yellow long-pass intraocular filters in many biofluorescent fish lineages and the substantive color vision capabilities of coral-reef fishes suggest that they are capable of detecting fluoresced light. We present species-specific emission patterns among closely related species, indicating that biofluorescence potentially functions in intraspecific communication and evidence that fluorescence can be used for camouflage. This research provides insight into the distribution, evolution, and phenotypic variability of biofluorescence in marine lineages and examines the role this variation may play.
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A Unified Framework for Association Analysis with Multiple Related Phenotypes
Stephens, Matthew
2013-01-01
We consider the problem of assessing associations between multiple related outcome variables, and a single explanatory variable of interest. This problem arises in many settings, including genetic association studies, where the explanatory variable is genotype at a genetic variant. We outline a framework for conducting this type of analysis, based on Bayesian model comparison and model averaging for multivariate regressions. This framework unifies several common approaches to this problem, and includes both standard univariate and standard multivariate association tests as special cases. The framework also unifies the problems of testing for associations and explaining associations – that is, identifying which outcome variables are associated with genotype. This provides an alternative to the usual, but conceptually unsatisfying, approach of resorting to univariate tests when explaining and interpreting significant multivariate findings. The method is computationally tractable genome-wide for modest numbers of phenotypes (e.g. 5–10), and can be applied to summary data, without access to raw genotype and phenotype data. We illustrate the methods on both simulated examples, and to a genome-wide association study of blood lipid traits where we identify 18 potential novel genetic associations that were not identified by univariate analyses of the same data. PMID:23861737
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The phenotypic variability in Rana temporaria decreases in response to drying habitats.
Miramontes-Sequeiros, Luz Calia; Palanca-Castán, Nicolás; Caamaño-Chinchilla, Laura; Palanca-Soler, Antonio
2018-01-15
In this study, we evaluated the diversity of skin coloration as a proxy for phenotypic diversity. The European common frog (Rana temporaria) populations from the Southern slope of central Pyrenees lie at the limit of the species distribution in latitude and altitude. We analysed the relationship of skin color typology with different environmental variables and found a large decrease in skin type variety in frogs developing in temporary water bodies when compared to those developing in permanent water bodies. Our results show that our method can be used as a non-invasive way to study phenotypic diversity and suggest that adaptation to an early metamorphosis in a rapidly-drying habitat can have negative effects on adult phenotypic diversity. In light of these results, we argue that access to permanent water bodies is important to prevent loss of diversity in anuran populations and reduce their vulnerability to environmental impacts as well as pathogens. Copyright © 2017 Elsevier B.V. All rights reserved.
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Dombrovsky, Aviv; Arthaud, Laury; Ledger, Terence N; Tares, Sophie; Robichon, Alain
2009-11-01
The aphid Acyrthosiphon pisum population is composed of different morphs, such as winged and wingless parthenogens, males, and sexual females. The combined effect of reduced photoperiodicity and cold in fall triggers the apparition of sexual morphs. In contrast they reproduce asexually in spring and summer. In our current study, we provide evidence that clonal individuals display phenotypic variability within asexual morph categories. We describe that clones sharing the same morphological features, which arose from the same founder mother, constitute a repertoire of variants with distinct behavioral and physiological traits. Our results suggest that the prevailing environmental conditions influence the recruitment of adaptive phenotypes from a cohort of clonal individuals exhibiting considerable molecular diversity. However, we observed that the variability might be reduced or enhanced by external factors, but is never abolished in accordance with a model of stochastically produced phenotypes. This overall mechanism allows the renewal of colonies from a few adapted individuals that survive drastic episodic changes in a fluctuating environment.
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Okada, Hirokazu; Ebhardt, H Alexander; Vonesch, Sibylle Chantal; Aebersold, Ruedi; Hafen, Ernst
2016-09-01
The manner by which genetic diversity within a population generates individual phenotypes is a fundamental question of biology. To advance the understanding of the genotype-phenotype relationships towards the level of biochemical processes, we perform a proteome-wide association study (PWAS) of a complex quantitative phenotype. We quantify the variation of wing imaginal disc proteomes in Drosophila genetic reference panel (DGRP) lines using SWATH mass spectrometry. In spite of the very large genetic variation (1/36 bp) between the lines, proteome variability is surprisingly small, indicating strong molecular resilience of protein expression patterns. Proteins associated with adult wing size form tight co-variation clusters that are enriched in fundamental biochemical processes. Wing size correlates with some basic metabolic functions, positively with glucose metabolism but negatively with mitochondrial respiration and not with ribosome biogenesis. Our study highlights the power of PWAS to filter functional variants from the large genetic variability in natural populations.
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Dombrovsky, Aviv; Arthaud, Laury; Ledger, Terence N.; Tares, Sophie; Robichon, Alain
2009-01-01
The aphid Acyrthosiphon pisum population is composed of different morphs, such as winged and wingless parthenogens, males, and sexual females. The combined effect of reduced photoperiodicity and cold in fall triggers the apparition of sexual morphs. In contrast they reproduce asexually in spring and summer. In our current study, we provide evidence that clonal individuals display phenotypic variability within asexual morph categories. We describe that clones sharing the same morphological features, which arose from the same founder mother, constitute a repertoire of variants with distinct behavioral and physiological traits. Our results suggest that the prevailing environmental conditions influence the recruitment of adaptive phenotypes from a cohort of clonal individuals exhibiting considerable molecular diversity. However, we observed that the variability might be reduced or enhanced by external factors, but is never abolished in accordance with a model of stochastically produced phenotypes. This overall mechanism allows the renewal of colonies from a few adapted individuals that survive drastic episodic changes in a fluctuating environment. PMID:19635846
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Allelic variation of the FRMD7 gene in congenital idiopathic nystagmus.
Self, James E; Shawkat, Fatima; Malpas, Crispin T; Thomas, N Simon; Harris, Christopher M; Hodgkins, Peter R; Chen, Xiaoli; Trump, Dorothy; Lotery, Andrew J
2007-09-01
To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.
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Present status and perspective of pharmacogenetics in Mexico.
Cuautle-Rodríguez, Patricia; Llerena, Adrián; Molina-Guarneros, Juan
2014-01-01
Drug costs account for up to 24% of the country's health expenditure and there are 13,000 registered drugs being prescribed. Diabetes is the main cause of death in the country, with over 85% of diabetic patients currently under drug treatment. The importance of knowing interindividual variability in drug metabolism on Mexican populations is thus evident. The purpose of this article is to provide an overlook of the current situation of pharmacogenetic research in Mexico, focusing on drug-metabolizing enzymes, and the possibility of developing a phenotyping cocktail for Mexican populations. So far, 21 pharmacogenetic studies on Mexican population samples (Mestizos and Amerindian) have been published. These have reported interindividual variability through phenotyping and/or genotyping cytochromes: CYP2D6, 2C19, 2C9, 2E1, and phase II enzymes UGT and NAT2. Some cytochromes with important clinical implications have not yet been phenotyped in Mexican populations. The development of a cocktail adapted to them could be a significant contribution to a larger knowledge on drug response variability at a lower price and shorter time. There are validated phenotyping cocktails that present several practical advantages, being valuable, safe, and inexpensive tools in drug metabolism characterization, which require only a single experiment to provide information on several cytochrome activities.
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Conrad, Douglas J; Bailey, Barbara A; Hardie, Jon A; Bakke, Per S; Eagan, Tomas M L; Aarli, Bernt B
2017-01-01
Clinical phenotyping, therapeutic investigations as well as genomic, airway secretion metabolomic and metagenomic investigations can benefit from robust, nonlinear modeling of FEV1 in individual subjects. We demonstrate the utility of measuring FEV1 dynamics in representative cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) populations. Individual FEV1 data from CF and COPD subjects were modeled by estimating median regression splines and their predicted first and second derivatives. Classes were created from variables that capture the dynamics of these curves in both cohorts. Nine FEV1 dynamic variables were identified from the splines and their predicted derivatives in individuals with CF (n = 177) and COPD (n = 374). Three FEV1 dynamic classes (i.e. stable, intermediate and hypervariable) were generated and described using these variables from both cohorts. In the CF cohort, the FEV1 hypervariable class (HV) was associated with a clinically unstable, female-dominated phenotypes while stable FEV1 class (S) individuals were highly associated with the male-dominated milder clinical phenotype. In the COPD cohort, associations were found between the FEV1 dynamic classes, the COPD GOLD grades, with exacerbation frequency and symptoms. Nonlinear modeling of FEV1 with splines provides new insights and is useful in characterizing CF and COPD clinical phenotypes.
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Gliem, Martin; Holz, Frank G; Stöhr, Heidi; Weber, Bernhard H F; Charbel Issa, Peter
2014-12-01
To describe the phenotypic variability in a consanguineous family with genetically confirmed X-linked retinoschisis. Five patients, including one homozygous female, were characterized by clinical examination, optical coherence tomography, fundus autofluorescence, mapping of macular pigment optical density, electroretinography, and DNA testing. The 36-year-old male index patient showed a ring of enhanced autofluorescence and outer retinal atrophy on optical coherence tomography. Electroretinography testing revealed a reduced a/b ratio. His mother presented with a central atrophic retina with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. The 40-year-old brother of the index patient and his 2 sons showed characteristic signs for X-linked retinoschisis, including retinal schisis and a reduced a/b ratio. Genetic testing revealed a c.293C>A mutation in the RS1 gene in all affected family members while the mother of the index patient was homozygous for this mutation. X-linked retinoschisis can present with a wide phenotypic variability. Here, detailed family history and genetic testing established the diagnosis of X-linked retinoschisis despite striking differences in phenotypic presentation in affected subjects, homozygosity of one affected female, and seemingly dominant inheritance in three subsequent generations because of multiple consanguinity.
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High-throughput discovery of novel developmental phenotypes.
Dickinson, Mary E; Flenniken, Ann M; Ji, Xiao; Teboul, Lydia; Wong, Michael D; White, Jacqueline K; Meehan, Terrence F; Weninger, Wolfgang J; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N; Bower, Lynette; Brown, James M; Caddle, L Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J; Denegre, James M; Doe, Brendan; Dolan, Mary E; Edie, Sarah M; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R; Hsu, Chih-Wei; Johnson, Sara J; Kalaga, Sowmya; Keith, Lance C; Lanoue, Louise; Lawson, Thomas N; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L; Newbigging, Susan; Nutter, Lauryl M J; Peterson, Kevin A; Ramirez-Solis, Ramiro; Rowland, Douglas J; Ryder, Edward; Samocha, Kaitlin E; Seavitt, John R; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G; Tocchini-Valentini, Glauco P; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C; Justice, Monica J; Parkinson, Helen E; Moore, Mark; Wells, Sara; Braun, Robert E; Svenson, Karen L; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R Mark; Brown, Steve D M; Adams, David J; Lloyd, K C Kent; McKerlie, Colin; Beaudet, Arthur L; Bućan, Maja; Murray, Stephen A
2016-09-22
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
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High-throughput discovery of novel developmental phenotypes
Dickinson, Mary E.; Flenniken, Ann M.; Ji, Xiao; Teboul, Lydia; Wong, Michael D.; White, Jacqueline K.; Meehan, Terrence F.; Weninger, Wolfgang J.; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N.; Bower, Lynette; Brown, James M.; Caddle, L. Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J.; Denegre, James M.; Doe, Brendan; Dolan, Mary E.; Edie, Sarah M.; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R.; Hsu, Chih-wei; Johnson, Sara J.; Kalaga, Sowmya; Keith, Lance C.; Lanoue, Louise; Lawson, Thomas N.; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L.; Newbigging, Susan; Nutter, Lauryl M.J.; Peterson, Kevin A.; Ramirez-Solis, Ramiro; Rowland, Douglas J.; Ryder, Edward; Samocha, Kaitlin E.; Seavitt, John R.; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B.; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G.; Tocchini-Valentini, Glauco P.; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C.; Justice, Monica J.; Parkinson, Helen E.; Moore, Mark; Wells, Sara; Braun, Robert E.; Svenson, Karen L.; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R. Mark; Brown, Steve D.M.; Adams, David J.; Lloyd, K.C. Kent; McKerlie, Colin; Beaudet, Arthur L.; Bucan, Maja; Murray, Stephen A.
2016-01-01
Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts. PMID:27626380
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Neurobehavioral phenotype in Prader-Willi syndrome.
Whittington, Joyce; Holland, Anthony
2010-11-15
The focus of this article is on the lifetime development of people with Prader-Willi syndrome (PWS) and specifically on the neurobehavioral phenotype. We consider studies of this aspect of the phenotype (the "behavioral phenotype" of the syndrome) that have confirmed that there are specific behaviors and psychiatric disorders, the propensities to which are increased in those with PWS, and cannot be accounted for by other variables such as IQ or adaptive behavior. Beginning with a description of what is observed in people with PWS, we review the evolving PWS phenotype and consider how some aspects of the phenotype might be best explained, and how this complex phenotype may relate to the equally complex genotype. We then consider in more detail some of the neurobehavioral aspects of the phenotype listed above that raise the greatest management problems for parents and carers. © 2010 Wiley-Liss, Inc.
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From top to bottom: Do Lake Trout diversify along a depth gradient in Great Bear Lake, NT, Canada?
Chavarie, Louise; Howland, Kimberly L.; Harris, Les N.; Hansen, Michael J.; Harford, William J.; Gallagher, Colin P.; Baillie, Shauna M.; Malley, Brendan; Tonn, William M.; Muir, Andrew M.; Krueger, Charles C.
2018-01-01
Depth is usually considered the main driver of Lake Trout intraspecific diversity across lakes in North America. Given that Great Bear Lake is one of the largest and deepest freshwater systems in North America, we predicted that Lake Trout intraspecific diversity to be organized along a depth axis within this system. Thus, we investigated whether a deep-water morph of Lake Trout co-existed with four shallow-water morphs previously described in Great Bear Lake. Morphology, neutral genetic variation, isotopic niches, and life-history traits of Lake Trout across depths (0–150 m) were compared among morphs. Due to the propensity of Lake Trout with high levels of morphological diversity to occupy multiple habitat niches, a novel multivariate grouping method using a suite of composite variables was applied in addition to two other commonly used grouping methods to classify individuals. Depth alone did not explain Lake Trout diversity in Great Bear Lake; a distinct fifth deep-water morph was not found. Rather, Lake Trout diversity followed an ecological continuum, with some evidence for adaptation to local conditions in deep-water habitat. Overall, trout caught from deep-water showed low levels of genetic and phenotypic differentiation from shallow-water trout, and displayed higher lipid content (C:N ratio) and occupied a higher trophic level that suggested an potential increase of piscivory (including cannibalism) than the previously described four morphs. Why phenotypic divergence between shallow- and deep-water Lake Trout was low is unknown, especially when the potential for phenotypic variation should be high in deep and large Great Bear Lake. Given that variation in complexity of freshwater environments has dramatic consequences for divergence, variation in the complexity in Great Bear Lake (i.e., shallow being more complex than deep), may explain the observed dichotomy in the expression of intraspecific phenotypic diversity between shallow- vs. deep-water habitats. The ambiguity surrounding mechanisms driving divergence of Lake Trout in Great Bear Lake should be seen as reflective of the highly variable nature of ecological opportunity and divergent natural selection itself.
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From top to bottom: Do Lake Trout diversify along a depth gradient in Great Bear Lake, NT, Canada?
Chavarie, Louise; Howland, Kimberly L; Harris, Les N; Hansen, Michael J; Harford, William J; Gallagher, Colin P; Baillie, Shauna M; Malley, Brendan; Tonn, William M; Muir, Andrew M; Krueger, Charles C
2018-01-01
Depth is usually considered the main driver of Lake Trout intraspecific diversity across lakes in North America. Given that Great Bear Lake is one of the largest and deepest freshwater systems in North America, we predicted that Lake Trout intraspecific diversity to be organized along a depth axis within this system. Thus, we investigated whether a deep-water morph of Lake Trout co-existed with four shallow-water morphs previously described in Great Bear Lake. Morphology, neutral genetic variation, isotopic niches, and life-history traits of Lake Trout across depths (0-150 m) were compared among morphs. Due to the propensity of Lake Trout with high levels of morphological diversity to occupy multiple habitat niches, a novel multivariate grouping method using a suite of composite variables was applied in addition to two other commonly used grouping methods to classify individuals. Depth alone did not explain Lake Trout diversity in Great Bear Lake; a distinct fifth deep-water morph was not found. Rather, Lake Trout diversity followed an ecological continuum, with some evidence for adaptation to local conditions in deep-water habitat. Overall, trout caught from deep-water showed low levels of genetic and phenotypic differentiation from shallow-water trout, and displayed higher lipid content (C:N ratio) and occupied a higher trophic level that suggested an potential increase of piscivory (including cannibalism) than the previously described four morphs. Why phenotypic divergence between shallow- and deep-water Lake Trout was low is unknown, especially when the potential for phenotypic variation should be high in deep and large Great Bear Lake. Given that variation in complexity of freshwater environments has dramatic consequences for divergence, variation in the complexity in Great Bear Lake (i.e., shallow being more complex than deep), may explain the observed dichotomy in the expression of intraspecific phenotypic diversity between shallow- vs. deep-water habitats. The ambiguity surrounding mechanisms driving divergence of Lake Trout in Great Bear Lake should be seen as reflective of the highly variable nature of ecological opportunity and divergent natural selection itself.
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From top to bottom: Do Lake Trout diversify along a depth gradient in Great Bear Lake, NT, Canada?
Howland, Kimberly L.; Harris, Les N.; Hansen, Michael J.; Harford, William J.; Gallagher, Colin P.; Baillie, Shauna M.; Malley, Brendan; Tonn, William M.; Muir, Andrew M.; Krueger, Charles C.
2018-01-01
Depth is usually considered the main driver of Lake Trout intraspecific diversity across lakes in North America. Given that Great Bear Lake is one of the largest and deepest freshwater systems in North America, we predicted that Lake Trout intraspecific diversity to be organized along a depth axis within this system. Thus, we investigated whether a deep-water morph of Lake Trout co-existed with four shallow-water morphs previously described in Great Bear Lake. Morphology, neutral genetic variation, isotopic niches, and life-history traits of Lake Trout across depths (0–150 m) were compared among morphs. Due to the propensity of Lake Trout with high levels of morphological diversity to occupy multiple habitat niches, a novel multivariate grouping method using a suite of composite variables was applied in addition to two other commonly used grouping methods to classify individuals. Depth alone did not explain Lake Trout diversity in Great Bear Lake; a distinct fifth deep-water morph was not found. Rather, Lake Trout diversity followed an ecological continuum, with some evidence for adaptation to local conditions in deep-water habitat. Overall, trout caught from deep-water showed low levels of genetic and phenotypic differentiation from shallow-water trout, and displayed higher lipid content (C:N ratio) and occupied a higher trophic level that suggested an potential increase of piscivory (including cannibalism) than the previously described four morphs. Why phenotypic divergence between shallow- and deep-water Lake Trout was low is unknown, especially when the potential for phenotypic variation should be high in deep and large Great Bear Lake. Given that variation in complexity of freshwater environments has dramatic consequences for divergence, variation in the complexity in Great Bear Lake (i.e., shallow being more complex than deep), may explain the observed dichotomy in the expression of intraspecific phenotypic diversity between shallow- vs. deep-water habitats. The ambiguity surrounding mechanisms driving divergence of Lake Trout in Great Bear Lake should be seen as reflective of the highly variable nature of ecological opportunity and divergent natural selection itself. PMID:29566015
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GiNA, an efficient and high-throughput software for horticultural phenotyping
USDA-ARS?s Scientific Manuscript database
Traditional methods for trait phenotyping have been a bottleneck for research in many crop species due to their intensive labor, high cost, complex implementation, lack of reproducibility and propensity to subjective bias. Recently, multiple high-throughput phenotyping platforms have been developed,...
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Diagnostic Challenges in Retinitis Pigmentosa: Genotypic Multiplicity and Phenotypic Variability
Chang, Susie; Vaccarella, Leah; Olatunji, Sunday; Cebulla, Colleen; Christoforidis, John
2011-01-01
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP. PMID:22131872
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Zimmermann, Matthias; Escrig, Stéphane; Hübschmann, Thomas; Kirf, Mathias K.; Brand, Andreas; Inglis, R. Fredrik; Musat, Niculina; Müller, Susann; Meibom, Anders; Ackermann, Martin; Schreiber, Frank
2015-01-01
Populations of genetically identical microorganisms residing in the same environment can display marked variability in their phenotypic traits; this phenomenon is termed phenotypic heterogeneity. The relevance of such heterogeneity in natural habitats is unknown, because phenotypic characterization of a sufficient number of single cells of the same species in complex microbial communities is technically difficult. We report a procedure that allows to measure phenotypic heterogeneity in bacterial populations from natural environments, and use it to analyze N2 and CO2 fixation of single cells of the green sulfur bacterium Chlorobium phaeobacteroides from the meromictic lake Lago di Cadagno. We incubated lake water with 15N2 and 13CO2 under in situ conditions with and without NH4+. Subsequently, we used flow cell sorting with auto-fluorescence gating based on a pure culture isolate to concentrate C. phaeobacteroides from its natural abundance of 0.2% to now 26.5% of total bacteria. C. phaeobacteroides cells were identified using catalyzed-reporter deposition fluorescence in situ hybridization (CARD-FISH) targeting the 16S rRNA in the sorted population with a species-specific probe. In a last step, we used nanometer-scale secondary ion mass spectrometry to measure the incorporation 15N and 13C stable isotopes in more than 252 cells. We found that C. phaeobacteroides fixes N2 in the absence of NH4+, but not in the presence of NH4+ as has previously been suggested. N2 and CO2 fixation were heterogeneous among cells and positively correlated indicating that N2 and CO2 fixation activity interact and positively facilitate each other in individual cells. However, because CARD-FISH identification cannot detect genetic variability among cells of the same species, we cannot exclude genetic variability as a source for phenotypic heterogeneity in this natural population. Our study demonstrates the technical feasibility of measuring phenotypic heterogeneity in a rare bacterial species in its natural habitat, thus opening the door to study the occurrence and relevance of phenotypic heterogeneity in nature. PMID:25932020
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[Characteristics of Bacillus cereus dissociants].
Doroshenko, E V; Loĭko, N G; Il'inskaia, O N; Kolpakov, A I; Gornova, I B; Klimanova, E V; El'-Registan, G I
2001-01-01
The autoregulation of the phenotypic (populational) variability of the Bacillus cereus strain 504 was studied. The isolated colonial morphotypes of this bacterium were found to differ in their growth characteristics and the synthesis of extracellular proteases. The phenotypic variabilities of vegetative proliferating cells and those germinated from endospores and cystlike refractory cells were different. Bacterial variants also differed in the production of the d1 and d2 factors (the autoinducers of dormancy and autolysis, respectively) and sensitivity to them. The possible role of these factors in the dissociation of microorganisms is discussed.
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Intrafamilial and interfamilial variability of phenotype in familial velo-cardio-facial syndrome
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hajianpour, M.J.; Lamb, A.; Covle, M.
Two half-sisters and their mother from one family, and two full-brothers and their mother from another family presented with features of velo-cardio-facial syndrome (VCSF)/DiGeorge syndrome (DS) with intrafamilial and interfamilial variability of phenotypic expression. None of these patients had an apparent cleft palate. Cardiac anomaly, jejunal atresia and hypocalcemia were present only in the newborn patient. Fluorescence in situ hybridization for VCFS/DS with probe D22S75 showed a deletion in the 22q11.2 region in patients available for the study.
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Phenotypic assortment in wild primate networks: implications for the dissemination of information.
Carter, Alecia J; Lee, Alexander E G; Marshall, Harry H; Ticó, Miquel Torrents; Cowlishaw, Guy
2015-05-01
Individuals' access to social information can depend on their social network. Homophily-a preference to associate with similar phenotypes-may cause assortment within social networks that could preclude information transfer from individuals who generate information to those who would benefit from acquiring it. Thus, understanding phenotypic assortment may lead to a greater understanding of the factors that could limit the transfer of information between individuals. We tested whether there was assortment in wild baboon (Papio ursinus) networks, using data collected from two troops over 6 years for six phenotypic traits-boldness, age, dominance rank, sex and the propensity to generate/exploit information-using two methods for defining a connection between individuals-time spent in proximity and grooming. Our analysis indicated that assortment was more common in grooming than proximity networks. In general, there was homophily for boldness, age, rank and the propensity to both generate and exploit information, but heterophily for sex. However, there was considerable variability both between troops and years. The patterns of homophily we observed for these phenotypes may impede information transfer between them. However, the inconsistency in the strength of assortment between troops and years suggests that the limitations to information flow may be quite variable.
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Expressivity of hearing loss in cases with Usher syndrome type IIA.
Sadeghi, André M; Cohn, Edward S; Kimberling, William J; Halvarsson, Glenn; Möller, Claes
2013-12-01
The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype-phenotype correlations. Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome.
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Comparison of the theoretical and real-world evolutionary potential of a genetic circuit
NASA Astrophysics Data System (ADS)
Razo-Mejia, M.; Boedicker, J. Q.; Jones, D.; DeLuna, A.; Kinney, J. B.; Phillips, R.
2014-04-01
With the development of next-generation sequencing technologies, many large scale experimental efforts aim to map genotypic variability among individuals. This natural variability in populations fuels many fundamental biological processes, ranging from evolutionary adaptation and speciation to the spread of genetic diseases and drug resistance. An interesting and important component of this variability is present within the regulatory regions of genes. As these regions evolve, accumulated mutations lead to modulation of gene expression, which may have consequences for the phenotype. A simple model system where the link between genetic variability, gene regulation and function can be studied in detail is missing. In this article we develop a model to explore how the sequence of the wild-type lac promoter dictates the fold-change in gene expression. The model combines single-base pair resolution maps of transcription factor and RNA polymerase binding energies with a comprehensive thermodynamic model of gene regulation. The model was validated by predicting and then measuring the variability of lac operon regulation in a collection of natural isolates. We then implement the model to analyze the sensitivity of the promoter sequence to the regulatory output, and predict the potential for regulation to evolve due to point mutations in the promoter region.
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Fourier, Anthony; Portelius, Erik; Zetterberg, Henrik; Blennow, Kaj; Quadrio, Isabelle; Perret-Liaudet, Armand
2015-09-20
A panel of cerebrospinal fluid (CSF) biomarkers including total Tau (t-Tau), phosphorylated Tau protein at residue 181 (p-Tau) and β-amyloid peptides (Aβ42 and Aβ40), is frequently used as an aid in Alzheimer's disease (AD) diagnosis for young patients with cognitive impairment, for predicting prodromal AD in mild cognitive impairment (MCI) subjects, for AD discrimination in atypical clinical phenotypes and for inclusion/exclusion and stratification of patients in clinical trials. Due to variability in absolute levels between laboratories, there is no consensus on medical cut-off value for the CSF AD signature. Thus, for full implementation of this core AD biomarker panel in clinical routine, this issue has to be solved. Variability can be explained both by pre-analytical and analytical factors. For example, the plastic tubes used for CSF collection and storage, the lack of reference material and the variability of the analytical protocols were identified as important sources of variability. The aim of this review is to highlight these pre-analytical and analytical factors and describe efforts done to counteract them in order to establish cut-off values for core CSF AD biomarkers. This review will give the current state of recommendations. Copyright © 2015. Published by Elsevier B.V.
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Cluster Analysis Identifies 3 Phenotypes within Allergic Asthma.
Sendín-Hernández, María Paz; Ávila-Zarza, Carmelo; Sanz, Catalina; García-Sánchez, Asunción; Marcos-Vadillo, Elena; Muñoz-Bellido, Francisco J; Laffond, Elena; Domingo, Christian; Isidoro-García, María; Dávila, Ignacio
Asthma is a heterogeneous chronic disease with different clinical expressions and responses to treatment. In recent years, several unbiased approaches based on clinical, physiological, and molecular features have described several phenotypes of asthma. Some phenotypes are allergic, but little is known about whether these phenotypes can be further subdivided. We aimed to phenotype patients with allergic asthma using an unbiased approach based on multivariate classification techniques (unsupervised hierarchical cluster analysis). From a total of 54 variables of 225 patients with well-characterized allergic asthma diagnosed following American Thoracic Society (ATS) recommendation, positive skin prick test to aeroallergens, and concordant symptoms, we finally selected 19 variables by multiple correspondence analyses. Then a cluster analysis was performed. Three groups were identified. Cluster 1 was constituted by patients with intermittent or mild persistent asthma, without family antecedents of atopy, asthma, or rhinitis. This group showed the lowest total IgE levels. Cluster 2 was constituted by patients with mild asthma with a family history of atopy, asthma, or rhinitis. Total IgE levels were intermediate. Cluster 3 included patients with moderate or severe persistent asthma that needed treatment with corticosteroids and long-acting β-agonists. This group showed the highest total IgE levels. We identified 3 phenotypes of allergic asthma in our population. Furthermore, we described 2 phenotypes of mild atopic asthma mainly differentiated by a family history of allergy. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes.
Mosley, Jonathan D; Shoemaker, M Benjamin; Wells, Quinn S; Darbar, Dawood; Shaffer, Christian M; Edwards, Todd L; Bastarache, Lisa; McCarty, Catherine A; Thompson, Will; Chute, Christopher G; Jarvik, Gail P; Crosslin, David R; Larson, Eric B; Kullo, Iftikhar J; Pacheco, Jennifer A; Peissig, Peggy L; Brilliant, Murray H; Linneman, James G; Witte, John S; Denny, Josh C; Roden, Dan M
2017-04-01
One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]). The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity. © 2017 American Heart Association, Inc.
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Kirillov, A A; Kirillova, N Yu
2015-01-01
Variability of the body size in females of the Cosmocerca ornata (Dujardin, 1845), a parasite of marsh frogs, is studied. The influence of both biotic (age, sex and a phenotype of the host, density of the parasite population) and abiotic (a season of the year, water temperature) factors on the formation of the body size structure in the C. ornata hemipopulation (infrapopulation) is demonstrated. The body size structure of the C. ornata hemipopulation is characterized by the low level of individual variability as within certain subpopulation groups of amphibians (sex, age and phenotype), so within the population of marsh frogs as a whole. The more distinct are the differences in biology and ecology of these host subpopulations, the more pronounced is the variability in the body size of C ornata.
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Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.
Kawarai, Toshitaka; Miyamoto, Ryosuke; Nakagawa, Eiji; Koichihara, Reiko; Sakamoto, Takashi; Mure, Hideo; Morigaki, Ryoma; Koizumi, Hidetaka; Oki, Ryosuke; Montecchiani, Celeste; Caltagirone, Carlo; Orlacchio, Antonio; Hattori, Ayako; Mashimo, Hideaki; Izumi, Yuishin; Mezaki, Takahiro; Kumada, Satoko; Taniguchi, Makoto; Yokochi, Fusako; Saitoh, Shinji; Goto, Satoshi; Kaji, Ryuji
2018-04-05
Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D.
Bolz, H; von Brederlow, B; Ramírez, A; Bryda, E C; Kutsche, K; Nothwang, H G; Seeliger, M; del C-Salcedó Cabrera, M; Vila, M C; Molina, O P; Gal, A; Kubisch, C
2001-01-01
Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.
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Arnold, Suzanne V; Li, Shu-Xia; Alexander, Karen P; Spertus, John A; Nallamothu, Brahmajee K; Curtis, Jeptha P; Kosiborod, Mikhail; Gupta, Aakriti; Wang, Tracy Y; Lin, Haiqun; Dharmarajan, Kumar; Strait, Kelly M; Lowe, Timothy J; Krumholz, Harlan M
2015-06-15
During a myocardial infarction, no single best approach of systemic anticoagulation is recommended, likely due to a lack of comparative effectiveness studies and trade-offs between treatments. We investigated the patterns of use and site-level variability in anticoagulant strategies (unfractionated heparin [UFH] only, low-molecular-weight heparin [LMWH] only, UFH+LMWH, any bivalirudin) of 63 796 patients with a principal diagnosis of myocardial infarction treated with an early invasive strategy with percutaneous coronary intervention at 257 hospitals. About half (47%) of patients received UFH only, 6% UFH+LMWH, 7% LMWH only, and 40% bivalirudin. Compared with UFH, the median odds ratio was 2.90 for LMWH+UFH, 4.70 for LMWH only, and 3.09 for bivalirudin, indicating that 2 "identical" patients would have a 3- to 4-fold greater likelihood of being treated with anticoagulants other than UFH at one hospital compared with another. We then categorized hospitals as low- or high-users of LMWH and bivalirudin. Using hierarchical, multivariate regression models, we found that low bivalirudin-using hospitals had higher unadjusted bleeding rates, but the risk-adjusted and anticoagulant-adjusted bleeding rates did not differ across the hospital anticoagulation phenotypes. Risk-standardized mortality and risk-standardized length of stay also did not differ across hospital phenotypes. We found substantial site-level variability in the choice of anticoagulants for invasively managed acute myocardial infarction patients, even after accounting for patient factors. No single hospital-use pattern was found to be clinically superior. More studies are needed to determine which patients would derive the greatest benefit from various anticoagulants and to support consistent treatment of patients with the optimal anticoagulant strategy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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Reis-Cunha, João Luís; Valdivia, Hugo O; Bartholomeu, Daniella Castanheira
2018-02-01
Trypanosomatids are a group of kinetoplastid parasites including some of great public health importance, causing debilitating and life-long lasting diseases that affect more than 24 million people worldwide. Among the trypanosomatids, Trypanosoma cruzi, Trypanosoma brucei and species from the Leishmania genus are the most well studied parasites, due to their high prevalence in human infections. These parasites have an extreme genomic and phenotypic variability, with a massive expansion in the copy number of species-specific multigene families enrolled in host-parasite interactions that mediate cellular invasion and immune evasion processes. As most trypanosomatids are heteroxenous, and therefore their lifecycles involve the transition between different hosts, these parasites have developed several strategies to ensure a rapid adaptation to changing environments. Among these strategies, a rapid shift in the repertoire of expressed genes, genetic variability and genome plasticity are key mechanisms. Trypanosomatid genomes are organized into large directional gene clusters that are transcribed polycistronically, where genes derived from the same polycistron may have very distinct mRNA levels. This particular mode of transcription implies that the control of gene expression operates mainly at post-transcriptional level. In this sense, gene duplications/losses were already associated with changes in mRNA levels in these parasites. Gene duplications also allow the generation of sequence variability, as the newly formed copy can diverge without loss of function of the original copy. Recently, aneuploidies have been shown to occur in several Leishmania species and T. cruzi strains. Although aneuploidies are usually associated with debilitating phenotypes in superior eukaryotes, recent data shows that it could also provide increased fitness in stress conditions and generate drug resistance in unicellular eukaryotes. In this review, we will focus on gene and chromosomal copy number variations and their relevance to the evolution of trypanosomatid parasites.
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Simonet, Jacqueline C; Sunnen, C Nicole; Wu, Jue; Golden, Jeffrey A; Marsh, Eric D
2015-09-01
Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Timms, Andrew E.; Conti, Valerio; Girisha, Katta M.; Martin, Beth; Olds, Carissa; Collins, Sarah; Park, Kaylee; Carter, Melissa; Krägeloh-Mann, Inge; Chitayat, David; Parikh, Aditi Shah; Bradshaw, Rachael; Torti, Erin; Braddock, Stephen; Burke, Leah; Ghedia, Sondhya; Stephan, Mark; Stewart, Fiona; Prasad, Chitra; Napier, Melanie; Saitta, Sulagna; Straussberg, Rachel; Gabbett, Michael; O’Connor, Bridget C.; Yin, Lim Jiin; Lai, Angeline Hwei Meeng; Martin, Nicole; McKinnon, Margaret; Addor, Marie-Claude; Schwartz, Charles E.; Lanoel, Agustina; Conway, Robert L.; Devriendt, Koenraad; Tatton-Brown, Katrina; Pierpont, Mary Ella; Painter, Michael; Worgan, Lisa; Reggin, James; Hennekam, Raoul; Pritchard, Colin C.; Aracena, Mariana; Gripp, Karen W.; Cordisco, Maria; Van Esch, Hilde; Garavelli, Livia; Curry, Cynthia; Goriely, Anne; Kayserilli, Hulya; Shendure, Jay; Graham, John; Guerrini, Renzo; Dobyns, William B.
2016-01-01
Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations. PMID:27631024
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Race is gendered: how covarying phenotypes and stereotypes bias sex categorization.
Johnson, Kerri L; Freeman, Jonathan B; Pauker, Kristin
2012-01-01
We argue that race and sex categories are psychologically and phenotypically confounded, affecting social categorizations and their efficiency. Sex categorization of faces was facilitated when the race category shared facial phenotypes or stereotypes with the correct sex category (e.g., Asian women and Black men) but was impaired when the race category shared incompatible phenotypes or stereotypes with the correct sex category (e.g., Asian men and Black women). These patterns were evident in the disambiguation of androgynous faces (Study 1) and the efficiency of judgments (Studies 1, 2, 4, and 5). These patterns emerged due to common facial phenotypes for the categories Black and men (Studies 3 and 5) and due to shared stereotypes among the categories Black and men and the categories Asian and women (Studies 4 and 5). These findings challenge the notion that social categories are perceived independent of one another and show, instead, that race is gendered.
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USDA-ARS?s Scientific Manuscript database
Flavobacterium columnare is the etiologic agent of columnaris disease and severely affects various freshwater aquaculture fish species worldwide. The objectives of this study were to determine the phenotypic characteristics and genetic variability among F. columnare isolates isolated from red tilapi...
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Replication and validation of genome-wide associations with feed efficiency of dairy cattle
USDA-ARS?s Scientific Manuscript database
Improving feed efficiency in dairy production is an important endeavor as it can reduce feed costs and mitigate negative impacts of production on the environment. Feed efficiency is a multivariate phenotype characterized by a variety of phenotypic variables such as dry matter intake, body weight gai...
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[Complex heterogeneity phenotypes and genotypes of glutaric aciduria type 1].
Wang, Qiao; Yang, Yan-Ling
2016-05-01
Glutaric aciduria type 1 is a rare autosomal recessive disorder. GCDH gene mutations cause glutaryl-CoA dehydrogenase deficiency and accumulation of glutaric acid and 3-hydroxyglutaric acid, resulting in damage of striatum and other brain nucleus and neurodegeneration. Patients with glutaric aciduria type 1 present with complex heterogeneous phenotypes and genotypes. The symptoms are extremely variable. The ages of the clinical onset of the patients range from the fetus period to adulthood. The patients with mild glutaric aciduria type 1 are almost asymptomatic before onset, however, severe glutaric aciduria type 1 may cause death or disability due to acute encephalopathy. Acute metabolic crisis in patients with underlying glutaric aciduria type 1 is often triggered by febrile illnesses, trauma, hunger, high-protein foods and vaccination during a vulnerable period of brain development in infancy or early childhood. The early-onset patients usually have a poor prognosis. Urinary organic acids analysis, blood acylcarnitines analysis and GCDH study are important for the diagnosis of this disorder. Neonatal screening is essential for the early diagnosis and the improvement of prognosis.
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Cliff-edge model of obstetric selection in humans.
Mitteroecker, Philipp; Huttegger, Simon M; Fischer, Barbara; Pavlicev, Mihaela
2016-12-20
The strikingly high incidence of obstructed labor due to the disproportion of fetal size and the mother's pelvic dimensions has puzzled evolutionary scientists for decades. Here we propose that these high rates are a direct consequence of the distinct characteristics of human obstetric selection. Neonatal size relative to the birth-relevant maternal dimensions is highly variable and positively associated with reproductive success until it reaches a critical value, beyond which natural delivery becomes impossible. As a consequence, the symmetric phenotype distribution cannot match the highly asymmetric, cliff-edged fitness distribution well: The optimal phenotype distribution that maximizes population mean fitness entails a fraction of individuals falling beyond the "fitness edge" (i.e., those with fetopelvic disproportion). Using a simple mathematical model, we show that weak directional selection for a large neonate, a narrow pelvic canal, or both is sufficient to account for the considerable incidence of fetopelvic disproportion. Based on this model, we predict that the regular use of Caesarean sections throughout the last decades has led to an evolutionary increase of fetopelvic disproportion rates by 10 to 20%.
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[Epigenetics 2.0: The multiple faces of the genome].
Rubinstein, Marcelo
2016-09-01
Epigenetics is the branch of genetics that studies the dynamic relationship between stable genotypes and varying phenotypes. To this end, epigenetics aims to discover the molecular mechanisms that explain how different nutrients and hormones, environmental changes, and emotional, social and cognitive experiences modify gene expression and behaviors, even permanently so. Psychiatry has learned that diseases with strong genetic predisposition, such as schizophrenia, show a concordance of around 50% between monozygotic twins, thus evidencing the importance of the genetic background and the presence of environmental variables that stimulate or block phenotypic development. The interest in epigenetics has increased during the last few years due to fundamental discoveries made in molecular and behavioral genetics, although within this framework factual knowledge coexists with fictional expectations and wrong concepts. Is it possible that epigenetic variants modify temperament and human behavior? May abused or neglected children develop long-lasting epigenetic marks in their DNA? May bipolar states correlate with different epigenetic signatures? Studying these subjects in not an easy task, but experiments performed in lab animals suggest that these conjectures are reasonable, although there is still a long distance between hypotheses and scientifically proven facts.
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Konno, Satoshi; Taniguchi, Natsuko; Makita, Hironi; Nakamaru, Yuji; Shimizu, Kaoruko; Shijubo, Noriharu; Fuke, Satoshi; Takeyabu, Kimihiro; Oguri, Mitsuru; Kimura, Hirokazu; Maeda, Yukiko; Suzuki, Masaru; Nagai, Katsura; Ito, Yoichi M; Wenzel, Sally E; Nishimura, Masaharu
2015-12-01
Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).
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The ecology of an adaptive radiation of three-spined stickleback from North Uist, Scotland.
Magalhaes, Isabel S; D'Agostino, Daniele; Hohenlohe, Paul A; MacColl, Andrew D C
2016-09-01
There has been a large focus on the genetics of traits involved in adaptation, but knowledge of the environmental variables leading to adaptive changes is surprisingly poor. Combined use of environmental data with morphological and genomic data should allow us to understand the extent to which patterns of phenotypic and genetic diversity within a species can be explained by the structure of the environment. Here, we analyse the variation of populations of three-spined stickleback from 27 freshwater lakes on North Uist, Scotland, that vary greatly in their environment, to understand how environmental and genetic constraints contribute to phenotypic divergence. We collected 35 individuals per population and 30 abiotic and biotic environmental parameters to characterize variation across lakes and analyse phenotype-environment associations. Additionally, we used RAD sequencing to estimate the genetic relationships among a subset of these populations. We found a large amount of phenotypic variation among populations, most prominently in armour and spine traits. Despite large variation in the abiotic environment, namely in ion composition, depth and dissolved organic Carbon, more phenotypic variation was explained by the biotic variables (presence of predators and density of predator and competitors), than by associated abiotic variables. Genetic structure among populations was partly geographic, with closer populations being more similar. Altogether, our results suggest that differences in body shape among stickleback populations are the result of both canalized genetic and plastic responses to environmental factors, which shape fish morphology in a predictable direction regardless of their genetic starting point. © 2016 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.
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Huang, Guomin; Rymer, Paul D; Duan, Honglang; Smith, Renee A; Tissue, David T
2015-10-01
Intraspecific variation in phenotypic plasticity is a critical determinant of plant species capacity to cope with climate change. A long-standing hypothesis states that greater levels of environmental variability will select for genotypes with greater phenotypic plasticity. However, few studies have examined how genotypes of woody species originating from contrasting environments respond to multiple climate change factors. Here, we investigated the main and interactive effects of elevated [CO2 ] (CE ) and elevated temperature (TE ) on growth and physiology of Coastal (warmer, less variable temperature environment) and Upland (cooler, more variable temperature environment) genotypes of an Australian woody species Telopea speciosissima. Both genotypes were positively responsive to CE (35% and 29% increase in whole-plant dry mass and leaf area, respectively), but only the Coastal genotype exhibited positive growth responses to TE . We found that the Coastal genotype exhibited greater growth response to TE (47% and 85% increase in whole-plant dry mass and leaf area, respectively) when compared with the Upland genotype (no change in dry mass or leaf area). No intraspecific variation in physiological plasticity was detected under CE or TE , and the interactive effects of CE and TE on intraspecific variation in phenotypic plasticity were also largely absent. Overall, TE was a more effective climate factor than CE in exposing genotypic variation in our woody species. Our results contradict the paradigm that genotypes from more variable climates will exhibit greater phenotypic plasticity in future climate regimes. © 2015 John Wiley & Sons Ltd.
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A case of antenatal Bartter syndrome with sensorineural deafness.
Lee, Hyun Seung; Cheong, Hae Il; Ki, Chang-Seok
2010-10-01
Bartter syndrome type IV, also known as Bartter syndrome with sensorineural deafness (BSND), is caused by loss-of-function mutations in the BSND gene, which encodes barttin, an accessory subunit of chloride channels located in the kidney and inner ear. Patients with BS IV have a highly variable clinical phenotype. This report concerns a Korean male patient with antenatal Bartter syndrome due to a homozygous BSND p.G47R mutation, who presented with severe perinatal symptoms followed by a relatively benign course with preserved renal function after early infancy. In addition, the clinical features and the laboratory data of the patient were compared with those of previously reported patients with the same mutation.
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de Almeida, Alex-Alan Furtado; Branco, Márcia Christina da Silva; Costa, Marcio Gilberto Cardoso; Ahnert, Dario
2017-01-01
Selecting parents and evaluating progenies is a very important step in breeding programs and involves approaches such as understanding the initial stages of growth and characterizing the variability among genotypes for different parameters, such as physiological, growth, biomass partitioning and nutrient translocation to the aerial part. In these cases, facilitating tools can be used to understand the involved gene dynamics, such as diallel crosses and genetic and phenotypic correlations. Our main hypothesis is that the contrasting phenotypes of these parental genotypes of cocoa used are due to genetic factors, and progenies derived from crosses of these parental genotypes are useful for breeding programs related to plant architecture, physiological parameters and translocation of mineral nutrients. We aimed to evaluate the combining abilities in progenies of cacao (Theobroma cacao L) originating from contrasting parents for canopy vigor. Emphasis was given to the evaluation of morphological and physiological parameters and the phenotypic and genotypic correlations to understand the dynamics of the action of the genes involved, as well as in expression profile from genes of gibberellins biosynthesis pathway in the parents. Fifteen F1 progenies were obtained from crosses of six clones (IMC 67, P4B, PUCALA, SCA 6, SCA 24 and SJ 02) that were evaluated in a randomized complete block design with four replicates of 12 plants per progeny, in a balanced half table diallel scheme. It is possible to identify and select plants and progenies of low, medium and high height, as there is expressive genetic variability for the evaluated parameters, some of these on higher additive effects, others on larger nonadditive effects and others under a balance of these effects. Most physiological parameters evaluated show that for selection of plants with the desired performance, no complex breeding methods would be necessary due to the high and medium heritability observed. Strong genetic components were observed from many of the correlations, which indicate the possibility to formulate selection indices for multi-traits, such as dwarfism or semidwarfism, tolerance to increase of leaf sodium concentrations and maintenance of the photosynthetic apparatus integrity under these conditions. Additionally, plants with higher carbon fixation, better water use, higher carboxylation efficiency and greater magnesium accumulation in leaves can be selected. PMID:28628670
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Pereira, Allan Silva; de Almeida, Alex-Alan Furtado; Branco, Márcia Christina da Silva; Costa, Marcio Gilberto Cardoso; Ahnert, Dario
2017-01-01
Selecting parents and evaluating progenies is a very important step in breeding programs and involves approaches such as understanding the initial stages of growth and characterizing the variability among genotypes for different parameters, such as physiological, growth, biomass partitioning and nutrient translocation to the aerial part. In these cases, facilitating tools can be used to understand the involved gene dynamics, such as diallel crosses and genetic and phenotypic correlations. Our main hypothesis is that the contrasting phenotypes of these parental genotypes of cocoa used are due to genetic factors, and progenies derived from crosses of these parental genotypes are useful for breeding programs related to plant architecture, physiological parameters and translocation of mineral nutrients. We aimed to evaluate the combining abilities in progenies of cacao (Theobroma cacao L) originating from contrasting parents for canopy vigor. Emphasis was given to the evaluation of morphological and physiological parameters and the phenotypic and genotypic correlations to understand the dynamics of the action of the genes involved, as well as in expression profile from genes of gibberellins biosynthesis pathway in the parents. Fifteen F1 progenies were obtained from crosses of six clones (IMC 67, P4B, PUCALA, SCA 6, SCA 24 and SJ 02) that were evaluated in a randomized complete block design with four replicates of 12 plants per progeny, in a balanced half table diallel scheme. It is possible to identify and select plants and progenies of low, medium and high height, as there is expressive genetic variability for the evaluated parameters, some of these on higher additive effects, others on larger nonadditive effects and others under a balance of these effects. Most physiological parameters evaluated show that for selection of plants with the desired performance, no complex breeding methods would be necessary due to the high and medium heritability observed. Strong genetic components were observed from many of the correlations, which indicate the possibility to formulate selection indices for multi-traits, such as dwarfism or semidwarfism, tolerance to increase of leaf sodium concentrations and maintenance of the photosynthetic apparatus integrity under these conditions. Additionally, plants with higher carbon fixation, better water use, higher carboxylation efficiency and greater magnesium accumulation in leaves can be selected.
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Madkhali, Aymen M.; Alkurbi, Mohammed O.; Szestak, Tadge; Bengtsson, Anja; Patil, Pradeep R.; Wu, Yang; Alharthi, Saeed; Jensen, Anja T. R.; Pleass, Richard; Craig, Alister G.
2014-01-01
The basis of severe malaria pathogenesis in part includes sequestration of Plasmodium falciparum-infected erythrocytes (IE) from the peripheral circulation. This phenomenon is mediated by the interaction between several endothelial receptors and one of the main parasite-derived variant antigens (PfEMP1) expressed on the surface of the infected erythrocyte membrane. One of the commonly used host receptors is ICAM-1, and it has been suggested that ICAM-1 has a role in cerebral malaria pathology, although the evidence to support this is not conclusive. The current study examined the cytoadherence patterns of lab-adapted patient isolates after selecting on ICAM-1. We investigated the binding phenotypes using variant ICAM-1 proteins including ICAM-1Ref, ICAM-1Kilifi, ICAM-1S22/A, ICAM-1L42/A and ICAM-1L44/A using static assays. The study also examined ICAM-1 blocking by four anti-ICAM-1 monoclonal antibodies (mAb) under static conditions. We also characterised the binding phenotypes using Human Dermal Microvascular Endothelial Cells (HDMEC) under flow conditions. The results show that different isolates have variant-specific binding phenotypes under both static and flow conditions, extending our previous observations that this variation might be due to variable contact residues on ICAM-1 being used by different parasite PfEMP1 variants. PMID:25360558
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Moussy, Alice; Cosette, Jérémie; Parmentier, Romuald; da Silva, Cindy; Corre, Guillaume; Richard, Angélique; Gandrillon, Olivier; Stockholm, Daniel
2017-01-01
Individual cells take lineage commitment decisions in a way that is not necessarily uniform. We address this issue by characterising transcriptional changes in cord blood-derived CD34+ cells at the single-cell level and integrating data with cell division history and morphological changes determined by time-lapse microscopy. We show that major transcriptional changes leading to a multilineage-primed gene expression state occur very rapidly during the first cell cycle. One of the 2 stable lineage-primed patterns emerges gradually in each cell with variable timing. Some cells reach a stable morphology and molecular phenotype by the end of the first cell cycle and transmit it clonally. Others fluctuate between the 2 phenotypes over several cell cycles. Our analysis highlights the dynamic nature and variable timing of cell fate commitment in hematopoietic cells, links the gene expression pattern to cell morphology, and identifies a new category of cells with fluctuating phenotypic characteristics, demonstrating the complexity of the fate decision process (which is different from a simple binary switch between 2 options, as it is usually envisioned). PMID:28749943
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Phenotypic Variations in the Foliar Chemical Profile of Persea americana Mill. cv. Hass.
García-Rodríguez, Yolanda Magdalena; Torres-Gurrola, Guadalupe; Meléndez-González, Claudio; Espinosa-García, Francisco J
2016-12-01
The Hass avocado tree Persea americana cv. Hass was derived from a single hybrid tree of P. americana var. drymifolia and P. americana var. guatemalensis, and it is propagated clonally by grafting. This cultivar is the most widely planted in the world but its profile of secondary metabolites has been studied rarely despite of its importance in plant protection. We illustrate the variability of the volatilome of mature leaves by describing the average chemical composition and the phenotypic variability found in 70 trees. Contrary to the uniformity expected in the Hass cultivar, high variability coefficients were found for most of the 36 detected foliar volatile compounds; furthermore we found six chemotypes grouping the foliar phenotypes of the sampled trees using hierarchical cluster analysis. About 48% of trees were grouped in one chemotype; five chemotypes grouped the remaining trees. The compounds that determined these chemotypes were: estragole, α-farnesene, β-caryophyllene, germacrene D, α-cubebene and eugenol. This striking variation in a cultivar propagated clonally is discussed in terms of somatic mutation. © 2016 Wiley-VHCA AG, Zurich, Switzerland.
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Karalunas, Sarah L.; Geurts, Hilde M.; Konrad, Kerstin; Bender, Stephan; Nigg, Joel T.
2014-01-01
Background Intraindividual variability in reaction time (RT) has received extensive discussion as an indicator of cognitive performance, a putative intermediate phenotype of many clinical disorders, and a possible trans-diagnostic phenotype that may elucidate shared risk factors for mechanisms of psychiatric illnesses. Scope and Methodology Using the examples of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), we discuss RT variability. We first present a new meta-analysis of RT variability in ASD with and without comorbid ADHD. We then discuss potential mechanisms that may account for RT variability and statistical models that disentangle the cognitive processes affecting RTs. We then report a second meta-analysis comparing ADHD and non-ADHD children on diffusion model parameters. We consider how findings inform the search for neural correlates of RT variability. Findings Results suggest that RT variability is increased in ASD only when children with comorbid ADHD are included in the sample. Furthermore, RT variability in ADHD is explained by moderate to large increases (d = 0.63–0.99) in the ex-Gaussian parameter τ and the diffusion parameter drift rate, as well as by smaller differences (d = 0.32) in the diffusion parameter of nondecision time. The former may suggest problems in state regulation or arousal and difficulty detecting signal from noise, whereas the latter may reflect contributions from deficits in motor organization or output. The neuroimaging literature converges with this multicomponent interpretation and also highlights the role of top-down control circuits. Conclusion We underscore the importance of considering the interactions between top-down control, state regulation (e.g. arousal), and motor preparation when interpreting RT variability and conclude that decomposition of the RT signal provides superior interpretive power and suggests mechanisms convergent with those implicated using other cognitive paradigms. We conclude with specific recommendations for the field for next steps in the study of RT variability in neurodevelopmental disorders. PMID:24628425
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Advergence in Müllerian mimicry: the case of the poison dart frogs of Northern Peru revisited
Chouteau, Mathieu; Summers, Kyle; Morales, Victor; Angers, Bernard
2011-01-01
Whether the evolution of similar aposematic signals in different unpalatable species (i.e. Müllerian mimicry) is because of phenotypic convergence or advergence continues to puzzle scientists. The poison dart frog Ranitomeya imitator provides a rare example in support of the hypothesis of advergence: this species was believed to mimic numerous distinct model species because of high phenotypic variability and low genetic divergence among populations. In this study, we test the evidence in support of advergence using a population genetic framework in two localities where R. imitator is sympatric with different model species, Ranitomeya ventrimaculata and Ranitomeya variabilis. Genetic analyses revealed incomplete sorting of mitochondrial haplotypes between the two model species. These two species are also less genetically differentiated than R. imitator populations on the basis of both mitochondrial and nuclear DNA comparisons. The genetic similarity between the model species suggests that they have either diverged more recently than R. imitator populations or that they are still connected by gene flow and were misidentified as different species. An analysis of phenotypic variability indicates that the model species are as variable as R. imitator. These results do not support the hypothesis of advergence by R. imitator. Although we cannot rule out phenotypic advergence in the evolution of Müllerian mimicry, this study reopens the discussion regarding the direction of the evolution of mimicry in the R. imitator system. PMID:21411452
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Lesch-Nyhan variant syndrome: variable presentation in 3 affected family members.
Sarafoglou, Kyriakie; Grosse-Redlinger, Krista; Boys, Christopher J; Charnas, Laurence; Otten, Noelle; Broock, Robyn; Nyhan, William L
2010-06-01
Lesch-Nyhan disease is an inborn error of purine metabolism that results from deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The heterogeneity of clinical phenotypes seen in HPRT deficiency corresponds to an inverse relationship between HPRT enzyme activity and clinical severity. With rare exception, each mutation produces a stereotypical pattern of clinical disease; onset of neurologic symptoms occurs during infancy and is thought to be nonprogressive. To document a family in which a single HPRT gene mutation has led to 3 different clinical and enzymatic phenotypes. Case report. Settings A university-based outpatient metabolic clinic and a biochemical genetics laboratory. Patients Three males (2 infants and their grandfather) from the same family with Lesch-Nyhan variant, including one of the oldest patients with Lesch-Nyhan variant at diagnosis (65 years). Clinical and biochemical observations. Sequencing of 5 family members revealed a novel mutation c.550G>T in exon 7 of the HPRT gene. The considerably variable clinical phenotype corresponded with the variable enzymatic activity in the 3 males, with the grandfather being the most severely affected. The different phenotypes encountered in the enzymatic analysis of cultured fibroblasts from a single mutation in the same family is unprecedented. The significant decrease in the grandfather's HPRT enzymatic activity compared with that of his grandchildren could be a function of the Hayflick Limit Theory of cell senescence.
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Burgermaster, Marissa; Contento, Isobel; Koch, Pamela; Mamykina, Lena
2018-01-17
Variability in individuals' responses to interventions may contribute to small average treatment effects of childhood obesity prevention interventions. But, neither the causes of this individual variability nor the mechanism by which it influences behavior are clear. We used qualitative methods to characterize variability in students' responses to participating in a childhood obesity prevention intervention and psychosocial characteristics related to the behavior change process. We interviewed 18 students participating in a school-based curriculum and policy behavior change intervention. Descriptive coding, summary, and case-ordered descriptive meta-matrices were used to group participants by their psychosocial responses to the intervention and associated behavior changes. Four psychosocial phenotypes of responses emerged: (a) Activated-successful behavior-changers with strong internal supports; (b) Inspired-motivated, but not fully successful behavior-changers with some internal supports, whose taste preferences and food environment overwhelmed their motivation; (c) Reinforced-already practiced target behaviors, were motivated, and had strong family support; and (d) Indifferent-uninterested in behavior change and only did target behaviors if family insisted. Our findings contribute to the field of behavioral medicine by suggesting the presence of specific subgroups of participants who respond differently to behavior change interventions and salient psychosocial characteristics that differentiate among these phenotypes. Future research should examine the utility of prospectively identifying psychosocial phenotypes for improving the tailoring of nutrition behavior change interventions. © Society of Behavioral Medicine 2018.
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Analysis of Genome-Wide Association Studies with Multiple Outcomes Using Penalization
Liu, Jin; Huang, Jian; Ma, Shuangge
2012-01-01
Genome-wide association studies have been extensively conducted, searching for markers for biologically meaningful outcomes and phenotypes. Penalization methods have been adopted in the analysis of the joint effects of a large number of SNPs (single nucleotide polymorphisms) and marker identification. This study is partly motivated by the analysis of heterogeneous stock mice dataset, in which multiple correlated phenotypes and a large number of SNPs are available. Existing penalization methods designed to analyze a single response variable cannot accommodate the correlation among multiple response variables. With multiple response variables sharing the same set of markers, joint modeling is first employed to accommodate the correlation. The group Lasso approach is adopted to select markers associated with all the outcome variables. An efficient computational algorithm is developed. Simulation study and analysis of the heterogeneous stock mice dataset show that the proposed method can outperform existing penalization methods. PMID:23272092
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The Evolution of Phenotypic Switching in Subdivided Populations
Carja, Oana; Liberman, Uri; Feldman, Marcus W.
2014-01-01
Stochastic switching is an example of phenotypic bet hedging, where offspring can express a phenotype different from that of their parents. Phenotypic switching is well documented in viruses, yeast, and bacteria and has been extensively studied when the selection pressures vary through time. However, there has been little work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here we use a population genetic model to explore the interaction of temporal and spatial variation in determining the evolutionary dynamics of phenotypic switching. We find that the stable switching rate is mainly determined by the rate of environmental change and the migration rate. This stable rate is also a decreasing function of the recombination rate, although this is a weaker effect than those of either the period of environmental change or the migration rate. This study highlights the interplay of spatial and temporal environmental variability, offering new insights into how migration can influence the evolution of phenotypic switching rates, mutation rates, or other sources of phenotypic variation. PMID:24496012
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Baranasic, Damir; Oppermann, Timo; Cheaib, Miriam; Cullum, John; Schmidt, Helmut
2014-01-01
ABSTRACT Antigenic or phenotypic variation is a widespread phenomenon of expression of variable surface protein coats on eukaryotic microbes. To clarify the mechanism behind mutually exclusive gene expression, we characterized the genetic properties of the surface antigen multigene family in the ciliate Paramecium tetraurelia and the epigenetic factors controlling expression and silencing. Genome analysis indicated that the multigene family consists of intrachromosomal and subtelomeric genes; both classes apparently derive from different gene duplication events: whole-genome and intrachromosomal duplication. Expression analysis provides evidence for telomere position effects, because only subtelomeric genes follow mutually exclusive transcription. Microarray analysis of cultures deficient in Rdr3, an RNA-dependent RNA polymerase, in comparison to serotype-pure wild-type cultures, shows cotranscription of a subset of subtelomeric genes, indicating that the telomere position effect is due to a selective occurrence of Rdr3-mediated silencing in subtelomeric regions. We present a model of surface antigen evolution by intrachromosomal gene duplication involving the maintenance of positive selection of structurally relevant regions. Further analysis of chromosome heterogeneity shows that alternative telomere addition regions clearly affect transcription of closely related genes. Consequently, chromosome fragmentation appears to be of crucial importance for surface antigen expression and evolution. Our data suggest that RNAi-mediated control of this genetic network by trans-acting RNAs allows rapid epigenetic adaptation by phenotypic variation in combination with long-term genetic adaptation by Darwinian evolution of antigen genes. PMID:25389173
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Santos, Daniel M V; Katzmarzyk, Peter T; Diego, Vincent P; Souza, Michele C; Chaves, Raquel N; Blangero, John; Maia, José A R
2013-01-01
Moderate-to-high levels of physical activity are established as preventive factors in metabolic syndrome development. However, there is variability in the phenotypic expression of metabolic syndrome under distinct physical activity conditions. In the present study we applied a Genotype X Environment interaction method to examine the presence of GxEE interaction in the phenotypic expression of metabolic syndrome. A total of 958 subjects, from 294 families of The Portuguese Healthy Family study, were included in the analysis. Total daily energy expenditure was assessed using a 3 day physical activity diary. Six metabolic syndrome related traits, including waist circumference, systolic blood pressure, glucose, HDL cholesterol, total cholesterol and triglycerides, were measured and adjusted for age and sex. GxEE examination was performed on SOLAR 4.3.1. All metabolic syndrome indicators were significantly heritable. The GxEE interaction model fitted the data better than the polygenic model (p<0.001) for waist circumference, systolic blood pressure, glucose, total cholesterol and triglycerides. For waist circumference, glucose, total cholesterol and triglycerides, the significant GxEE interaction was due to rejection of the variance homogeneity hypothesis. For waist circumference and glucose, GxEE was also significant by the rejection of the genetic correlation hypothesis. The results showed that metabolic syndrome traits expression is significantly influenced by the interaction established between total daily energy expenditure and genotypes. Physical activity may be considered an environmental variable that promotes metabolic differences between individuals that are distinctively active.
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Phenotypic plasticity facilitates resistance to climate change in a highly variable environment.
Richter, Sarah; Kipfer, Tabea; Wohlgemuth, Thomas; Calderón Guerrero, Carlos; Ghazoul, Jaboury; Moser, Barbara
2012-05-01
Increased summer drought will exacerbate the regeneration of many tree species at their lower latitudinal and altitudinal distribution limits. In vulnerable habitats, introduction of more drought-tolerant provenances or species is currently considered to accelerate tree species migration and facilitate forest persistence. Trade-offs between drought adaptation and growth plasticity might, however, limit the effectiveness of assisted migration, especially if introductions focus on provenances or species from different climatic regions. We tested in a common garden experiment the performance of Pinus sylvestris seedlings from the continental Central Alps under increased temperatures and extended spring and/or summer drought, and compared seedling emergence, survival and biomass allocation to that of P. sylvestris and closely related Pinus nigra from a Mediterranean seed source. Soil heating had only minor effects on seedling performance but high spring precipitation doubled the number of continental P. sylvestris seedlings present after the summer drought. At the same time, twice as many seedlings of the Mediterranean than the continental P. sylvestris provenance were present, which was due to both higher emergence and lower mortality under dry conditions. Both P. sylvestris provenances allocated similar amounts of biomass to roots when grown under low summer precipitation. Mediterranean seedlings, however, revealed lower phenotypic plasticity than continental seedlings under high precipitation, which might limit their competitive ability in continental Alpine forests in non-drought years. By contrast, high variability in the response of individual seedlings to summer drought indicates the potential of continental P. sylvestris provenances to adapt to changing environmental conditions.
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Phenotypic plasticity in a population of odonates.
Bowman, Randi M; Schmidt, Sharol; Weeks, Chelsea; Clark, Hunter; Brown, Christopher; Latta, Leigh C; Edgehouse, Michael
2018-05-31
The maintenance of phenotypic plasticity within a species ensures survival through environmental flux. Plastic strategies are increasingly important given the number and magnitude of modern anthropogenic threats to the environment. We tested for phenotypic plasticity in the odonate Argia vivida in response to resource limitation. By limiting food availability, effectively inducing hunger, we were able to quantify shifts in agonistic behavior during intraspecific interactions. Scoring behavior in one-on-one combat trials after 1 and 4 days without food revealed phenotypic plasticity. Three classes of genotypes were identified, genotypes exhibiting either increased aggression, decreased aggression, or no phenotypic plasticity, in response to resource limitation. The variable plastic strategies in this population of odonates likely aids in maintaining fitness in fluctuating environments.
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The Neuroanatomy of the Autistic Phenotype
ERIC Educational Resources Information Center
Fahim, Cherine; Meguid, Nagwa A.; Nashaat, Neveen H.; Yoon, Uicheul; Mancini-Marie, Adham; Evans, Alan C.
2012-01-01
The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X…
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Daddy issues: paternal effects on phenotype
Rando, Oliver J.
2012-01-01
The once-popular, then heretical, idea that ancestral environment can affect the phenotype of future generations is coming back into vogue, due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. PMID:23141533
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Phenotypic variability in a panel of strawberry cultivars from North America and the European Union
USDA-ARS?s Scientific Manuscript database
The phenotypic diversity in 96 antique and modern cultivars from the European Union and North America was evaluated in Michigan and Oregon, in 2011 and 2012. A total of thirty-five fruit and developmental characteristics were measured. Significant differences (p < 0.05) were observed among cultivars...
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Spectrum of phenotypic anomalies in four families with deletion of the SHOX enhancer region.
Gatta, Valentina; Palka, Chiara; Chiavaroli, Valentina; Franchi, Sara; Cannataro, Giovanni; Savastano, Massimo; Cotroneo, Antonio Raffaele; Chiarelli, Francesco; Mohn, Angelika; Stuppia, Liborio
2014-07-23
SHOX alterations have been reported in 67% of patients affected by Léri-Weill dyschondrosteosis (LWD), with a larger prevalence of gene deletions than point mutations. It has been recently demonstrated that these deletions can involve the SHOX enhancer region, rather that the coding region, with variable phenotype of the affected patients.Here, we report a SHOX gene analysis carried out by MLPA in 14 LWD patients from 4 families with variable phenotype. All patients presented a SHOX enhancer deletion. In particular, a patient with a severe bilateral Madelung deformity without short stature showed a homozygous alteration identical to the recently described 47.5 kb PAR1 deletion. Moreover, we identified, for the first time, in three related patients with a severe bilateral Madelung deformity, a smaller deletion than the 47.5 kb PAR1 deletion encompassing the same enhancer region (ECR1/CNE7). Data reported in this study provide new information about the spectrum of phenotypic alterations showed by LWD patients with different deletions of the SHOX enhancer region.
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Spectrum of phenotypic anomalies in four families with deletion of the SHOX enhancer region
2014-01-01
Background SHOX alterations have been reported in 67% of patients affected by Léri-Weill dyschondrosteosis (LWD), with a larger prevalence of gene deletions than point mutations. It has been recently demonstrated that these deletions can involve the SHOX enhancer region, rather that the coding region, with variable phenotype of the affected patients. Here, we report a SHOX gene analysis carried out by MLPA in 14 LWD patients from 4 families with variable phenotype. Case presentation All patients presented a SHOX enhancer deletion. In particular, a patient with a severe bilateral Madelung deformity without short stature showed a homozygous alteration identical to the recently described 47.5 kb PAR1 deletion. Moreover, we identified, for the first time, in three related patients with a severe bilateral Madelung deformity, a smaller deletion than the 47.5 kb PAR1 deletion encompassing the same enhancer region (ECR1/CNE7). Conclusions Data reported in this study provide new information about the spectrum of phenotypic alterations showed by LWD patients with different deletions of the SHOX enhancer region. PMID:25056248
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Cohen, Mark; Appleby, Brian; Safar, Jiri G
2016-01-01
Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.
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Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice
Wilson, Robert; Geyer, Stefan H.; Reissig, Lukas; Rose, Julia; Szumska, Dorota; Hardman, Emily; Prin, Fabrice; McGuire, Christina; Ramirez-Solis, Ramiro; White, Jacqui; Galli, Antonella; Tudor, Catherine; Tuck, Elizabeth; Mazzeo, Cecilia Icoresi; Smith, James C.; Robertson, Elizabeth; Adams, David J.; Mohun, Timothy; Weninger, Wolfgang J.
2017-01-01
Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all mutant embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve. Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates. PMID:27996060
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Front acceleration by dynamic selection in Fisher population waves
NASA Astrophysics Data System (ADS)
Bénichou, O.; Calvez, V.; Meunier, N.; Voituriez, R.
2012-10-01
We introduce a minimal model of population range expansion in which the phenotypes of individuals present no selective advantage and differ only in their diffusion rate. We show that such neutral phenotypic variability (i.e., that does not modify the growth rate) alone can yield phenotype segregation at the front edge, even in absence of genetic noise, and significantly impact the dynamical properties of the expansion wave. We present an exact asymptotic traveling wave solution and show analytically that phenotype segregation accelerates the front propagation. The results are compatible with field observations such as invasions of cane toads in Australia or bush crickets in Britain.
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Forabosco, F; Bozzi, R; Boettcher, P; Filippini, F; Bijma, P; Van Arendonk, J A M
2005-09-01
The objectives of this study were 1) to propose a profit function for Italian Chianina beef cattle; 2) to derive economic values for some biological variables in beef cows, specifically, production expressed as the number of calves born alive per year (NACY), age at the insemination that resulted in the birth of the first calf (FI), and length of productive life (LPL); and 3) to investigate the relationship between the phenotypic profit function and type traits as early predictors of profitability in the Chianina beef cattle population. The average profit was 196 Euros/(cow.yr) for the length of productive life (LPL) and was obtained as the difference between the average income of 1,375 Euros/(cow.yr) for LPL and costs of 1,178 Euros/(cow.yr) of LPL. The mean LPL was equal to 5.97 yr, so the average total phenotypic profit per cow on a lifetime basis was 1,175 Euros. A normative approach was used to derive the economic weights for the biological variables. The most important trait was the number of calves born alive (+4.03.cow(-1).yr(-1) and +24.06 Euros/cow). An increase of 1 d in LPL was associated with an increase of +0.19 Euros/(cow.yr) and +1.65 Euros/cow on a lifetime basis. Increasing FI by 1 d decreased profit by 0.42 Euros/(cow.yr) and 2.51 Euros/cow. Phenotypic profit per cow had a heritability of 0.29. Heritabilities for eight muscularity traits ranged from 0.16 to 0.23, and for the seven body size traits between 0.21 and 0.30. The conformation trait final score can be used as an early predictor of profitability. The sale price of the animal and differences in the revenue and costs of offspring due to muscularity should be included in a future profit function.
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2017-01-01
Induced mutagenesis was employed to create genetic variation in the lentil cultivars for yield improvement. The assessments were made on genetic variability, character association, and genetic divergence among the twelve mutagenized populations and one parent population of each of the two lentil cultivars, developed by single and combination treatments with gamma rays and hydrazine hydrates. Analysis of variance revealed significant inter-population differences for the observed quantitative phenotypic traits. The sample mean of six treatment populations in each of the cultivar exhibited highly superior quantitative phenotypic traits compared to their parent cultivars. The higher values of heritability and genetic advance with a high genotypic coefficient of variation for most of the yield attributing traits confirmed the possibilities of lentil yield improvement through phenotypic selection. The number of pods and seeds per plant appeared to be priority traits in selection for higher yield due to their strong direct association with yield. The cluster analysis divided the total populations into three divergent groups in each lentil cultivar with parent genotypes in an independent group showing the high efficacy of the mutagens. Considering the highest contribution of yield trait to the genetic divergence among the clustered population, it was confirmed that the mutagenic treatments created a wide heritable variation for the trait in the mutant populations. The selection of high yielding mutants from the mutant populations of DPL 62 (100 Gy) and Pant L 406 (100Gy + 0.1% HZ) in the subsequent generation is expected to give elite lentil cultivars. Also, hybridization between members of the divergent group would produce diverse segregants for crop improvement. Apart from this, the induced mutations at loci controlling economically important traits in the selected high yielding mutants have successfully contributed in diversifying the accessible lentil genetic base and will definitely be of immense value to the future lentil breeding programmes in India. PMID:28922405
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Aleixandre, Pau; Hernández Montoya, Julio; Milá, Borja
2013-01-01
The evolutionary divergence of island populations, and in particular the tempo and relative importance of neutral and selective factors, is of central interest to the study of speciation. The rate of phenotypic evolution upon island colonization can vary greatly among taxa, and cases of convergent evolution can further confound the inference of correct evolutionary histories. Given the potential lability of phenotypic characters, molecular dating of insular lineages analyzed in a phylogenetic framework provides a critical tool to test hypotheses of phenotypic divergence since colonization. The Guadalupe junco is the only insular form of the polymorphic dark-eyed junco (Junco hyemalis), and shares eye and plumage color with continental morphs, yet presents an enlarged bill and reduced body size. Here we use variation in mtDNA sequence, morphological traits and song variables to test whether the Guadalupe junco evolved rapidly following a recent colonization by a mainland form of the dark-eyed junco, or instead represents a well-differentiated "cryptic" lineage adapted to the insular environment through long-term isolation, with plumage coloration a result of evolutionary convergence. We found high mtDNA divergence of the island lineage with respect to both continental J. hyemalis and J. phaeonotus, representing a history of isolation of about 600,000 years. The island lineage was also significantly differentiated in morphological and male song variables. Moreover, and contrary to predictions regarding diversity loss on small oceanic islands, we document relatively high levels of both haplotypic and song-unit diversity on Guadalupe Island despite long-term isolation in a very small geographic area. In contrast to prevailing taxonomy, the Guadalupe junco is an old, well-differentiated evolutionary lineage, whose similarity to mainland juncos in plumage and eye color is due to evolutionary convergence. Our findings confirm the role of remote islands in driving divergence and speciation, but also their potential role as repositories of ancestral diversity.
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Sy, Sherwin K B; Heuberger, Jules; Shilbayeh, Sireen; Conrado, Daniela J; Derendorf, Hartmut
2013-10-01
The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose- and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The time-dependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.
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The differential view of genotype–phenotype relationships
Orgogozo, Virginie; Morizot, Baptiste; Martin, Arnaud
2015-01-01
An integrative view of diversity and singularity in the living world requires a better understanding of the intricate link between genotypes and phenotypes. Here we re-emphasize the old standpoint that the genotype–phenotype (GP) relationship is best viewed as a connection between two differences, one at the genetic level and one at the phenotypic level. As of today, predominant thinking in biology research is that multiple genes interact with multiple environmental variables (such as abiotic factors, culture, or symbionts) to produce the phenotype. Often, the problem of linking genotypes and phenotypes is framed in terms of genotype and phenotype maps, and such graphical representations implicitly bring us away from the differential view of GP relationships. Here we show that the differential view of GP relationships is a useful explanatory framework in the context of pervasive pleiotropy, epistasis, and environmental effects. In such cases, it is relevant to view GP relationships as differences embedded into differences. Thinking in terms of differences clarifies the comparison between environmental and genetic effects on phenotypes and helps to further understand the connection between genotypes and phenotypes. PMID:26042146
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5p13 microduplication syndrome: a new case and better clinical definition of the syndrome.
Novara, Francesca; Alfei, Enrico; D'Arrigo, Stefano; Pantaleoni, Chiara; Beri, Silvana; Achille, Valentina; Sciacca, Francesca L; Giorda, Roberto; Zuffardi, Orsetta; Ciccone, Roberto
2013-01-01
Chromosome 5p13 duplication syndrome (OMIM #613174), a contiguous gene syndrome involving duplication of several genes on chromosome 5p13 including NIPBL (OMIM 608667), has been described in rare patients with developmental delay and learning disability, behavioral problems and peculiar facial dysmorphisms. 5p13 duplications described so far present with variable sizes, from 0.25 to 13.6 Mb, and contain a variable number of genes. Here we report another patient with 5p13 duplication syndrome including NIPBL gene only. Proband's phenotype overlapped that reported in patients with 5p13 microduplication syndrome and especially that of subjects with smaller duplications. Moreover, we better define genotype-phenotype relationship associated with this duplication and confirmed that NIPBL was likely the major dosage sensitive gene for the 5p13 microduplication phenotype. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
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Phenotypic variability of the cat eye syndrome. Case report and review of the literature.
Rosias, P R; Sijstermans, J M; Theunissen, P M; Pulles-Heintzberger, C F; De Die-Smulders, C E; Engelen, J J; Van Der Meer, S B
2001-01-01
We present a male infant with preauricular skin tags and pits, downslanting palpebral fissures, hypertelorism, ectopic anus, hypospadias, and hypoplastic left heart syndrome. The clinical features in our patient show phenotypic overlap with the cat eye syndrome, as illustrated by the review of 105 reported cases. Cytogenetic analysis revealed a supernumerary marker chromosome, which was identified by microdissection and fluorescence in situ hybridization as an isodicentric chromosome 22(pter --> q11.2::q11.2 --> pter). It was proved with probes specific for the cat eye syndrome critical region that this region was present in quadruplicate in the propositus. We conclude that CES is characterized by large phenotypic variability, ranging from near normal to severe malformations, as reflected in the neurodevelopmental outcome. Preauricular skin tags and/or pits are the most consistent features, and suggest the presence of a supernumerary bisatellited marker chromosome 22 derived from duplication of the CES critical region.
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ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R
2014-01-01
Aims Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. Methods We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Results Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). Conclusions We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice. PMID:24697814
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Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma.
Schatz, Michael; Hsu, Jin-Wen Y; Zeiger, Robert S; Chen, Wansu; Dorenbaum, Alejandro; Chipps, Bradley E; Haselkorn, Tmirah
2014-06-01
Asthma phenotyping can facilitate understanding of disease pathogenesis and potential targeted therapies. To further characterize the distinguishing features of phenotypic groups in difficult-to-treat asthma. Children ages 6-11 years (n = 518) and adolescents and adults ages ≥12 years (n = 3612) with severe or difficult-to-treat asthma from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study were evaluated in this post hoc cluster analysis. Analyzed variables included sex, race, atopy, age of asthma onset, smoking (adolescents and adults), passive smoke exposure (children), obesity, and aspirin sensitivity. Cluster analysis used the hierarchical clustering algorithm with the Ward minimum variance method. The results were compared among clusters by χ(2) analysis; variables with significant (P < .05) differences among clusters were considered as distinguishing feature candidates. Associations among clusters and asthma-related health outcomes were assessed in multivariable analyses by adjusting for socioeconomic status, environmental exposures, and intensity of therapy. Five clusters were identified in each age stratum. Sex, atopic status, and nonwhite race were distinguishing variables in both strata; passive smoke exposure was distinguishing in children and aspirin sensitivity in adolescents and adults. Clusters were not related to outcomes in children, but 2 adult and adolescent clusters distinguished by nonwhite race and aspirin sensitivity manifested poorer quality of life (P < .0001), and the aspirin-sensitive cluster experienced more frequent asthma exacerbations (P < .0001). Distinct phenotypes appear to exist in patients with severe or difficult-to-treat asthma, which is related to outcomes in adolescents and adults but not in children. The study of the therapeutic implications of these phenotypes is warranted. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella
2015-01-01
Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579
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Ecosensitivity and genetic polymorphism of somatic traits in the perinatal development of twins.
Waszak, Małgorzata; Cieślik, Krystyna; Skrzypczak-Zielińska, Marzena; Szalata, Marlena; Wielgus, Karolina; Kempiak, Joanna; Bręborowicz, Grzegorz; Słomski, Ryszard
2016-04-01
In view of criticism regarding the usefulness of heritability coefficients, the aim of this study was to analyze separately the information on genetic and environmental variability. Such an approach, based on the normalization of trait's variability for its value, is determined by the coefficients of genetic polymorphism (Pg) and ecosensitivity (De). The studied material included 1263 twin pairs of both sexes (among them 424 pairs of monozygotic twins and 839 pairs of dizygotic twins) born between the 22nd and 41st week of gestation. Variability of six somatic traits was analyzed. The zygosity of same-sex twins was determined based on the polymorphism of DNA from lymphocytes of the umbilical cord blood, obtained at birth. The coefficients of genetic polymorphism and ecosensitivity for analyzed traits of male and female twins born at various months of gestation were calculated. Our study revealed that a contribution of the genetic component predominated over that of the environmental component in determining the phenotypic variability of somatic traits of newborns from twin pregnancies. The genetically determined phenotypic variability in male twins was greater than in the females. The genetic polymorphism and ecosensitivity of somatic traits were relatively stable during the period of fetal ontogeny analyzed in this study. Only in the case of body weight, a slight increase in the genetic contribution of polygenes to the phenotypic variance could be observed with gestational age, along with a slight decrease in the influence of environmental factors. Copyright © 2015 Elsevier GmbH. All rights reserved.
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Genetic characterization of fig tree mutants with molecular markers.
Rodrigues, M G F; Martins, A B G; Desidério, J A; Bertoni, B W; Alves, M C
2012-08-06
The fig (Ficus carica L.) is a fruit tree of great world importance and, therefore, the genetic improvement becomes an important field of research for better crops, being necessary to gather information on this species, mainly regarding its genetic variability so that appropriate propagation projects and management are made. The improvement programs of fig trees using conventional procedures in order to obtain new cultivars are rare in many countries, such as Brazil, especially due to the little genetic variability and to the difficulties in obtaining plants from gamete fusion once the wasp Blastophaga psenes, responsible for the natural pollinating, is not found in Brazil. In this way, the mutagenic genetic improvement becomes a solution of it. For this reason, in an experiment conducted earlier, fig plants formed by cuttings treated with gamma ray were selected based on their agronomic characteristics of interest. We determined the genetic variability in these fig tree selections, using RAPD and AFLP molecular markers, comparing them to each other and to the Roxo-de-Valinhos, used as the standard. For the reactions of DNA amplification, 140 RAPD primers and 12 primer combinations for AFLP analysis were used. The selections did not differ genetically between themselves and between them and the Roxo-de-Valinhos cultivar. Techniques that can detect polymorphism between treatments, such as DNA sequencing, must be tested. The phenotypic variation of plants may be due to epigenetic variation, necessitating the use of techniques with methylation-sensitive restriction enzymes.
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Mandible shape in hybrid mice.
Renaud, Sabrina; Alibert, Paul; Auffray, Jean-Christophe
2009-09-01
Hybridisation between closely related species is frequently seen as retarding evolutionary divergence and can also promote it by creating novel phenotypes due to new genetic combinations and developmental interactions. We therefore investigated how hybridisation affects the shape of the mouse mandible, a well-known feature in evo-devo studies. Parental groups corresponded to two strains of the European mouse sub-species Mus musculus domesticus and Mus musculus musculus. Parents and hybrids were bred in controlled conditions. The mandibles of F(1) hybrids are mostly intermediate between parental phenotypes as expected for a complex multigenic character. Nevertheless, a transgressive effect as well as an increased phenotypic variance characterise the hybrids. This suggests that hybridisation between the two subspecies could lead to a higher phenotypic variance due to complex interactions among the parental genomes including non-additive genetic effects. The major direction of variance is conserved, however, among hybrids and parent groups. Hybridisation may thus play a role in the production of original transgressive phenotypes occurring following pre-existing patterns of variance.
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Extreme intrafamilial variability of Saudi brothers with primary hyperoxaluria type 1.
Alfadhel, Majid; Alhasan, Khalid A; Alotaibi, Mohammed; Al Fakeeh, Khalid
2012-01-01
Primary hyperoxaluria type 1 (PH1) is characterized by progressive renal insufficiency culminating in end-stage renal disease, and a wide range of clinical features related to systemic oxalosis in different organs. It is caused by autosomal recessive deficiency of alanine:glyoxylate aminotransferase due to a defect in AGXT gene. Two brothers (one 6 months old; the other 2 years old) presented with acute renal failure and urinary tract infection respectively. PH1 was confirmed by high urinary oxalate level, demonstration of oxalate crystals in bone biopsy, and pathogenic homozygous known AGXT gene mutation. Despite the same genetic background, same sex, and shared environment, the outcome of the two siblings differs widely. While one of them died earlier with end-stage renal disease and multiorgan failure caused by systemic oxalosis, the older brother is pyridoxine responsive with normal development and renal function. Clinicians should be aware of extreme intrafamilial variability of PH1 and international registries are needed to characterize the genotype-phenotype correlation in such disorder.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.
Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography.Our derivation, which is based on the rate-summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills mature pine trees.more » This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less
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Bourla, A; Ferreri, F; Ogorzelec, L; Guinchard, C; Mouchabac, S
2018-04-01
The search for objective clinical signs is a constant practitioners' and researchers' concern in psychiatry. New technologies (embedded sensors, artificial intelligence) give an easier access to untapped information such as passive data (i.e. that do not require patient intervention). The concept of "digital phenotype" is emerging in psychiatry: a psychomotor alteration translated by accelerometer's modifications contrasting with the usual functioning of the subject, or the graphorrhea of patients presenting a manic episode which is replaced by an increase of SMS sent. Our main objective is to highlight the digital phenotype of mood disorders by means of a selective review of the literature. We conducted a selective review of the literature by querying the PubMed database until February 2017 with the terms [Computer] [Computerized] [Machine] [Automatic] [Automated] [Heart rate variability] [HRV] [actigraphy] [actimetry] [digital] [motion] [temperature] [Mood] [Bipolar] [Depression] [Depressive]. Eight hundred and forty-nine articles were submitted for evaluation, 37 articles were included. For unipolar disorders, smartphones can diagnose depression with excellent accuracy by combining GPS and call log data. Actigraphic measurements showing daytime alteration in basal function while ECG sensors assessing variation in heart rate variability (HRV) and body temperature appear to be useful tools to diagnose a depressive episode. For bipolar disorders, systems which combine several sensors are described: MONARCA, PRIORI, SIMBA and PSYCHE. All these systems combine passive and active data on smartphones. From a synthesis of these data, a digital phenotype of the disorders is proposed based on the accelerometer and the GPS, the ECG, the body temperature, the use of the smartphone and the voice. This digital phenotype thus brings into question certain clinical paradigms in which psychiatrists evolve. All these systems can be used to computerize the clinical characteristics of the various mental states studied, sometimes with greater precision than a clinician could do. Most authors recommend the use of passive data rather than active data in the context of bipolar disorders because automatically generated data reduce biases and limit the feeling of intrusion that self-questionnaires may cause. The impact of these technologies questions the psychiatrist's professional culture, defined as a specific language and a set of common values. We address issues related to these changes. Impact on psychiatrists could be important because their unity seems to be questioned due to technologies that profoundly modify the collect and process of clinical data. Copyright © 2017. Published by Elsevier Masson SAS.
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Xu, Yao; Jiang, Yu; Shi, Tao; Cai, Hanfang; Lan, Xianyong; Zhao, Xin; Plath, Martin; Chen, Hong
2017-01-01
Whole-genome sequencing provides a powerful tool to obtain more genetic variability that could produce a range of benefits for cattle breeding industry. Nanyang (Bos indicus) and Qinchuan (Bos taurus) are two important Chinese indigenous cattle breeds with distinct phenotypes. To identify the genetic characteristics responsible for variation in phenotypes between the two breeds, in the present study, we for the first time sequenced the genomes of four Nanyang and four Qinchuan cattle with 10 to 12 fold on average of 97.86% and 98.98% coverage of genomes, respectively. Comparison with the Bos_taurus_UMD_3.1 reference assembly yielded 9,010,096 SNPs for Nanyang, and 6,965,062 for Qinchuan cattle, 51% and 29% of which were novel SNPs, respectively. A total of 154,934 and 115,032 small indels (1 to 3 bp) were found in the Nanyang and Qinchuan genomes, respectively. The SNP and indel distribution revealed that Nanyang showed a genetically high diversity as compared to Qinchuan cattle. Furthermore, a total of 2,907 putative cases of copy number variation (CNV) were identified by aligning Nanyang to Qinchuan genome, 783 of which (27%) encompassed the coding regions of 495 functional genes. The gene ontology (GO) analysis revealed that many CNV genes were enriched in the immune system and environment adaptability. Among several CNV genes related to lipid transport and fat metabolism, Lepin receptor gene (LEPR) overlapping with CNV_1815 showed remarkably higher copy number in Qinchuan than Nanyang (log2 (ratio) = -2.34988; P value = 1.53E-102). Further qPCR and association analysis investigated that the copy number of the LEPR gene presented positive correlations with transcriptional expression and phenotypic traits, suggesting the LEPR CNV may contribute to the higher fat deposition in muscles of Qinchuan cattle. Our findings provide evidence that the distinct phenotypes of Nanyang and Qinchuan breeds may be due to the different genetic variations including SNPs, indels and CNV.
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Sanga, Sandeep; Frieboes, Hermann B.; Zheng, Xiaoming; Gatenby, Robert; Bearer, Elaine L.; Cristini, Vittorio
2007-01-01
Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically review advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we propose and discuss a multi-scale, i.e., from the molecular to the gross tumor scale, mathematical and computational “first-principle” approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We demonstrate that this methodology, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as phenotype-diagnostic tool and thus to predict collective and individual tumor cell invasion of surrounding host. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior. PMID:17629503
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Jiang, Yu; Shi, Tao; Cai, Hanfang; Lan, Xianyong; Zhao, Xin; Plath, Martin; Chen, Hong
2017-01-01
Whole-genome sequencing provides a powerful tool to obtain more genetic variability that could produce a range of benefits for cattle breeding industry. Nanyang (Bos indicus) and Qinchuan (Bos taurus) are two important Chinese indigenous cattle breeds with distinct phenotypes. To identify the genetic characteristics responsible for variation in phenotypes between the two breeds, in the present study, we for the first time sequenced the genomes of four Nanyang and four Qinchuan cattle with 10 to 12 fold on average of 97.86% and 98.98% coverage of genomes, respectively. Comparison with the Bos_taurus_UMD_3.1 reference assembly yielded 9,010,096 SNPs for Nanyang, and 6,965,062 for Qinchuan cattle, 51% and 29% of which were novel SNPs, respectively. A total of 154,934 and 115,032 small indels (1 to 3 bp) were found in the Nanyang and Qinchuan genomes, respectively. The SNP and indel distribution revealed that Nanyang showed a genetically high diversity as compared to Qinchuan cattle. Furthermore, a total of 2,907 putative cases of copy number variation (CNV) were identified by aligning Nanyang to Qinchuan genome, 783 of which (27%) encompassed the coding regions of 495 functional genes. The gene ontology (GO) analysis revealed that many CNV genes were enriched in the immune system and environment adaptability. Among several CNV genes related to lipid transport and fat metabolism, Lepin receptor gene (LEPR) overlapping with CNV_1815 showed remarkably higher copy number in Qinchuan than Nanyang (log2 (ratio) = -2.34988; P value = 1.53E-102). Further qPCR and association analysis investigated that the copy number of the LEPR gene presented positive correlations with transcriptional expression and phenotypic traits, suggesting the LEPR CNV may contribute to the higher fat deposition in muscles of Qinchuan cattle. Our findings provide evidence that the distinct phenotypes of Nanyang and Qinchuan breeds may be due to the different genetic variations including SNPs, indels and CNV. PMID:28841720
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Golpe, Rafael; Sanjuán López, Pilar; Cano Jiménez, Esteban; Castro Añón, Olalla; Pérez de Llano, Luis A
2014-08-01
Exposure to biomass smoke is a risk factor for chronic obstructive pulmonary disease (COPD). It is unknown whether COPD caused by biomass smoke has different characteristics to COPD caused by tobacco smoke. To determine clinical differences between these two types of the disease. Retrospective observational study of 499 patients with a diagnosis of COPD due to biomass or tobacco smoke. The clinical variables of both groups were compared. There were 122 subjects (24.4%) in the biomass smoke group and 377 (75.5%) in the tobacco smoke group. In the tobacco group, the percentage of males was higher (91.2% vs 41.8%, P<.0001) and the age was lower (70.6 vs 76.2 years, P<.0001). Body mass index and FEV1% values were higher in the biomass group (29.4±5.7 vs 28.0±5.1, P=.01, and 55.6±15.6 vs 47.1±17.1, P<.0001, respectively). The mixed COPD-asthma phenotype was more common in the biomass group (21.3% vs 5%, P<.0001), although this difference disappeared when corrected for gender. The emphysema phenotype was more common in the tobacco group (45.9% vs 31.9%, P=.009). The prevalence of the chronic bronchitis and exacerbator phenotypes, the comorbidity burden and the rate of hospital admissions were the same in both groups. Differences were observed between COPD caused by biomass and COPD caused by tobacco smoke, although these may be attributed in part to uneven gender distribution between the groups. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.
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Pinto, Rebecca; Rijsdijk, Fruhling; Ronald, Angelica; Asherson, Philip; Kuntsi, Jonna
2016-02-01
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) frequently co-occur. However, due to previous exclusionary diagnostic criteria, little is known about the underlying causes of this covariation. Twin studies assessing ADHD symptoms and autistic-like traits (ALTs) suggest substantial genetic overlap, but have largely failed to take into account the genetic heterogeneity of symptom subscales. This study aimed to clarify the phenotypic and genetic relations between ADHD and ASD by distinguishing between symptom subscales that characterise the two disorders. Moreover, we aimed to investigate whether ADHD-related cognitive impairments show a relationship with ALT symptom subscales; and whether potential shared cognitive impairments underlie the genetic risk shared between the ADHD and ALT symptoms. Multivariate structural equation modelling was conducted on a population-based sample of 1312 twins aged 7-10. Social-communication ALTs correlated moderately with both ADHD symptom domains (phenotypic correlations around 0.30) and showed substantial genetic overlap with both inattention and hyperactivity-impulsivity (genetic correlation = 0.52 and 0.44, respectively). In addition to previously reported associations with ADHD traits, reaction time variability (RTV) showed significant phenotypic (0.18) and genetic (0.32) association with social-communication ALTs. RTV captured a significant proportion (24 %) of the genetic influences shared between inattention and social-communication ALTs. Our findings suggest that social-communication ALTs underlie the previously observed phenotypic and genetic covariation between ALTs and ADHD symptoms. RTV is not specific to ADHD symptoms, but is also associated with social-communication ALTs and can, in part, contribute to an explanation of the co-occurrence of ASD and ADHD.
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Demirbilek, Huseyin; Ozbek, M Nuri; Demir, Korcan; Kotan, L Damla; Cesur, Yasar; Dogan, Murat; Temiz, Fatih; Mengen, Eda; Gurbuz, Fatih; Yuksel, Bilgin; Topaloglu, A Kemal
2015-03-01
The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism. Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented. One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases. We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH. © 2014 John Wiley & Sons Ltd.
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Kimball T. Harper; John D. Shane; John R. Jones
1985-01-01
Quaking aspen, or trembling aspen (Populus tremuloides), was named and described by Michaux in 1803. It exhibits marked phenotypic variability throughout its transcontinental range. Numerous authors, especially the early ones, tried to give order to the variability by subdividing it taxonomically. Quahng aspen has been subdivided by various...
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Subtypes in 22q11.2 Deletion Syndrome Associated with Behaviour and Neurofacial Morphology
ERIC Educational Resources Information Center
Sinderberry, Brooke; Brown, Scott; Hammond, Peter; Stevens, Angela F.; Schall, Ulrich; Murphy, Declan G. M.; Murphy, Kieran C.; Campbell, Linda E.
2013-01-01
22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among…
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Stress-based animal models of depression: Do we actually know what we are doing?
Yin, Xin; Guven, Nuri; Dietis, Nikolas
2016-12-01
Depression is one of the leading causes of disability and a significant health-concern worldwide. Much of our current understanding on the pathogenesis of depression and the pharmacology of antidepressant drugs is based on pre-clinical models. Three of the most popular stress-based rodent models are the forced swimming test, the chronic mild stress paradigm and the learned helplessness model. Despite their recognizable advantages and limitations, they are associated with an immense variability due to the high number of design parameters that define them. Only few studies have reported how minor modifications of these parameters affect the model phenotype. Thus, the existing variability in how these models are used has been a strong barrier for drug development as well as benchmark and evaluation of these pre-clinical models of depression. It also has been the source of confusing variability in the experimental outcomes between research groups using the same models. In this review, we summarize the known variability in the experimental protocols, identify the main and relevant parameters for each model and describe the variable values using characteristic examples. Our view of depression and our efforts to discover novel and effective antidepressants is largely based on our detailed knowledge of these testing paradigms, and requires a sound understanding around the importance of individual parameters to optimize and improve these pre-clinical models. Copyright © 2016 Elsevier B.V. All rights reserved.
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Gene Variants Associated with Antisocial Behaviour: A Latent Variable Approach
ERIC Educational Resources Information Center
Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V.; Lee, Maria; Yrigollen, Carolyn M.; Pakstis, Andrew J.; Katsovich, Liliya; Olds, David L.; Grigorenko, Elena L.; Leckman, James F.
2013-01-01
Objective: The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Methods: Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a…
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Stevenson, David A.; Viskochil, David H.; Rope, Alan F.; Carey, John C.
2011-01-01
NF-Noonan syndrome (NFNS) has been described as a unique phenotype, combining manifestations of neurofibromatosis type 1 (NF1) and Noonan syndromes, which are separate syndromes. Potential etiologies of NF-Noonan syndrome include a discrete syndrome of distinct etiology, co-segregation of two mutated common genes, variable clinical expressivity of NF1, and/or allelic heterogeneity. We present an informative family with an unusual NF1 mutation with variable features of NF1 and Noonan syndrome. We hypothesize that an NF1 mutant allele can lead to diagnostic manifestations of Noonan syndrome, supporting the hypothesis that NF1 allelic heterogeneity causes NFNS. PMID:16542390
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The molecular genetics of von Willebrand disease.
Berber, Ergül
2012-12-01
Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.
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Sub-Optimal Treatment of Bacterial Biofilms
Song, Tianyan; Duperthuy, Marylise; Wai, Sun Nyunt
2016-01-01
Bacterial biofilm is an emerging clinical problem recognized in the treatment of infectious diseases within the last two decades. The appearance of microbial biofilm in clinical settings is steadily increasing due to several reasons including the increased use of quality of life-improving artificial devices. In contrast to infections caused by planktonic bacteria that respond relatively well to standard antibiotic therapy, biofilm-forming bacteria tend to cause chronic infections whereby infections persist despite seemingly adequate antibiotic therapy. This review briefly describes the responses of biofilm matrix components and biofilm-associated bacteria towards sub-lethal concentrations of antimicrobial agents, which may include the generation of genetic and phenotypic variabilities. Clinical implications of bacterial biofilms in relation to antibiotic treatments are also discussed. PMID:27338489
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Agol, V I
1993-01-01
The poliovirus genome exhibits tremendous plasticity, which is particularly evident when mutations diminishing the growth potential are introduced into the genome. An amazing variability can be observed even among the genomes derived from a single plaque. Not less amazing is the stability of the viral RNA sequences, which could be revealed, for example, upon the analysis of populations of a given viral strain separated by many cycles of reproduction in different laboratories but under standard conditions. This stability is obviously due to very strong selection for the "fit" phenotype. Implications of both the stability and instability of the poliovirus genome for the design, production and use of live poliovirus vaccines are briefly discussed.
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Two Cases of Partial Trisomy 4p and Partial Trisomy 14q
Kim, Yeo-Hyang; Kim, Heung-Sik; Ryoo, Nam-Hee
2013-01-01
We present clinical and cytogenetic data on 2 cases of partial trisomy 4p and partial trisomy 14q. Both patients had an extra der(14)t(4;14)(p15.31;q12) chromosome due to a 3:1 segregation from a balanced translocation carrier mother. Array analyses indicated that their chromosomal breakpoints were similar, but there was no relationship between the 2 families. Both patients showed prominent growth retardation and psychomotor developmental delay. Other phenotypic manifestations were generally mild and variable; for example, patient 1 had a short palpebral fissure and low-set ears whereas patient 2 had a round face, asymmetric eyes, small ears, a short neck, finger/toe abnormalities, and behavioral problems. PMID:23301226
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Melo, Cláudia; Gama-de-Sousa, Susana; Almeida, Filipa; Rendeiro, Paula; Tavares, Purificação; Cardoso, Helena; Carvalho, Sónia
2013-10-15
Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted. © 2013 Elsevier B.V. All rights reserved.
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Heussinger, Nicole; Saake, Marc; Mennecke, Angelika; Dörr, Helmuth-Günther; Trollmann, Regina
2017-02-01
The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD. The clinical phenotype and manifestations of epilepsy were assessed in a Caucasian family with CRTD. DNA sequencing and creatine metabolism analysis confirmed the diagnosis. Cerebral magnetic resonance imaging (cMRI) with voxel-based morphometry and magnetic resonance spectroscopy was performed in all family members. An SLC6A8 missense mutation (c.1169C>T; p.Pro390Leu, exon 8) was detected in four of five individuals. Both male siblings were hemizygous, the mother and the affected sister heterozygous for the mutation. Structural cMRI was normal, whereas voxel-based morphometry analysis showed reduced white matter volume below the first percentile of the reference population of 290 subjects in the more severely affected boy compared with family members and controls. Normalized creatine concentration differed significantly between the individuals (P < 0.005). There is a broad phenotypic variability in CRTD even in family members with the same mutation. Differences in mental development could be related to atrophy of the subcortical white matter. Copyright © 2016 Elsevier Inc. All rights reserved.
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Qin, Xinghu; Hao, Kun; Ma, Jingchuan; Huang, Xunbing; Tu, Xiongbing; Ali, Md. Panna; Pittendrigh, Barry R.; Cao, Guangchun; Wang, Guangjun; Nong, Xiangqun; Whitman, Douglas W.; Zhang, Zehua
2017-01-01
While ecological adaptation in insects can be reflected by plasticity of phenotype, determining the causes and molecular mechanisms for phenotypic plasticity (PP) remains a crucial and still difficult question in ecology, especially where control of insect pests is involved. Oedaleus asiaticus is one of the most dominant pests in the Inner Mongolia steppe and represents an excellent system to study phenotypic plasticity. To better understand ecological factors affecting grasshopper phenotypic plasticity and its molecular control, we conducted a full transcriptional screening of O. asiaticus grasshoppers reared in four different grassland patches in Inner Mongolia. Grasshoppers showed different degrees of PP associated with unique gene expressions and different habitat plant community compositions. Grasshopper performance variables were susceptible to habitat environment conditions and closely associated with plant architectures. Intriguingly, eco-transcriptome analysis revealed five potential candidate genes playing important roles in grasshopper performance, with gene expression closely relating to PP and plant community factors. By linking the grasshopper performances to gene profiles and ecological factors using canonical regression, we first demonstrated the eco-transcriptomic architecture (ETA) of grasshopper phenotypic traits (ETAGPTs). ETAGPTs revealed plant food type, plant density, coverage, and height were the main ecological factors influencing PP, while insect cuticle protein (ICP), negative elongation factor A (NELFA), and lactase-phlorizin hydrolase (LCT) were the key genes associated with PP. Our study gives a clear picture of gene-environment interaction in the formation and maintenance of PP and enriches our understanding of the transcriptional events underlying molecular control of rapid phenotypic plasticity associated with environmental variability. The findings of this study may also provide new targets for pest control and highlight the significance of ecological management practice on grassland conservation. PMID:29066978
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Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz
2012-02-01
We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia. Copyright © 2011 Wiley Periodicals, Inc.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Feigenbaum, A.; Chitayat, D.; Robinson, B.
1996-04-24
We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A{r_arrow}G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins` mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has hadmore » recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA{sup Leu(UUR)} A{r_arrow}G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA{sup Leu(UUR)} A{r_arrow}G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother`s pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult. 33 refs., 1 tab.« less
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Daddy issues: paternal effects on phenotype.
Rando, Oliver J
2012-11-09
The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. Copyright © 2012 Elsevier Inc. All rights reserved.
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Phenotypic models of evolution and development: geometry as destiny.
François, Paul; Siggia, Eric D
2012-12-01
Quantitative models of development that consider all relevant genes typically are difficult to fit to embryonic data alone and have many redundant parameters. Computational evolution supplies models of phenotype with relatively few variables and parameters that allows the patterning dynamics to be reduced to a geometrical picture for how the state of a cell moves. The clock and wavefront model, that defines the phenotype of somitogenesis, can be represented as a sequence of two discrete dynamical transitions (bifurcations). The expression-time to space map for Hox genes and the posterior dominance rule are phenotypes that naturally follow from computational evolution without considering the genetics of Hox regulation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Axelrod, Kevin; Sanchez, Alvaro; Gore, Jeff
2015-08-24
Microorganisms often exhibit a history-dependent phenotypic response after exposure to a stimulus which can be imperative for proper function. However, cells frequently experience unexpected environmental perturbations that might induce phenotypic switching. How cells maintain phenotypic states in the face of environmental fluctuations remains an open question. Here, we use environmental perturbations to characterize the resilience of phenotypic states in a synthetic gene network near a critical transition. We find that far from the critical transition an environmental perturbation may induce little to no phenotypic switching, whereas close to the critical transition the same perturbation can cause many cells to switch phenotypic states. This loss of resilience was observed for perturbations that interact directly with the gene circuit as well as for a variety of generic perturbations-such as salt, ethanol, or temperature shocks-that alter the state of the cell more broadly. We obtain qualitatively similar findings in natural gene circuits, such as the yeast GAL network. Our findings illustrate how phenotypic memory can become destabilized by environmental variability near a critical transition.
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Messai, Habib; Farman, Muhammad; Sarraj-Laabidi, Abir; Hammami-Semmar, Asma; Semmar, Nabil
2016-11-17
Olive oils (OOs) show high chemical variability due to several factors of genetic, environmental and anthropic types. Genetic and environmental factors are responsible for natural compositions and polymorphic diversification resulting in different varietal patterns and phenotypes. Anthropic factors, however, are at the origin of different blends' preparation leading to normative, labelled or adulterated commercial products. Control of complex OO samples requires their (i) characterization by specific markers; (ii) authentication by fingerprint patterns; and (iii) monitoring by traceability analysis. These quality control and management aims require the use of several multivariate statistical tools: specificity highlighting requires ordination methods; authentication checking calls for classification and pattern recognition methods; traceability analysis implies the use of network-based approaches able to separate or extract mixed information and memorized signals from complex matrices. This chapter presents a review of different chemometrics methods applied for the control of OO variability from metabolic and physical-chemical measured characteristics. The different chemometrics methods are illustrated by different study cases on monovarietal and blended OO originated from different countries. Chemometrics tools offer multiple ways for quantitative evaluations and qualitative control of complex chemical variability of OO in relation to several intrinsic and extrinsic factors.
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Gene variants associated with antisocial behaviour: A latent variable approach
Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V.; Lee, Maria; Yrigollen, Carolyn M.; Pakstis, Andrew J.; Katsovich, Liliya; Olds, David L.; Grigorenko, Elena L.; Leckman, James F.
2013-01-01
Objective The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Methods Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation program in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours, and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. Results Eight single-nucleotide polymorphisms (SNPs) from 8 genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all 8 genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid, and cholinergic signaling as well as stress response pathways in mediating susceptibility to antisocial behaviour. Conclusions This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential “co-action” of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the etiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a ‘shared’ variance across genetic risk alleles associated with complex neuropsychiatric dimensional phenotypes using relatively small numbers of well-characterized research participants. PMID:23822756
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Barton, James C; Barton, Ellen H; Acton, Ronald T
2006-01-01
Background In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. Methods We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable), report of ethanol consumption (as a dichotomous variable), percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. Results In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable) was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p < 0.0001), but not with reports of Native American ancestry or reports of ethanol consumption. Loge serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p < 0.0001) (p < 0.0001; ANOVA of regression). Conclusion We conclude that the iron-related phenotypes of hemochromatosis probands with HFE C282Y homozygosity are similar in those with and without Native American ancestry reports. PMID:16533407
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Gatenby, Robert A; Silva, Ariosto S; Gillies, Robert J; Frieden, B Roy
2009-06-01
A number of successful systemic therapies are available for treatment of disseminated cancers. However, tumor response is often transient, and therapy frequently fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Although cancers are highly dynamic systems, cancer therapy is typically administered according to a fixed, linear protocol. Here we examine an adaptive therapeutic approach that evolves in response to the temporal and spatial variability of tumor microenvironment and cellular phenotype as well as therapy-induced perturbations. Initial mathematical models find that when resistant phenotypes arise in the untreated tumor, they are typically present in small numbers because they are less fit than the sensitive population. This reflects the "cost" of phenotypic resistance such as additional substrate and energy used to up-regulate xenobiotic metabolism, and therefore not available for proliferation, or the growth inhibitory nature of environments (i.e., ischemia or hypoxia) that confer resistance on phenotypically sensitive cells. Thus, in the Darwinian environment of a cancer, the fitter chemosensitive cells will ordinarily proliferate at the expense of the less fit chemoresistant cells. The models show that, if resistant populations are present before administration of therapy, treatments designed to kill maximum numbers of cancer cells remove this inhibitory effect and actually promote more rapid growth of the resistant populations. We present an alternative approach in which treatment is continuously modulated to achieve a fixed tumor population. The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitive cells to survive so that they, in turn, suppress proliferation of the less fit but chemoresistant subpopulations. Computer simulations show that this strategy can result in prolonged survival that is substantially greater than that of high dose density or metronomic therapies. The feasibility of adaptive therapy is supported by in vivo experiments. [Cancer Res 2009;69(11):4894-903] Major FindingsWe present mathematical analysis of the evolutionary dynamics of tumor populations with and without therapy. Analytic solutions and numerical simulations show that, with pretreatment, therapy-resistant cancer subpopulations are present due to phenotypic or microenvironmental factors; maximum dose density chemotherapy hastens rapid expansion of resistant populations. The models predict that host survival can be maximized if "treatment-for-cure strategy" is replaced by "treatment-for-stability." Specifically, the models predict that an optimal treatment strategy will modulate therapy to maintain a stable population of chemosensitive cells that can, in turn, suppress the growth of resistant populations under normal tumor conditions (i.e., when therapy-induced toxicity is absent). In vivo experiments using OVCAR xenografts treated with carboplatin show that adaptive therapy is feasible and, in this system, can produce long-term survival.
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Reid, Emma S; Papandreou, Apostolos; Drury, Suzanne; Boustred, Christopher; Yue, Wyatt W; Wedatilake, Yehani; Beesley, Clare; Jacques, Thomas S; Anderson, Glenn; Abulhoul, Lara; Broomfield, Alex; Cleary, Maureen; Grunewald, Stephanie; Varadkar, Sophia M; Lench, Nick; Rahman, Shamima; Gissen, Paul; Clayton, Peter T; Mills, Philippa B
2016-11-01
Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.
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Estep, Anne L; Tidyman, William E; Teitell, Michael A; Cotter, Philip D; Rauen, Katherine A
2006-01-01
Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. (c) 2005 Wiley-Liss, Inc.
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USDA-ARS?s Scientific Manuscript database
Developmental ethanol exposure is able to induce Fetal Alcohol Spectrum Disorder (FASD) phenotypes in Japanese rice fish (Oryzias latipes). This study investigated possible differential expression of cannabinoid receptor (cnr) mRNAs during Japanese rice fish embryogenesis and variability to ethanol-...
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Oyarzabal, Alfonso; Martínez-Pardo, Mercedes; Merinero, Begoña; Navarrete, Rosa; Desviat, Lourdes R; Ugarte, Magdalena; Rodríguez-Pombo, Pilar
2013-02-01
This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). The disease-causing mutation was identified in a patient with a mild variant phenotype, involving a gene not previously associated with MSUD. SNP array-based genotyping showed a copy-neutral homozygous pattern for chromosome 4 compatible with uniparental isodisomy. Mutation analysis of the candidate gene, PPM1K, revealed a homozygous c.417_418delTA change predicted to result in a truncated, unstable protein. No PP2Cm mutant protein was detected in immunocytochemical or Western blot expression analyses. The transient expression of wild-type PPM1K in PP2Cm-deficient fibroblasts recovered 35% of normal BCKDH activity. As PP2Cm has been described essential for cell survival, apoptosis and metabolism, the impact of its deficiency on specific metabolic stress variables was evaluated in PP2Cm-deficient fibroblasts. Increases were seen in ROS levels along with the activation of specific stress-signaling MAP kinases. Similar to that described for the pyruvate dehydrogenase complex, a defect in the regulation of BCKDH caused the aberrant metabolism of its substrate, contributing to the patient's MSUD phenotype--and perhaps others. © 2012 WILEY PERIODICALS, INC.
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Takasawa, Kei; Igarashi, Maki; Ono, Makoto; Takemoto, Akira; Takada, Shuji; Yamataka, Atsuyuki; Ogata, Tsutomu; Morio, Tomohiro; Fukami, Maki; Kashimada, Kenichi
2017-01-01
Recently, a heterozygous missense mutation in NR5A1, p.R92W, was identified as a cause of 46,XX testicular/ovo-testicular disorders of sexual development (DSD). We report a sibling pair with 46,XX DSD due to an NR5A1 mutation with distinct phenotypes, including external and internal genitalia and gonads, for whom different rearing sexes were selected. Thus, the phenotypes of p.R92W vary, even within a family. The father of the patients showed oligozoospermia with the p.R92W mutation, suggesting that in 46,XY individuals, the mutation would cause various gonadal phenotypes. We review and discuss the general role of the R92W mutation in sexual development. © 2018 S. Karger AG, Basel.
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Talaga-Ćwiertnia, Katarzyna; Bulanda, Małgorzata
2018-01-01
Vancomycin-resistant Enterococcus faecium (VREfm) strains have become an important hospital pathogen due to their rapid spread, high mortality rate associated with infections and limited therapeutic options. Vancomycin resistance is predominantly mediated by VanA or VanB phenotypes, which differ as regards maintaining sensitivity to teicoplanin in the VanB phenotype. The majority of VREfm cases in the United States, Europe, Korea, South America and Africa are currently caused by the VanA phenotype. However, the epidemics in Australia and Singapore are chiefly brought about by the VanB phenotype. The rate of VREfm isolate spread varies greatly. The greatest percentage of VREfm is now recorded in the USA, Ireland and Australia. Supervision of VRE is implemented to varying degrees. Therefore, the epidemiological situation in some countries is difficult to assess due to limited data or lack thereof.
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Breeding to adapt agriculture to climate change: affordable phenotyping solutions.
Araus, José L; Kefauver, Shawn C
2018-05-28
Breeding is one of the central pillars of adaptation of crops to climate change. However, phenotyping is a key bottleneck that is limiting breeding efficiency. The awareness of phenotyping as a breeding limitation is not only sustained by the lack of adequate approaches, but also by the perception that phenotyping is an expensive activity. Phenotyping is not just dependent on the choice of appropriate traits and tools (e.g. sensors) but relies on how these tools are deployed on their carrying platforms, the speed and volume of data extraction and analysis (throughput), the handling of spatial variability and characterization of environmental conditions, and finally how all the information is integrated and processed. Affordable high throughput phenotyping aims to achieve reasonably priced solutions for all the components comprising the phenotyping pipeline. This mini-review will cover current and imminent solutions for all these components, from the increasing use of conventional digital RGB cameras, within the category of sensors, to open-access cloud-structured data processing and the use of smartphones. Emphasis will be placed on field phenotyping, which is really the main application for day-to-day phenotyping. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Age Dependent Variability in Gene Expression in Fischer 344 Rat Retina.
Recent evidence suggests older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response d...
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Plastic flies: the regulation and evolution of trait variability in Drosophila.
Shingleton, Alexander W; Tang, Hui Yuan
2012-01-01
Individuals within species and populations vary. Such variation arises through environmental and genetic factors and ensures that no two individuals are identical. However, it is clear that not all traits show the same degree of intraspecific variation. Some traits, in particular secondary sexual characteristics used by males to compete for and attract females, are extremely variable among individuals in a population. Other traits, for example brain size in mammals, are not. Recent research has begun to explore the possibility that the extent of phenotypic variation (here referred to as "variability") may be a character itself and subject to natural selection. While these studies support the concept of variability as an evolvable trait, controversy remains over what precisely the trait is. At the heart of this controversy is the fact that there are very few examples of developmental mechanisms that regulate trait variability in response to any source of variation, be it environmental or genetic. Here, we describe a recent study from our laboratory that identifies such a mechanism. We then place the study in the context of current research on the regulation of trait variability, and discuss the implications for our understanding of the developmental regulation and evolution of phenotypic variation.
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Zhou, Jin J.; Cho, Michael H.; Lange, Christoph; Lutz, Sharon; Silverman, Edwin K.; Laird, Nan M.
2015-01-01
Many correlated disease variables are analyzed jointly in genetic studies in the hope of increasing power to detect causal genetic variants. One approach involves assessing the relationship between each phenotype and each single nucleotide polymorphism (SNP) individually and using a Bonferroni correction for the effective number of tests conducted. Alternatively, one can apply a multivariate regression or a dimension reduction technique, such as principal component analysis (PCA), and test for the association with the principal components (PC) of the phenotypes rather than the individual phenotypes. Inspired by the previous approaches of combining phenotypes to maximize heritability at individual SNPs, in this paper, we propose to construct a maximally heritable phenotype (MaxH) by taking advantage of the estimated total heritability and co-heritability. The heritability and co-heritability only need to be estimated once, therefore our method is applicable to genome-wide scans. MaxH phenotype is a linear combination of the individual phenotypes with increased heritability and power over the phenotypes being combined. Simulations show that the heritability and power achieved agree well with the theory for large samples and two phenotypes. We compare our approach with commonly used methods and assess both the heritability and the power of the MaxH phenotype. Moreover we provide suggestions for how to choose the phenotypes for combination. An application of our approach to a COPD genome-wide association study shows the practical relevance. PMID:26111731
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Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly
2015-03-01
Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation. © 2015 Wiley Periodicals, Inc.
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Leite, P S S; Rodrigues, R; Silva, R N O; Pimenta, S; Medeiros, A M; Bento, C S; Gonçalves, L S A
2016-10-05
Capsicum baccatum is one of the most important chili peppers in South America, since this region is considered to be the center of origin and diversity of this species. In Brazil, C. baccatum has been widely explored by family farmers and there are different local names for each fruit phenotype, such as cambuci and dedo-de-moça (lady's finger). Although very popular among farmers and consumers, C. baccatum has been less extensively studied than other Capsicum species. This study describes the phenotypic and genotypic variability in C. baccatum var. pendulum accessions. Twenty-nine accessions from the Universidade Estadual do Norte Fluminense Darcy Ribeiro gene bank, and one commercial genotype ('BRS-Mari') were evaluated for 53 morphoagronomic descriptors (31 qualitative and 22 quantitative traits). In addition, accessions were genotyped using 30 microsatellite primers. Three accessions from the C. annuum complex were included in the molecular characterization. Nine of 31 qualitative descriptors were monomorphic, while all quantitative descriptors were highly significant different between accessions (P < 0.01). Using the unweighted pair group method using arithmetic averages, four groups were obtained based on multicategoric variables and five groups were obtained based on quantitative variables. In the genotyping analysis, 12 polymorphic simple sequence repeat primers amplified in C. baccatum with dissimilarity between accessions ranging from 0.13 to 0.91, permitting the formation of two distinct groups for Bayesian analysis. These results indicate wide variability among the accessions comparing phenotypic and genotypic data and revealed distinct patterns of dissimilarity between matrices, indicating that both steps are valuable for the characterization of C. baccatum var. pendulum accessions.
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Phenotypic Variability Among Café-au-lait Macules in NF1
Boyd, Kevin P.; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R.; Theos, Amy
2009-01-01
Background Cafe-au-lait macules (CALMs) in NF1 are an early and accessible phenotype in NF1, but have not been extensively studied. Objective To more fully characterize the phenotype of CALMs in patients with NF1. Methods Twenty-four patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the Genetics Department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin (M) based on its absorption of visible light. The major response was defined as the difference between the mean M from the CALM and the mean M from the surrounding skin. The major response for each spot was compared to spots within an individual and across individuals in the study population. Results There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, <0.0001) and secondly to interpersonal variability (33.0%, <0.0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. Limitations The study was performed on a small population of patients and the method utilized has not yet been used extensively for this purpose. Conclusions CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. PMID:20605257
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Ashili, Shashanka P.; Houkal, Jeff; Smith, Dean; Mohammadreza, Aida; Lee, Kristen B.; Forrester, Jessica; Kumar, Ashok; Anis, Yasser H.; Paulson, Thomas G.; Youngbull, Cody A.; Tian, Yanqing; Holl, Mark R.; Johnson, Roger H.; Meldrum, Deirdre R.
2012-01-01
Abstract. Intercellular heterogeneity is a key factor in a variety of core cellular processes including proliferation, stimulus response, carcinogenesis, and drug resistance. However, cell-to-cell variability studies at the single-cell level have been hampered by the lack of enabling experimental techniques. We present a measurement platform that features the capability to quantify oxygen consumption rates of individual, non-interacting and interacting cells under normoxic and hypoxic conditions. It is based on real-time concentration measurements of metabolites of interest by means of extracellular optical sensors in cell-isolating microwells of subnanoliter volume. We present the results of a series of measurements of oxygen consumption rates (OCRs) of individual non-interacting and interacting human epithelial cells. We measured the effects of cell-to-cell interactions by using the system’s capability to isolate two and three cells in a single well. The major advantages of the approach are: 1. ratiometric, intensity-based characterization of the metabolic phenotype at the single-cell level, 2. minimal invasiveness due to the distant positioning of sensors, and 3. ability to study the effects of cell-cell interactions on cellular respiration rates. PMID:22502580
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Kelbauskas, Laimonas; Ashili, Shashanka P; Houkal, Jeff; Smith, Dean; Mohammadreza, Aida; Lee, Kristen B; Forrester, Jessica; Kumar, Ashok; Anis, Yasser H; Paulson, Thomas G; Youngbull, Cody A; Tian, Yanqing; Holl, Mark R; Johnson, Roger H; Meldrum, Deirdre R
2012-03-01
Intercellular heterogeneity is a key factor in a variety of core cellular processes including proliferation, stimulus response, carcinogenesis, and drug resistance. However, cell-to-cell variability studies at the single-cell level have been hampered by the lack of enabling experimental techniques. We present a measurement platform that features the capability to quantify oxygen consumption rates of individual, non-interacting and interacting cells under normoxic and hypoxic conditions. It is based on real-time concentration measurements of metabolites of interest by means of extracellular optical sensors in cell-isolating microwells of subnanoliter volume. We present the results of a series of measurements of oxygen consumption rates (OCRs) of individual non-interacting and interacting human epithelial cells. We measured the effects of cell-to-cell interactions by using the system's capability to isolate two and three cells in a single well. The major advantages of the approach are: 1. ratiometric, intensity-based characterization of the metabolic phenotype at the single-cell level, 2. minimal invasiveness due to the distant positioning of sensors, and 3. ability to study the effects of cell-cell interactions on cellular respiration rates. © 2012 Society of Photo-Optical Instrumentation Engineers (SPIE).
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GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.
Lindberg, Olle R; McKinney, Andrew; Engler, Jane R; Koshkakaryan, Gayane; Gong, Henry; Robinson, Aaron E; Ewald, Andrew J; Huillard, Emmanuelle; David James, C; Molinaro, Annette M; Shieh, Joseph T; Phillips, Joanna J
2016-11-29
Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness.
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Snowshoe hares display limited phenotypic plasticity to mismatch in seasonal camouflage
Zimova, Marketa; Mills, L. Scott; Lukacs, Paul M.; Mitchell, Michael S.
2014-01-01
As duration of snow cover decreases owing to climate change, species undergoing seasonal colour moults can become colour mismatched with their background. The immediate adaptive solution to this mismatch is phenotypic plasticity, either in phenology of seasonal colour moults or in behaviours that reduce mismatch or its consequences. We observed nearly 200 snowshoe hares across a wide range of snow conditions and two study sites in Montana, USA, and found minimal plasticity in response to mismatch between coat colour and background. We found that moult phenology varied between study sites, likely due to differences in photoperiod and climate, but was largely fixed within study sites with only minimal plasticity to snow conditions during the spring white-to-brown moult. We also found no evidence that hares modify their behaviour in response to colour mismatch. Hiding and fleeing behaviours and resting spot preference of hares were more affected by variables related to season, site and concealment by vegetation, than by colour mismatch. We conclude that plasticity in moult phenology and behaviours in snowshoe hares is insufficient for adaptation to camouflage mismatch, suggesting that any future adaptation to climate change will require natural selection on moult phenology or behaviour.
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Resistance to thyroid hormone due to defective thyroid receptor alpha.
Moran, Carla; Chatterjee, Krishna
2015-08-01
Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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[A case of partial 1p36.1 deletion and partial trisomy 6p diagnosed by karyotype].
Fernández Pineda, Monica; Ramírez-Cheyne, Julián; Isaza, Carolina; Saldarriaga, Wilmar
The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.
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Joffret, Marie-Line; Jégouic, Sophie; Bessaud, Maël; Balanant, Jean; Tran, Coralie; Caro, Valerie; Holmblat, Barbara; Razafindratsimandresy, Richter; Reynes, Jean-Marc; Rakoto-Andrianarivelo, Mala; Delpeyroux, Francis
2012-05-01
Five cases of poliomyelitis due to type 2 or 3 recombinant vaccine-derived polioviruses (VDPVs) were reported in the Toliara province of Madagascar in 2005. We sequenced the genome of the VDPVs isolated from the patients and from 12 healthy children and characterized phenotypic aspects, including pathogenicity, in mice transgenic for the poliovirus receptor. We identified 6 highly complex mosaic recombinant lineages composed of sequences derived from different vaccine polioviruses and other species C human enteroviruses (HEV-Cs). Most had some recombinant genome features in common and contained nucleotide sequences closely related to certain cocirculating coxsackie A virus isolates. However, they differed in terms of their recombinant characteristics or nucleotide substitutions and phenotypic features. All VDPVs were neurovirulent in mice. This study confirms the genetic relationship between type 2 and 3 VDPVs, indicating that both types can be involved in a single outbreak of disease. Our results highlight the various ways in which a vaccine-derived poliovirus may become pathogenic in complex viral ecosystems, through frequent recombination events and mutations. Intertypic recombination between cocirculating HEV-Cs (including polioviruses) appears to be a common mechanism of genetic plasticity underlying transverse genetic variability.
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Massonnet, Catherine; Vile, Denis; Fabre, Juliette; Hannah, Matthew A.; Caldana, Camila; Lisec, Jan; Beemster, Gerrit T.S.; Meyer, Rhonda C.; Messerli, Gaëlle; Gronlund, Jesper T.; Perkovic, Josip; Wigmore, Emma; May, Sean; Bevan, Michael W.; Meyer, Christian; Rubio-Díaz, Silvia; Weigel, Detlef; Micol, José Luis; Buchanan-Wollaston, Vicky; Fiorani, Fabio; Walsh, Sean; Rinn, Bernd; Gruissem, Wilhelm; Hilson, Pierre; Hennig, Lars; Willmitzer, Lothar; Granier, Christine
2010-01-01
A major goal of the life sciences is to understand how molecular processes control phenotypes. Because understanding biological systems relies on the work of multiple laboratories, biologists implicitly assume that organisms with the same genotype will display similar phenotypes when grown in comparable conditions. We investigated to what extent this holds true for leaf growth variables and metabolite and transcriptome profiles of three Arabidopsis (Arabidopsis thaliana) genotypes grown in 10 laboratories using a standardized and detailed protocol. A core group of four laboratories generated similar leaf growth phenotypes, demonstrating that standardization is possible. But some laboratories presented significant differences in some leaf growth variables, sometimes changing the genotype ranking. Metabolite profiles derived from the same leaf displayed a strong genotype × environment (laboratory) component. Genotypes could be separated on the basis of their metabolic signature, but only when the analysis was limited to samples derived from one laboratory. Transcriptome data revealed considerable plant-to-plant variation, but the standardization ensured that interlaboratory variation was not considerably larger than intralaboratory variation. The different impacts of the standardization on phenotypes and molecular profiles could result from differences of temporal scale between processes involved at these organizational levels. Our findings underscore the challenge of describing, monitoring, and precisely controlling environmental conditions but also demonstrate that dedicated efforts can result in reproducible data across multiple laboratories. Finally, our comparative analysis revealed that small variations in growing conditions (light quality principally) and handling of plants can account for significant differences in phenotypes and molecular profiles obtained in independent laboratories. PMID:20200072
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An Multivariate Distance-Based Analytic Framework for Connectome-Wide Association Studies
Shehzad, Zarrar; Kelly, Clare; Reiss, Philip T.; Craddock, R. Cameron; Emerson, John W.; McMahon, Katie; Copland, David A.; Castellanos, F. Xavier; Milham, Michael P.
2014-01-01
The identification of phenotypic associations in high-dimensional brain connectivity data represents the next frontier in the neuroimaging connectomics era. Exploration of brain-phenotype relationships remains limited by statistical approaches that are computationally intensive, depend on a priori hypotheses, or require stringent correction for multiple comparisons. Here, we propose a computationally efficient, data-driven technique for connectome-wide association studies (CWAS) that provides a comprehensive voxel-wise survey of brain-behavior relationships across the connectome; the approach identifies voxels whose whole-brain connectivity patterns vary significantly with a phenotypic variable. Using resting state fMRI data, we demonstrate the utility of our analytic framework by identifying significant connectivity-phenotype relationships for full-scale IQ and assessing their overlap with existent neuroimaging findings, as synthesized by openly available automated meta-analysis (www.neurosynth.org). The results appeared to be robust to the removal of nuisance covariates (i.e., mean connectivity, global signal, and motion) and varying brain resolution (i.e., voxelwise results are highly similar to results using 800 parcellations). We show that CWAS findings can be used to guide subsequent seed-based correlation analyses. Finally, we demonstrate the applicability of the approach by examining CWAS for three additional datasets, each encompassing a distinct phenotypic variable: neurotypical development, Attention-Deficit/Hyperactivity Disorder diagnostic status, and L-dopa pharmacological manipulation. For each phenotype, our approach to CWAS identified distinct connectome-wide association profiles, not previously attainable in a single study utilizing traditional univariate approaches. As a computationally efficient, extensible, and scalable method, our CWAS framework can accelerate the discovery of brain-behavior relationships in the connectome. PMID:24583255
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Aposematism and crypsis are not enough to explain dorsal polymorphism in the Iberian adder
NASA Astrophysics Data System (ADS)
Martínez-Freiría, Fernando; Pérez i de Lanuza, Guillem; Pimenta, António A.; Pinto, Tiago; Santos, Xavier
2017-11-01
Aposematic organisms can show phenotypic variability across their distributional ranges. The ecological advantages of this variability have been scarcely studied in vipers. We explored this issue in Vipera seoanei, a species that exhibits five geographically structured dorsal colour phenotypes across Northern Iberia: two zigzag patterned (Classic and Cantabrica), one dorsal-strip patterned (Bilineata), one even grey (Uniform), and one melanistic (Melanistic). We compared predation rates (raptors and mammals) on plasticine models resembling each colour phenotype in three localities. Visual modelling techniques were used to infer detectability (i.e. conspicuousness) of each model type for visually guided predators (i.e. diurnal raptors). We hypothesize that predation rates will be lower for the two zigzag models (aposematism hypothesis) and that models with higher detectability would show higher predation rates (detectability hypothesis). Classic and Bilineata models were the most conspicuous, while Cantabrica and Uniform were the less. Melanistic presented an intermediate conspicuousness. Predation rate was low (3.24% of models) although there was variation in attack frequency among models. Zigzag models were scarcely predated supporting the aposematic role of the zigzag pattern in European vipers to reduce predation (aposematism hypothesis). From the non-zigzag models, high predation occurred on Bilineata and Melanistic models, and low on Uniform models, partially supporting our detectability hypothesis. These results suggest particular evolutionary advantages for non-zigzag phenotypes such as better performance of Melanistic phenotypes in cold environments or better crypsis of Uniform phenotypes. Polymorphism in V. seoanei may respond to a complex number of forces acting differentially across an environmental gradient.
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TESTOSTERONE AND SPORT: CURRENT PERSPECTIVES
Wood, Ruth I.; Stanton, Steven J.
2011-01-01
Testosterone and other anabolic-androgenic steroids enhance athletic performance in men and women. As a result, exogenous androgen is banned from most competitive sports. However, due to variability in endogenous secretion, and similarities with exogenous testosterone, it has been challenging to establish allowable limits for testosterone in competition. Endogenous androgen production is dynamically regulated by both exercise and winning in competition. Furthermore, testosterone may promote athletic performance, not only through its long-term anabolic actions, but also through rapid effects on behavior. In women, excess production of endogenous testosterone due to inborn disorders of sexual development (DSD) may convey a competitive advantage. For many years, female competitors have been subject to tests of sexual genotype and phenotype known as gender verification. Although gender verification has not identified any normal man competing as a woman, this process has identified women athletes with DSD. As understanding of DSD has expanded in recent years, women with DSD are increasingly able to continue athletic competition. PMID:21983229
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Phenotypic plasticity in sex pheromone production in Bicyclus anynana butterflies.
Dion, Emilie; Monteiro, Antónia; Yew, Joanne Y
2016-12-14
Phenotypic plasticity refers to the environmental control of phenotypes. Cues experienced during development (developmental plasticity) or during adulthood (acclimatization) can both affect adult phenotypes. Phenotypic plasticity has been described in many traits but examples of developmental plasticity in physiological traits, in particular, remain scarce. We examined developmental plasticity and acclimatization in pheromone production in the butterfly Bicyclus anynana in response to rearing temperature. B. anynana lives in the African tropics where warm rearing temperatures of the wet season produce active males that court and females that choose, whereas cooler temperatures of the dry season lead to choosy less active males and courting females. We hypothesized that if male pheromone production is costly, it should be reduced in the dry season form. After describing the ultrastructure of pheromone producing cells, we showed that dry season males produced significantly less sex pheromones than wet season males, partly due to acclimatization and partly due to developmental plasticity. Variation in levels of one of the compounds is associated with differential regulation of a pheromone biosynthetic enzyme gene. This plasticity might be an adaptation to minimize pheromone production costs during the stressful dry season.
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Jones, Kyle B.; Goodwin, Alice F.; Landan, Maya; Seidel, Kerstin; Tran, Dong-Kha; Hogue, Jacob; Chavez, Miquella; Fete, Mary; Yu, Wenli; Hussein, Tarek; Johnson, Ramsey; Huttner, Kenneth; Jheon, Andrew H.; Klein, Ophir D.
2015-01-01
Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non-invasive techniques presented in our study will improve upon larger genotype-phenotype studies and in the assessment of future therapies in XL-HED. PMID:23687000
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John R. Jones; Norbert V. DeByle
1985-01-01
The broad genotypic variability in quaking aspen (Populus tremuloides Michx.), that results in equally broad phenotypic variability among clones is important to the ecology and management of this species. This chapter considers principles of aspen genetics and variation, variation in aspen over its range, and local variation among clones. For a more...
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Advanced phenotyping and phenotype data analysis for the study of plant growth and development.
Rahaman, Md Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming
2015-01-01
Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis.
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Kindler syndrome: extension of FERMT1 mutational spectrum and natural history.
Has, Cristina; Castiglia, Daniele; del Rio, Marcela; Diez, Marta Garcia; Piccinni, Eugenia; Kiritsi, Dimitra; Kohlhase, Jürgen; Itin, Peter; Martin, Ludovic; Fischer, Judith; Zambruno, Giovanna; Bruckner-Tuderman, Leena
2011-11-01
Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications. © 2011 Wiley Periodicals, Inc.
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From mild ataxia to huntington disease phenocopy: the multiple faces of spinocerebellar ataxia 17.
Koutsis, Georgios; Panas, Marios; Paraskevas, George P; Bougea, Anastasia M; Kladi, Athina; Karadima, Georgia; Kapaki, Elisabeth
2014-01-01
Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.
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From Mild Ataxia to Huntington Disease Phenocopy: The Multiple Faces of Spinocerebellar Ataxia 17
Panas, Marios; Paraskevas, George P.; Bougea, Anastasia M.; Karadima, Georgia; Kapaki, Elisabeth
2014-01-01
Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family. PMID:25349749
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Qin, Shengfang; Wang, Xueyan; Li, Yunxing; Wei, Ping; Chen, Chun; Zeng, Lan
2016-02-01
To explore the genetics mechanism for the phenotypic variability in a patient carrying a rare ring chromosome 9. The karyotype of the patient was analyzed with cytogenetics method. Presence of sex chromosome was confirmed with fluorescence in situ hybridization. The SRY gene was subjected to PCR amplification and direct sequencing. Potential deletion and duplication were detected with array-based comparative genomic hybridization (array-CGH). The karyotype of the patient has comprised 6 types of cell lines containing a ring chromosome 9. The SRY gene sequence was normal. By array-CGH, the patient has carried a hemizygous deletion at 9p24.3-p23 (174 201-9 721 761) encompassing 30 genes from Online Mendelian Inheritance in Man. The phenotypic variability of the 9p deletion syndrome in conjunct with ring chromosome 9 may be attributable to multiple factors including loss of chromosomal material, insufficient dosage of genes, instability of ring chromosome, and pattern of inheritance.
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Dental management of amelogenesis imperfecta patients: a primer on genotype-phenotype correlations.
Ng, F K; Messer, L B
2009-01-01
Amelogenesis imperfecta (AI) represents a group of hereditary conditions which affects enamel formation in the primary and permanent dentitions. Mutations in genes critical for amelogenesis result in diverse phenotypes characterized by variably thin and/or defective enamel. To date, mutations in 5 genes are known to cause AI in humans. Understanding the molecular etiologies and associated inheritance patterns can assist in the early diagnosis of this condition. Recognition of genotype-phenotype correlations will allow clinicians to guide genetic testing and select appropriate management strategies for patients who express different phenotypes. The purpose of this paper was to provide a narrative review of the current literature on amelogenesis imperfecta, particularly regarding recent advances in the identification of candidate genes and the patterns of inheritance.
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Allelic and Phenotypic Heterogeneity in ABCA4 mutations
Burke, Tomas R; Tsang, Stephen H
2011-01-01
Since the discovery of the ABCA4 gene as the cause of autosomal recessive Stargardt disease/fundus flavimaculatus much has been written of the phenotypic variability in ABCA4 retinopathy. In this review the authors discuss the findings seen on examination and the disease features detected using various clinical tests. Important differential diagnoses are presented and unusual presentations of ABCA4 disease highlighted. PMID:21510770
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Phenotypes of organ involvement in sarcoidosis.
Schupp, Jonas Christian; Freitag-Wolf, Sandra; Bargagli, Elena; Mihailović-Vučinić, Violeta; Rottoli, Paola; Grubanovic, Aleksandar; Müller, Annegret; Jochens, Arne; Tittmann, Lukas; Schnerch, Jasmin; Olivieri, Carmela; Fischer, Annegret; Jovanovic, Dragana; Filipovic, Snežana; Videnovic-Ivanovic, Jelica; Bresser, Paul; Jonkers, René; O'Reilly, Kate; Ho, Ling-Pei; Gaede, Karoline I; Zabel, Peter; Dubaniewicz, Anna; Marshall, Ben; Kieszko, Robert; Milanowski, Janusz; Günther, Andreas; Weihrich, Anette; Petrek, Martin; Kolek, Vitezslav; Keane, Michael P; O'Beirne, Sarah; Donnelly, Seamas; Haraldsdottir, Sigridur Olina; Jorundsdottir, Kristin B; Costabel, Ulrich; Bonella, Francesco; Wallaert, Benoît; Grah, Christian; Peroš-Golubičić, Tatjana; Luisetti, Mauritio; Kadija, Zamir; Pabst, Stefan; Grohé, Christian; Strausz, János; Vašáková, Martina; Sterclova, Martina; Millar, Ann; Homolka, Jiří; Slováková, Alena; Kendrick, Yvonne; Crawshaw, Anjali; Wuyts, Wim; Spencer, Lisa; Pfeifer, Michael; Valeyre, Dominique; Poletti, Venerino; Wirtz, Hubertus; Prasse, Antje; Schreiber, Stefan; Krawczak, Michael; Müller-Quernheim, Joachim
2018-01-01
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies. Copyright ©ERS 2018.
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Karadima, Georgia; Koutsis, Georgios; Raftopoulou, Maria; Floroskufi, Paraskewi; Karletidi, Karolina-Maria; Panas, Marios
2014-06-15
Charcot-Marie-Tooth (CMT) disease, the most common hereditary neuropathy, is clinically and genetically heterogeneous. X-linked CMT (CMTX) is usually caused by mutations in the gap junction protein b 1 gene (GJB1) coding for connexin 32 (Cx32). The clinical manifestations of CMTX are characterized by significant variability, with some patients exhibiting central nervous system (CNS) involvement. We report four novel mutations in GJB1, c.191G>A (p.Cys64Tyr), c.508G>T (p.Val170Phe), c.778A>G (p.Lys260Glu) and c.300C>G (p.His100Gln) identified in four unrelated Greek families. These mutations were characterized by variable phenotypic expression, including a family with the Roussy-Lévy syndrome, and three of them were associated with mild clinical CNS manifestations. Copyright © 2014. Published by Elsevier B.V.
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Purchase, Craig F; Moreau, Darek T R
2012-01-01
Genetic variation for phenotypic plasticity is ubiquitous and important. However, the scale of such variation including the relative variability present in reaction norms among different hierarchies of biological organization (e.g., individuals, populations, and closely related species) is unknown. Complicating interpretation is a trade-off in environmental scale. As plasticity can only be inferred over the range of environments tested, experiments focusing on fine tuned responses to normal or benign conditions may miss cryptic phenotypic variation expressed under novel or stressful environments. Here, we sought to discern the presence and shape of plasticity in the performance of brown trout sperm as a function of optimal to extremely stressful river pH, and demarcate if the reaction norm varies among genotypes. Our overarching goal was to determine if deteriorating environmental quality increases expressed variation among individuals. A more applied aim was to ascertain whether maintaining sperm performance over a wide pH range could help explain how brown trout are able to invade diverse river systems when transplanted outside of their native range. Individuals differed in their reaction norms of phenotypic expression of an important trait in response to environmental change. Cryptic variation was revealed under stressful conditions, evidenced through increasing among-individual variability. Importantly, data on population averages masked this variability in plasticity. In addition, canalized reaction norms in sperm swimming velocities of many individuals over a very large range in water chemistry may help explain why brown trout are able to colonize a wide variety of habitats. PMID:23145341
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2011-10-01
the hypothesis that SJL mice would have impaired neuronal dendrite generation, as has been observed in autism . This was our prediction due to the...phenotype for Autism and related alterations in CNS development PRINCIPAL INVESTIGATOR: Mark D. Noble, Ph.D. CONTRACTING...SUBTITLE Redox abnormalities as a vulnerability phenotype for Autism 5a. CONTRACT NUMBER And related alterations in CNS development 5b. GRANT
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Schinwelski, M; Kierdaszuk, B; Dulski, J; Tońska, K; Kodroń, A; Sitek, E J; Bartnik, E; Kamińska, A; Kwieciński, H; Sławek, J
2015-08-01
Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.
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Stabilization of the wheel running phenotype in mice.
Bowen, Robert S; Cates, Brittany E; Combs, Eric B; Dillard, Bryce M; Epting, Jessica T; Foster, Brittany R; Patterson, Shawnee V; Spivey, Thomas P
2016-03-01
Increased physical activity is well known to improve health and wellness by modifying the risks for many chronic diseases. Rodent wheel running behavior is a beneficial surrogate model to evaluate the biology of daily physical activity in humans. Upon initial exposure to a running wheel, individual mice differentially respond to the experience, which confounds the normal activity patterns exhibited in this otherwise repeatable phenotype. To promote phenotypic stability, a minimum seven-day (or greater) acclimation period is utilized. Although phenotypic stabilization is achieved during this 7-day period, data to support acclimation periods of this length are not currently available in the literature. The purpose of this project is to evaluate the wheel running response in C57BL/6j mice immediately following exposure to a running wheel. Twenty-eight male and thirty female C57BL/6j mice (Jackson Laboratory, Bar Harbor, ME) were acquired at eight weeks of age and were housed individually with free access to running wheels. Wheel running distance (km), duration (min), and speed (m∙min(-1)) were measured daily for fourteen days following initial housing. One-way ANOVAs were used to evaluate day-to-day differences in each wheel running character. Limits of agreement and mean difference statistics were calculated between days 1-13 (acclimating) and day 14 (acclimated) to assess day-to-day agreement between each parameter. Wheel running distance (males: F=5.653, p=2.14 × 10(-9); females: F=8.217, p=1.20 × 10(-14)), duration (males: F=2.613, p=0.001; females: F=4.529, p=3.28 × 10(-7)), and speed (males: F=7.803, p=1.22 × 10(-13); females: F=13.140, p=2.00 × 10(-16)) exhibited day-to-day differences. Tukey's HSD post-hoc testing indicated differences between early (males: days 1-3; females: days 1-6) and later (males: days >3; females: days >6) wheel running periods in distance and speed. Duration only exhibited an anomalous difference between wheel running on day 13 and wheel running on days 1 through 4 in males. In females, duration exhibited anomalous differences due to abnormally depressed wheel running on day 6 and abnormally elevated wheel running on day 14. Limits of agreement and mean difference statistics indicated stable phenotypic variability with an up-trending daily mean for distance and speed that stabilized within the first three days in males and within eight days in females. Duration exhibited stable variability after nine days in males and after seven days in females. Although it is common practice to allow a prolonged (≥ seven day) acclimation period prior to recording wheel running data, the current study suggests that phenotypic stabilization of all three indices is achieved at different times with distance and speed exhibiting stability by day three in males and day eight in females. Duration exhibits stability by day nine in males and day seven in females. Copyright © 2015 Elsevier Inc. All rights reserved.
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To characterize intra or within subject reproducibility and variability To characterize inter or across subject variability by adenoma phenotype (normal vs. adenoma) To evaluate biomarker expression in relation to long term adenoma recurrence
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Post, Andrew R.; Kurc, Tahsin; Cholleti, Sharath; Gao, Jingjing; Lin, Xia; Bornstein, William; Cantrell, Dedra; Levine, David; Hohmann, Sam; Saltz, Joel H.
2013-01-01
Objective To create an analytics platform for specifying and detecting clinical phenotypes and other derived variables in electronic health record (EHR) data for quality improvement investigations. Materials and Methods We have developed an architecture for an Analytic Information Warehouse (AIW). It supports transforming data represented in different physical schemas into a common data model, specifying derived variables in terms of the common model to enable their reuse, computing derived variables while enforcing invariants and ensuring correctness and consistency of data transformations, long-term curation of derived data, and export of derived data into standard analysis tools. It includes software that implements these features and a computing environment that enables secure high-performance access to and processing of large datasets extracted from EHRs. Results We have implemented and deployed the architecture in production locally. The software is available as open source. We have used it as part of hospital operations in a project to reduce rates of hospital readmission within 30 days. The project examined the association of over 100 derived variables representing disease and co-morbidity phenotypes with readmissions in five years of data from our institution’s clinical data warehouse and the UHC Clinical Database (CDB). The CDB contains administrative data from over 200 hospitals that are in academic medical centers or affiliated with such centers. Discussion and Conclusion A widely available platform for managing and detecting phenotypes in EHR data could accelerate the use of such data in quality improvement and comparative effectiveness studies. PMID:23402960
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Axelrod, Kevin; Sanchez, Alvaro; Gore, Jeff
2015-01-01
Microorganisms often exhibit a history-dependent phenotypic response after exposure to a stimulus which can be imperative for proper function. However, cells frequently experience unexpected environmental perturbations that might induce phenotypic switching. How cells maintain phenotypic states in the face of environmental fluctuations remains an open question. Here, we use environmental perturbations to characterize the resilience of phenotypic states in a synthetic gene network near a critical transition. We find that far from the critical transition an environmental perturbation may induce little to no phenotypic switching, whereas close to the critical transition the same perturbation can cause many cells to switch phenotypic states. This loss of resilience was observed for perturbations that interact directly with the gene circuit as well as for a variety of generic perturbations-such as salt, ethanol, or temperature shocks-that alter the state of the cell more broadly. We obtain qualitatively similar findings in natural gene circuits, such as the yeast GAL network. Our findings illustrate how phenotypic memory can become destabilized by environmental variability near a critical transition. DOI: http://dx.doi.org/10.7554/eLife.07935.001 PMID:26302311
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Mohammadi, Mohammadreza; Zarafshan, Hadi
2014-04-01
Siblings of children with autism are at a greater risk of experiencing behavioral and social problems. Previous researches had focused on environmental variables such as family history of autism spectrum disorders (ASDs), behavior problems in the child with an ASD, parental mental health problems, stressful life events and "broader autism phenotype" (BAP), while variables like parenting style and family function that are shown to influence children's behavioral and psychosocial adjustment are overlooked. The aim of the present study was to reveal how parenting style and family function as well as BAP effect psychological adjustment of siblings of children with autism. The Participants included 65 parents who had one child with an Autism Spectrum Disorder and one typically developing child. Of the children with ASDs, 40 were boys and 25 were girls; and they were diagnosed with ASDs by a psychiatrist based on DSM-IV-TR criteria and Autism Diagnostic Interview-Revised (ADI-R). The Persian versions of the six scales were used to collect data from the families. Pearson's correlation test and regression analysis were used to determine which variables were related to the psychological adjustment of sibling of children with ASDs and which variables predicted it better. Significant relationships were found between Strengths and Difficulties Questionnaire (SDQ) total difficulties, prosocial behaviors and ASDs symptoms severity, parenting styles and some aspects of family function. In addition, siblings who had more BAP characteristics had more behavior problems and less prosocial behavior. Behavioral problems increased and prosocial behavior decreased with permissive parenting style. Besides, both of authoritarian and authoritative parenting styles led to a decrease in behavioral problems and an increase in prosocial behaviors. Our findings revealed that some aspects of family function (affective responsiveness, roles, problem solving and behavior control) were significantly correlated with behavioral problems and prosocial behaviors in typically developing (TD) siblings of children with ASDs. Siblings of children with ASDs, due to genetic liability, are at a greater risk of psychological maladjustment. Furthermore, environmental factors like parenting styles and family function also have a significant effect on psychological maladjustment.
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De Cinque, Marianna; Palumbo, Orazio; Mazzucco, Ermelinda; Simone, Antonella; Palumbo, Pietro; Ciavatta, Renata; Maria, Giuliana; Ferese, Rosangela; Gambardella, Stefano; Angiolillo, Antonella; Carella, Massimo; Garofalo, Silvio
2017-01-01
Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype–phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes. PMID:29270193
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NASA Astrophysics Data System (ADS)
Mohd Asaari, Mohd Shahrimie; Mishra, Puneet; Mertens, Stien; Dhondt, Stijn; Inzé, Dirk; Wuyts, Nathalie; Scheunders, Paul
2018-04-01
The potential of close-range hyperspectral imaging (HSI) as a tool for detecting early drought stress responses in plants grown in a high-throughput plant phenotyping platform (HTPPP) was explored. Reflectance spectra from leaves in close-range imaging are highly influenced by plant geometry and its specific alignment towards the imaging system. This induces high uninformative variability in the recorded signals, whereas the spectral signature informing on plant biological traits remains undisclosed. A linear reflectance model that describes the effect of the distance and orientation of each pixel of a plant with respect to the imaging system was applied. By solving this model for the linear coefficients, the spectra were corrected for the uninformative illumination effects. This approach, however, was constrained by the requirement of a reference spectrum, which was difficult to obtain. As an alternative, the standard normal variate (SNV) normalisation method was applied to reduce this uninformative variability. Once the envisioned illumination effects were eliminated, the remaining differences in plant spectra were assumed to be related to changes in plant traits. To distinguish the stress-related phenomena from regular growth dynamics, a spectral analysis procedure was developed based on clustering, a supervised band selection, and a direct calculation of a spectral similarity measure against a reference. To test the significance of the discrimination between healthy and stressed plants, a statistical test was conducted using a one-way analysis of variance (ANOVA) technique. The proposed analysis techniques was validated with HSI data of maize plants (Zea mays L.) acquired in a HTPPP for early detection of drought stress in maize plant. Results showed that the pre-processing of reflectance spectra with the SNV effectively reduces the variability due to the expected illumination effects. The proposed spectral analysis method on the normalized spectra successfully detected drought stress from the third day of drought induction, confirming the potential of HSI for drought stress detection studies and further supporting its adoption in HTPPP.
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Gal, Moran; Levanon, Erez Y; Hujeirat, Yasir; Khayat, Morad; Pe'er, Jacob; Shalev, Stavit
2014-12-01
Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway. © 2014 Wiley Periodicals, Inc.
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Zaremba, J; Feil, S; Juszko, J; Myga, W; van Duijnhoven, G; Berger, W
1998-09-01
To describe the phenotypic variability in a Polish Norrie disease (ND) family associated with the missense mutation A63D. A patient with spared vision from a Polish ND family underwent detailed ophthalmological examinations including slit-lamp biomicroscopy, ultrasound (USG), angiography, Goldmann kinetic visual field, and electroretinography (ERG). Mutation screening was carried out using the single-strand conformation polymorphism (SSCP) technique and subsequent DNA sequencing of the coding part of the ND gene. A mutation was detected (exon 3, A63D) in a large Polish family with 12 affected males, all but one presenting with classical ND symptoms. In one male, partially preserved vision was observed up to 40 years of age (distance acuity of the right eye 1/50 and left eye 2/50). Slit-lamp examination revealed remnants of a persistent primary vitreous and hyaloid artery. Upon angiography, the retina was vascularized within the posterior pole but not in the periphery. The ERG revealed pathological changes characteristic for chorioretinal degenerations. Within one family, individuals with identical sequence alterations in the ND gene can show remarkable phenotypic variability of the ocular symptoms. These findings indicate the involvement of additional factors (epigenetic or genetic) in ocular pathogenesis of ND.
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Delgado-Lista, Javier; Perez-Martinez, Pablo; Solivera, Juan; Garcia-Rios, Antonio; Perez-Caballero, A I; Lovegrove, Julie A; Drevon, Christian A; Defoort, Catherine; Blaak, Ellen E; Dembinska-Kieć, Aldona; Risérus, Ulf; Herruzo-Gomez, Ezequiel; Camargo, Antonio; Ordovas, Jose M; Roche, Helen; Lopez-Miranda, José
2014-02-01
Metabolic syndrome (MetS) is a high-prevalence condition characterized by altered energy metabolism, insulin resistance, and elevated cardiovascular risk. Although many individual single nucleotide polymorphisms (SNPs) have been linked to certain MetS features, there are few studies analyzing the influence of SNPs on carbohydrate metabolism in MetS. A total of 904 SNPs (tag SNPs and functional SNPs) were tested for influence on 8 fasting and dynamic markers of carbohydrate metabolism, by performance of an intravenous glucose tolerance test in 450 participants in the LIPGENE study. From 382 initial gene-phenotype associations between SNPs and any phenotypic variables, 61 (16% of the preselected variables) remained significant after bootstrapping. Top SNPs affecting glucose metabolism variables were as follows: fasting glucose, rs26125 (PPARGC1B); fasting insulin, rs4759277 (LRP1); C-peptide, rs4759277 (LRP1); homeostasis assessment of insulin resistance, rs4759277 (LRP1); quantitative insulin sensitivity check index, rs184003 (AGER); sensitivity index, rs7301876 (ABCC9), acute insulin response to glucose, rs290481 (TCF7L2); and disposition index, rs12691 (CEBPA). We describe here the top SNPs linked to phenotypic features in carbohydrate metabolism among approximately 1000 candidate gene variations in fasting and postprandial samples of 450 patients with MetS from the LIPGENE study.
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Phenotypic Plasticity of Leaf Shape along a Temperature Gradient in Acer rubrum
Royer, Dana L.; Meyerson, Laura A.; Robertson, Kevin M.; Adams, Jonathan M.
2009-01-01
Both phenotypic plasticity and genetic determination can be important for understanding how plants respond to environmental change. However, little is known about the plastic response of leaf teeth and leaf dissection to temperature. This gap is critical because these leaf traits are commonly used to reconstruct paleoclimate from fossils, and such studies tacitly assume that traits measured from fossils reflect the environment at the time of their deposition, even during periods of rapid climate change. We measured leaf size and shape in Acer rubrum derived from four seed sources with a broad temperature range and grown for two years in two gardens with contrasting climates (Rhode Island and Florida). Leaves in the Rhode Island garden have more teeth and are more highly dissected than leaves in Florida from the same seed source. Plasticity in these variables accounts for at least 6–19 % of the total variance, while genetic differences among ecotypes probably account for at most 69–87 %. This study highlights the role of phenotypic plasticity in leaf-climate relationships. We suggest that variables related to tooth count and leaf dissection in A. rubrum can respond quickly to climate change, which increases confidence in paleoclimate methods that use these variables. PMID:19893620
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Louwers, Y V; Lao, O; Fauser, B C J M; Kayser, M; Laven, J S E
2014-10-01
It is well established that ethnicity is associated with the phenotype of polycystic ovary syndrome (PCOS). Self-reported ethnicity was shown to be an inaccurate proxy for ethnic origin in other disease traits, and it remains unclear how in PCOS patients self-reported ethnicity compares with a biological proxy such as genetic ancestry. We compared the impact of self-reported ethnicity versus genetic ancestry on PCOS and tested which of these 2 classifications better predicts the variability in phenotypic characteristics of PCOS. A total of 1499 PCOS patients from The Netherlands, comprising 11 self-reported ethnic groups of European, African, American, and Asian descent were genotyped with the Illumina 610K Quad BeadChip and merged with the data genotyped with the Illumina HumanHap650K available for the reference panel collected by the Human Genome Diversity Project (HGDP), in a collaboration with the Centre Etude Polymorphism Humain (CEPH), including 53 populations for ancestry reference. Algorithms for inferring genetic relationships among individuals, including multidimensional scaling and ADMIXTURE, were applied to recover genetic ancestry for each individual. Regression analysis was used to determine the best predictor for the variability in PCOS characteristics. The association between self-reported ethnicity and genetic ancestry was moderate. For amenorrhea, total follicle count, body mass index, SHBG, dehydroepiandrosterone sulfate, and insulin, mainly genetic ancestry clusters ended up in the final models (P values < .004), indicating that they explain a larger proportion of variability of these PCOS characteristics compared with self-reported ethnicity. Especially variability of insulin levels seems predominantly explained by genetic ancestry. Self-reported ancestry is not a perfect proxy for genetic ancestry in patients with PCOS, emphasizing that by using genetic ancestry data instead of self-reported ethnicity, PCOS-relevant misclassification can be avoided. Moreover, because genetic ancestry explained a larger proportion of phenotypic variability associated with PCOS than self-reported ethnicity, future studies should focus on genetic ancestry verification of PCOS patients for research questions and treatment as well as preventive strategies in these women.
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Epigenetic supersimilarity of monozygotic twin pairs
USDA-ARS?s Scientific Manuscript database
Monozygotic twins have long been studied to estimate heritability and explore epigenetic influences on phenotypic variation. The phenotypic and epigenetic similarities of monozygotic twins have been assumed to be largely due to their genetic identity. Here, by analyzing data from a genome-scale stud...
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Ortega-Mayagoitia, Elizabeth; Hernández-Martínez, Osvaldo; Ciros-Pérez, Jorge
2018-01-01
According to the Climatic Variability Hypothesis [CVH], thermal plasticity should be wider in organisms from temperate environments, but is unlikely to occur in tropical latitudes where temperature fluctuations are narrow. In copepods, food availability has been suggested as the main driver of phenotypic variability in adult size if the range of temperature change is less than 14°C. Leptodiaptomus garciai is a calanoid copepod inhabiting Lake Alchichica, a monomictic, tropical lake in Mexico that experiences regular, narrow temperature fluctuations but wide changes in phytoplankton availability. We investigated whether the seasonal fluctuations of temperature and food produce phenotypic variation in the life-history traits of this tropical species. We sampled L. garciai throughout a year and measured female size, egg size and number, and hatching success, along with temperature and phytoplankton biomass. The amplitude of the plastic responses was estimated with the Phenotypic Plasticity Index. This index was also computed for a published dataset of 84 copepod populations to look if there is a relationship between the amplitude of the phenotypic plasticity of adult size and seasonal change in temperature. The temperature annual range in Lake Alchichica was 3.2°C, whereas phytoplankton abundance varied 17-fold. A strong pattern of thermal plasticity in egg size and adult female size followed the inverse relationship with temperature commonly observed in temperate environments, although its adaptive value was not demonstrated. Egg number, relative reproductive effort and number of nauplii per female were clearly plastic to food availability, allowing organisms to increase their fitness. When comparing copepod species from different latitudes, we found that the magnitude of thermal plasticity of adult size is not related to the range of temperature variation; furthermore, thermal plasticity exists even in environments of limited temperature variation, where the response is more intense compared to temperate populations.
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Hernández-Martínez, Osvaldo; Ciros-Pérez, Jorge
2018-01-01
According to the Climatic Variability Hypothesis [CVH], thermal plasticity should be wider in organisms from temperate environments, but is unlikely to occur in tropical latitudes where temperature fluctuations are narrow. In copepods, food availability has been suggested as the main driver of phenotypic variability in adult size if the range of temperature change is less than 14°C. Leptodiaptomus garciai is a calanoid copepod inhabiting Lake Alchichica, a monomictic, tropical lake in Mexico that experiences regular, narrow temperature fluctuations but wide changes in phytoplankton availability. We investigated whether the seasonal fluctuations of temperature and food produce phenotypic variation in the life-history traits of this tropical species. We sampled L. garciai throughout a year and measured female size, egg size and number, and hatching success, along with temperature and phytoplankton biomass. The amplitude of the plastic responses was estimated with the Phenotypic Plasticity Index. This index was also computed for a published dataset of 84 copepod populations to look if there is a relationship between the amplitude of the phenotypic plasticity of adult size and seasonal change in temperature. The temperature annual range in Lake Alchichica was 3.2°C, whereas phytoplankton abundance varied 17-fold. A strong pattern of thermal plasticity in egg size and adult female size followed the inverse relationship with temperature commonly observed in temperate environments, although its adaptive value was not demonstrated. Egg number, relative reproductive effort and number of nauplii per female were clearly plastic to food availability, allowing organisms to increase their fitness. When comparing copepod species from different latitudes, we found that the magnitude of thermal plasticity of adult size is not related to the range of temperature variation; furthermore, thermal plasticity exists even in environments of limited temperature variation, where the response is more intense compared to temperate populations. PMID:29708999
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Testing evolutionary hypotheses for phenotypic divergence using landscape genetics.
Funk, W Chris; Murphy, Melanie A
2010-02-01
Understanding the evolutionary causes of phenotypic variation among populations has long been a central theme in evolutionary biology. Several factors can influence phenotypic divergence, including geographic isolation, genetic drift, divergent natural or sexual selection, and phenotypic plasticity. But the relative importance of these factors in generating phenotypic divergence in nature is still a tantalizing and unresolved problem in evolutionary biology. The origin and maintenance of phenotypic divergence is also at the root of many ongoing debates in evolutionary biology, such as the extent to which gene flow constrains adaptive divergence (Garant et al. 2007) and the relative importance of genetic drift, natural selection, and sexual selection in initiating reproductive isolation and speciation (Coyne & Orr 2004). In this issue, Wang & Summers (2010) test the causes of one of the most fantastic examples of phenotypic divergence in nature: colour pattern divergence among populations of the strawberry poison frog (Dendrobates pumilio) in Panama and Costa Rica (Fig. 1). This study provides a beautiful example of the use of the emerging field of landscape genetics to differentiate among hypotheses for phenotypic divergence. Using landscape genetic analyses, Wang & Summers were able to reject the hypotheses that colour pattern divergence is due to isolation-by-distance (IBD) or landscape resistance. Instead, the hypothesis left standing is that colour divergence is due to divergent selection, in turn driving reproductive isolation among populations with different colour morphs. More generally, this study provides a wonderful example of how the emerging field of landscape genetics, which has primarily been applied to questions in conservation and ecology, now plays an essential role in evolutionary research.
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Butnariu, Lăcrămioara; Rusu, Cristina; Caba, Lavinia; Pânzaru, Monica; Braha, Elena; Grămescu, Mihaela; Popescu, Roxana; Bujoranu, C; Gorduza, E V
2013-01-01
Trisomy X (47,XXX) is a gonosomal aneuploidy characterized by the presence of an extra X chromosome in a female person. Usually the diagnosis is established made postnatally by chromosome analysis in patients with suggestive clinical signs. Clinical signs vary by age. In prepubertal patients have a growth retardation associated with uncharacteristic facial dysmorphism, mild mental retardation with behavioral disorders, plus clinical signs of ovarian dysgenesis, postpubertal. We analyzed retrospectively the genotype - phenotype correlations for a selected group of 36 patients diagnosed with trisomy X (homogeneous or mosaic) by cytogenetic methods (X chromatin and karyotype). Analysis of the clinical data of 36 patients diagnosed with trisomy X and correlation with the results of X chromatin and karyotype. Clinical signs detected in patients with homogeneous trisomy X 47,XXX (22.22%), mosaic 46,XX/47,XXX (16.66%) or 47,XXX/48,XXXX (5.55%) were prepubertal, growth retardation associated with dysmorphic facial (upslanted palpebral fissure, epichantus, thin lips) and postpubertal, signs of ovarian dysgenesis (secondary amenorrhea, early menopause). The phenotype of patients with different gonosomal mosaic corresponding to Turner syndrome, incorporating a cell line with trisomy X (55.55%) was variable, correlated with the type of chromosomal abnormalities detected. The results of our study are similar to those obtained in other studies and emphasizes that phenotypic variability of patients with trisomy X feature makes it difficult to genotype - phenotype correlations.
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Diversity of ARSACS mutations in French-Canadians.
Thiffault, I; Dicaire, M J; Tetreault, M; Huang, K N; Demers-Lamarche, J; Bernard, G; Duquette, A; Larivière, R; Gehring, K; Montpetit, A; McPherson, P S; Richter, A; Montermini, L; Mercier, J; Mitchell, G A; Dupré, N; Prévost, C; Bouchard, J P; Mathieu, J; Brais, B
2013-01-01
The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.
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Quillet, Edwige; Bégout, Marie-Laure; Aupérin, Benoit; Khaw, Hooi Ling; Millot, Sandie; Valotaire, Claudiane; Kernéis, Thierry; Labbé, Laurent; Prunet, Patrick; Dupont-Nivet, Mathilde
2017-01-01
Adaptive phenotypic plasticity is a key component of the ability of organisms to cope with changing environmental conditions. Fish have been shown to exhibit a substantial level of phenotypic plasticity in response to abiotic and biotic factors. In the present study, we investigate the link between environmental sensitivity assessed globally (revealed by phenotypic variation in body weight) and more targeted physiological and behavioral indicators that are generally used to assess the sensitivity of a fish to environmental stressors. We took advantage of original biological material, the rainbow trout isogenic lines, which allowed the disentangling of the genetic and environmental parts of the phenotypic variance. Ten lines were characterized for the changes of body weight variability (weight measurements taken every month during 18 months), the plasma cortisol response to confinement stress (3 challenges) and a set of selected behavioral indicators. This study unambiguously demonstrated the existence of genetic determinism of environmental sensitivity, with some lines being particularly sensitive to environmental fluctuations and others rather insensitive. Correlations between coefficient of variation (CV) for body weight and behavioral and physiological traits were observed. This confirmed that CV for body weight could be used as an indicator of environmental sensitivity. As the relationship between indicators (CV weight, risk-taking, exploration and cortisol) was shown to be likely depending on the nature and intensity of the stressor, the joint use of several indicators should help to investigate the biological complexity of environmental sensitivity. PMID:29253015
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Lucarelli, Marco; Bruno, Sabina Maria; Pierandrei, Silvia; Ferraguti, Giampiero; Stamato, Antonella; Narzi, Fabiana; Amato, Annalisa; Cimino, Giuseppe; Bertasi, Serenella; Quattrucci, Serena; Strom, Roberto
2015-01-01
Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype–phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype–phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype–phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID:25910067
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lindsay, E.A.; Shaffer, L.G.; Greenberg, F.
DiGeorge anomaly (DGA) and velo-cardio-facial syndrome (VCFS) are frequently associated with monosomy of chromosome region 22q11. Most patients have a submicroscopic deletion, recently estimated to be at least 1-2 Mb. It is not clear whether individuals who present with only some of the features of these conditions have the deletion, and if so, whether the size of the deletion varies from those with more classic phenotypes. We have used fluorescence in situ hybridization (FISH) to assess the deletion status of 85 individuals referred to us for molecular analysis, with a wide range of DGA-like or VCFS-like clinical features. The testmore » probe used was the cosmid sc11.1, which detects two loci about 2 Mb apart in 22q11.2. Twenty-four patients carried the deletion. Of the deleted patients, most had classic DGA or VCFS phenotypes, but 6 deleted patients had mild phenotypes, including 2 with minor facial anomalies and velopharyngeal incompetence as the only presenting signs. Despite the great phenotypic variability among the deleted patients, none had a deletion smaller than the 2-Mb region defined by sc11.1. Smaller deletions were not detected in patients with particularly suggestive phenotypes who were not deleted for sc11.1, even when tested with two other probes from the DGA/VCFS region. 24 refs., 2 figs., 2 tabs.« less
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Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene.
Graul-Neumann, Luitgard M; Hausser, Ingrid; Essayie, Maximilian; Rauch, Anita; Kraus, Cornelia
2008-04-15
Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. Only seven ADCL families with mutations in the elastin gene (ELN) have been described previously. We present morphological and molecular genetic studies in a cutis laxa kindred with a previously undescribed highly variable phenotype caused by a novel ELN mutation c.1621 C > T. The proband presented with severe cutis laxa, severe congenital lung disease previously undescribed in ADCL and pulmonary artery disease, which is often seen in ARCL but rare in ADCL. He also developed infantile spasms (OMIM 308350; West syndrome), which we consider a coincidental association although recessive cutis laxa or even digenic inheritance cannot be excluded. Electron microscopy of the proband's dermis revealed only mild rarefication of elastic fibers (in contrast to most recessive cutis laxa types). Apart from mild elastic fiber fragmentation, dermal morphology of the proband's father was within normal range. Molecular analysis of the ELN gene using genomic DNA from blood and RNA from cultured skin fibroblasts indicated a novel splice site mutation in the proband and his clinically healthy father. Analysis of ELN expression in fibroblasts provided evidence for a dominant-negative effect in the child, while due to an unknown mechanism, the father showed haploinsufficiency which might explain the significant clinical variability. Copyright 2008 Wiley-Liss, Inc.
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Giacomin, Renata M.; Ruas, Paulo M.; Ruas, Eduardo A.; Barbieri, Rosa L.; Rodrigues, Rosana
2018-01-01
Capsicum baccatum is one of the main pepper species grown and consumed in South America. In Brazil, it is commonly cultivated by family farmers, using mostly the genotypes bishop's hat genotypes (locally cambuci) and red chili pepper (dedo-de-moça). This study had the objective of characterizing 116 C. baccatum accessions from different regions of Brazil, based on morphological fruit descriptors and AFLP (Amplified Fragment Length Polymorphisms) markers. Broad phenotypic variability among the C. baccatum accessions was detected when using morphological fruit descriptors. The Ward modified location model (Ward-MLM) discriminated five groups, based mainly on fruit shape. Six combinations of AFLP primers detected polymorphism in 97.93% of the 2466 identified bands, indicating the high genetic variability in the accessions. The UPGMA coincided with the Bayesian clustering analysis and three large groups were formed, separating the wild variety C. baccatum var. praetermissum from the other accessions. There was no relation between genetic distance and geographical origin of the accessions, probably due to the intense exchange of fruits and seeds between farmers. Morphological descriptors used together with AFLP markers proved efficient in detecting the levels of genetic variability among the accessions maintained in the germplasm collections. These results can be used as an additional source of helpful information to be exploited in C. baccatum breeding programs. PMID:29758023
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Oral Appliance Treatment Response and Polysomnographic Phenotypes of Obstructive Sleep Apnea
Sutherland, Kate; Takaya, Hisashi; Qian, Jin; Petocz, Peter; Ng, Andrew T.; Cistulli, Peter A.
2015-01-01
Study Objectives: Mandibular advancement splints (MAS) are an effective treatment for obstructive sleep apnea (OSA); however, therapeutic response is variable. Younger age, female gender, less obesity, and milder and supine-dependent OSA have variably been associated with treatment success in relatively small samples. Our objective was to utilize a large cohort of MAS treated patients (1) to compare efficacy across patients with different phenotypes of OSA and (2) to assess demographic, anthropometric, and polysomnography variables as treatment response predictors. Methods: Retrospective analysis of MAS-treated patients participating in clinical trials in sleep centers in Sydney, Australia between years 2000–2013. All studies used equivalent customized two-piece MAS devices and treatment protocols. Treatment response was defined as (1) apnea-hypopnea index (AHI) < 5/h, (2) AHI < 10/h and ≥ 50% reduction, and (3) ≥ 50% AHI reduction. Results: A total of 425 patients (109 female) were included (age 51.2 ± 10.9 years, BMI 29.2 ± 5.0 kg/m2). MAS reduced AHI by 50.3% ± 50.7% across the group. Supine-predominant OSA patients had lower treatment response rates than non-positional OSA (e.g., 36% vs. 59% for AHI < 10/h). REM-predominant OSA showed a lower response rate than either NREM or non-stage dependent OSA. In prediction modelling, age, baseline AHI, and anthropometric variables were predictive of MAS treatment outcome but not OSA phenotype. Gender was not associated with treatment outcome. Conclusions: Lower MAS treatment response rates were observed in supine and REM sleep. In a large sample, we confirm that demographic, anthropometric, and polysomnographic data only weakly inform about MAS efficacy, supporting the need for alternative objective prediction methods to reliably select patients for MAS treatment. Citation: Sutherland K, Takaya H, Qian J, Petocz P, Ng AT, Cistulli PA. Oral appliance treatment response and polysomnographic phenotypes of obstructive sleep apnea. J Clin Sleep Med 2015;11(8):861–868. PMID:25845897
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Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T
2016-10-01
Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.
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Nowacka-Woszuk, J; Switonski, M
2010-02-01
Numerous mutations of the human androgen receptor (AR) gene cause an intersexual phenotype, called the androgen insensitivity syndrome. The intersexual phenotype is also quite often diagnosed in dogs. The aim of this study was to conduct a comparative analysis of the entire coding sequence (eight exons) of the AR gene in healthy and four intersex dogs, as well as in three other canids (the red fox, arctic fox and Chinese raccoon dog). The coding sequence of the studied species appeared to be conserved (similarity above 97%) and polymorphism was found in exon 1 only. Altogether, 2 SNPs were identified in healthy dogs, 14 in red foxes, 16 in arctic foxes and 6 were found in Chinese raccoon dogs, respectively. Moreover, a variable number of tandem repeats (CAG and CAA), encoding an array of glutamines, was also observed in this exon. The CAA codon numbers were invariable within species, but the CAG repeats were polymorphic. The highest number of the CAG and CAA repeats was found in dogs (from 40 to 42) and the observed variability was similar in intersex and healthy dogs. In the other canids the variability fell within the following ranges: 29-37 (red fox), 37-39 (arctic fox) and 29-32 (Chinese raccoon dog). In addition, a polymorphic microsatellite marker in intron 2 was found in the dog, red fox and Chinese raccoon dog. It was concluded that the polymorphism level of the AR gene in the dog was lower than in the other canids and none of the detected polymorphisms, including variability of the CAG tandem repeats, could be related with the intersexual phenotype of the studied dogs.
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Phenotypic variability among café-au-lait macules in neurofibromatosis type 1.
Boyd, Kevin P; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R; Theos, Amy
2010-09-01
Café-au-lait macules (CALMs) in neurofibromatosis type 1 (NF1) are an early and accessible phenotype in NF1, but have not been extensively studied. We sought to more fully characterize the phenotype of CALMs in patients with NF1. In all, 24 patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the genetics department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin based on its absorption of visible light. The major response was defined as the difference between the mean melanin from the CALM and the mean melanin from the surrounding skin. The major response for each spot was compared with spots within an individual and across individuals in the study population. There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, P < .0001) and secondly to interpersonal variability (33.0%, P < .0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. The study was performed on a small population of patients and the method has not yet been used extensively for this purpose. CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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The role of phenotype structure in the population dynamics of gypsy moth in the Lower Dnieper region
Nikolaj M. Derevyanko
1991-01-01
One of the characteristic features of the gypsy moth population in the Lower Dnieper area is its variable larval coloring. Phenotype frequency has been recorded over the years in separate micropopulations at different density levels. The data show the population to consist mainly of gray larvae in all life stages, and their abundance varying from 85 to 99.6 percent....
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Vertically transmitted fecal IgA levels distinguish extra-chromosomal phenotypic variation
Wallace, Meghan A.; D, Carey-Ann; Burnham; Virgin, Herbert W.; Stappenbeck, Thaddeus S.
2014-01-01
Summary The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control1-5. In many cases, the microbiota is the presumed culprit of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice6,7. In conventionally raised mice, the microbiome is transmitted from the dam2,8,9. Here we show that microbially–driven dichotomous fecal IgA levels in WT mice within the same facility mimic the effects of chromosomal mutations. We observed in multiple facilities that vertically-transmissible bacteria in IgA-Low mice dominantly lowered fecal IgA levels in IgA-High mice after cohousing or fecal transplantation. In response to injury, IgA-Low mice showed increased damage that was transferable by fecal transplantation and driven by fecal IgA differences. We found that bacteria from IgA-Low mice degraded the secretory component (SC) of SIgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose fecal IgA as one marker of microbial variability and conclude that cohousing and/or fecal transplantation enables analysis of progeny from different dams. PMID:25686606
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Rietschel, Liz; Streit, Fabian; Zhu, Gu; McAloney, Kerrie; Frank, Josef; Couvy-Duchesne, Baptiste; Witt, Stephanie H; Binz, Tina M; McGrath, John; Hickie, Ian B; Hansell, Narelle K; Wright, Margaret J; Gillespie, Nathan A; Forstner, Andreas J; Schulze, Thomas G; Wüst, Stefan; Nöthen, Markus M; Baumgartner, Markus R; Walker, Brian R; Crawford, Andrew A; Colodro-Conde, Lucía; Medland, Sarah E; Martin, Nicholas G; Rietschel, Marcella
2017-11-10
Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
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Platform for combined analysis of functional and biomolecular phenotypes of the same cell.
Kelbauskas, L; Ashili, S; Zeng, J; Rezaie, A; Lee, K; Derkach, D; Ueberroth, B; Gao, W; Paulson, T; Wang, H; Tian, Y; Smith, D; Reid, B; Meldrum, Deirdre R
2017-03-16
Functional and molecular cell-to-cell variability is pivotal at the cellular, tissue and whole-organism levels. Yet, the ultimate goal of directly correlating the function of the individual cell with its biomolecular profile remains elusive. We present a platform for integrated analysis of functional and transcriptional phenotypes in the same single cells. We investigated changes in the cellular respiration and gene expression diversity resulting from adaptation to repeated episodes of acute hypoxia in a premalignant progression model. We find differential, progression stage-specific alterations in phenotypic heterogeneity and identify cells with aberrant phenotypes. To our knowledge, this study is the first demonstration of an integrated approach to elucidate how heterogeneity at the transcriptional level manifests in the physiologic profile of individual cells in the context of disease progression.
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Ars, Elisabet; Torra, Roser
2017-10-01
A significant percentage of adults (10%) and children (20%) on renal replacement therapy have an inherited kidney disease (IKD). The new genomic era, ushered in by the next generation sequencing techniques, has contributed to the identification of new genes and facilitated the genetic diagnosis of the highly heterogeneous IKDs. Consequently, it has also allowed the reclassification of diseases and has broadened the phenotypic spectrum of many classical IKDs. Various genetic, epigenetic and environmental factors may explain 'atypical' phenotypes. In this article, we examine different mechanisms that may contribute to phenotypic variability and also provide case examples that illustrate them. The aim of the article is to raise awareness, among nephrologists and geneticists, of rare presentations that IKDs may show, to facilitate diagnosis.
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Shimada, Aya; Takagi, Masaki; Nagashima, Yuka; Miyai, Kentaro; Hasegawa, Yukihiro
2016-01-01
Mutations in OTX2 cause hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency (CPHD), which are commonly detected in association with severe eye abnormalities, including anophthalmia or microphthalmia. Pituitary phenotypes of OTX2 mutation carriers are highly variable; however, ACTH deficiency during the neonatal period is not common in previous reports. We report a novel missense OTX2 (R89P) mutation in a CPHD patient with severe hypoglycemia in the neonatal period due to ACTH deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery (ICA). We identified a novel heterozygous mutation in OTX2 (c.266G>C, p.R89P). R89P OTX2 showed markedly reduced transcriptional activity of HESX1 and POU1F1 reporters compared with wild-type OTX2. A dominant negative effect was noted only in the transcription analysis with POU1F1 promoter. Electrophoretic mobility shift assay experiments showed that R89P OTX2 abrogated DNA-binding ability. OTX2 mutations can cause ACTH deficiency in the neonatal period. Our study also shows that OTX2 mutations are associated with agenesis of the ICA. To the best of our knowledge, this is the first report of a transcription factor gene mutation, which was identified due to agenesis of the ICA of a patient with CPHD. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in OTX2. © 2016 S. Karger AG, Basel.
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Orlenko, Alena; Chi, Peter B; Liberles, David A
2017-05-25
Understanding the genotype-phenotype map is fundamental to our understanding of genomes. Genes do not function independently, but rather as part of networks or pathways. In the case of metabolic pathways, flux through the pathway is an important next layer of biological organization up from the individual gene or protein. Flux control in metabolic pathways, reflecting the importance of mutation to individual enzyme genes, may be evolutionarily variable due to the role of mutation-selection-drift balance. The evolutionary stability of rate limiting steps and the patterns of inter-molecular co-evolution were evaluated in a simulated pathway with a system out of equilibrium due to fluctuating selection, population size, or positive directional selection, to contrast with those under stabilizing selection. Depending upon the underlying population genetic regime, fluctuating population size was found to increase the evolutionary stability of rate limiting steps in some scenarios. This result was linked to patterns of local adaptation of the population. Further, during positive directional selection, as with more complex mutational scenarios, an increase in the observation of inter-molecular co-evolution was observed. Differences in patterns of evolution when systems are in and out of equilibrium, including during positive directional selection may lead to predictable differences in observed patterns for divergent evolutionary scenarios. In particular, this result might be harnessed to detect differences between compensatory processes and directional processes at the pathway level based upon evolutionary observations in individual proteins. Detecting functional shifts in pathways reflects an important milestone in predicting when changes in genotypes result in changes in phenotypes.
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Coevolutionary dynamics of phenotypic diversity and contingent cooperation
Wang, Long
2017-01-01
Phenotypic diversity is considered beneficial to the evolution of contingent cooperation, in which cooperators channel their help preferentially towards others of similar phenotypes. However, it remains largely unclear how phenotypic variation arises in the first place and thus leads to the construction of phenotypic complexity. Here we propose a mathematical model to study the coevolutionary dynamics of phenotypic diversity and contingent cooperation. Unlike previous models, our model does not assume any prescribed level of phenotypic diversity, but rather lets it be an evolvable trait. Each individual expresses one phenotype at a time and only the phenotypes expressed are visible to others. Moreover, individuals can differ in their potential of phenotypic variation, which is characterized by the number of distinct phenotypes they can randomly switch to. Each individual incurs a cost proportional to the number of potentially expressible phenotypes so as to retain phenotypic variation and expression. Our results show that phenotypic diversity coevolves with contingent cooperation under a wide range of conditions and that there exists an optimal level of phenotypic diversity best promoting contingent cooperation. It pays for contingent cooperators to elevate their potential of phenotypic variation, thereby increasing their opportunities of establishing cooperation via novel phenotypes, as these new phenotypes serve as secret tags that are difficult for defector to discover and chase after. We also find that evolved high levels of phenotypic diversity can occasionally collapse due to the invasion of defector mutants, suggesting that cooperation and phenotypic diversity can mutually reinforce each other. Thus, our results provide new insights into better understanding the coevolution of cooperation and phenotypic diversity. PMID:28141806
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Forno, Erick; Gogna, Mudita; Cepeda, Alfonso; Yañez, Anahi; Solé, Dirceu; Cooper, Philip; Avila, Lydiana; Soto-Quiros, Manuel; Castro-Rodriguez, Jose A; Celedón, Juan C
2015-09-01
Consistent with the diversity of Latin America, there is profound variability in asthma burden among and within countries in this region. Regional variation in asthma prevalence is likely multifactorial and due to genetics, perinatal exposures, diet, obesity, tobacco use, indoor and outdoor pollutants, psychosocial stress and microbial or parasitic infections. Similarly, non-uniform progress in asthma management leads to regional variability in disease morbidity. Future studies of distinct asthma phenotypes should follow-up well-characterised Latin American subgroups and examine risk factors that are unique or common in Latin America (eg, stress and violence, parasitic infections and use of biomass fuels for cooking). Because most Latin American countries share the same barriers to asthma management, concerted and multifaceted public health and research efforts are needed, including approaches to curtail tobacco use, campaigns to improve asthma treatment, broadening access to care and clinical trials of non-pharmacological interventions (eg, replacing biomass fuels with gas or electric stoves). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Extreme intrafamilial variability of Saudi brothers with primary hyperoxaluria type 1
Alfadhel, Majid; Alhasan, Khalid A; Alotaibi, Mohammed; Al Fakeeh, Khalid
2012-01-01
Background Primary hyperoxaluria type 1 (PH1) is characterized by progressive renal insufficiency culminating in end-stage renal disease, and a wide range of clinical features related to systemic oxalosis in different organs. It is caused by autosomal recessive deficiency of alanine:glyoxylate aminotransferase due to a defect in AGXT gene. Case report Two brothers (one 6 months old; the other 2 years old) presented with acute renal failure and urinary tract infection respectively. PH1 was confirmed by high urinary oxalate level, demonstration of oxalate crystals in bone biopsy, and pathogenic homozygous known AGXT gene mutation. Despite the same genetic background, same sex, and shared environment, the outcome of the two siblings differs widely. While one of them died earlier with end-stage renal disease and multiorgan failure caused by systemic oxalosis, the older brother is pyridoxine responsive with normal development and renal function. Conclusion Clinicians should be aware of extreme intrafamilial variability of PH1 and international registries are needed to characterize the genotype-phenotype correlation in such disorder. PMID:22956877
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Alacrima as a Harbinger of Adrenal Insufficiency in a Child with Allgrove (AAA) Syndrome
Brown, Brande; Agdere, Levon; Muntean, Cornelia; David, Karen
2016-01-01
Patient: Female, 6 Final Diagnosis: Allgrove syndrome Symptoms: Achalasia • adrenal insufficiency • alacrima Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Rare disease Background: Allgrove syndrome, or triple “A” syndrome (3A syndrome), is a rare autosomal recessive syndrome with variable phenotype, and an estimated prevalence of 1 per 1,000,000 individuals. Patients usually display the triad of achalasia, alacrima, and adrenocorticotropin (ACTH) insensitive adrenal insufficiency, though the presentation is inconsistent. Case Report: Here, the authors report a case of Allgrove syndrome in a pediatric patient with delayed diagnosis in order to raise awareness of this potentially fatal disease as a differential diagnosis of alacrima. Conclusions: The prevalence of Allgrove syndrome may be much higher as a result of underdiagnosis and missed diagnosis due to the variable presentation and sudden unexplained childhood death from adrenal crisis. The authors review the characteristic symptoms of Allgrove syndrome in relation to the case study in order to avoid missed or delayed diagnosis, potentially decreasing morbidity, and mortality in those affected by this disease. PMID:27698338
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Phenotypic plasticity in sex pheromone production in Bicyclus anynana butterflies
Dion, Emilie; Monteiro, Antónia; Yew, Joanne Y.
2016-01-01
Phenotypic plasticity refers to the environmental control of phenotypes. Cues experienced during development (developmental plasticity) or during adulthood (acclimatization) can both affect adult phenotypes. Phenotypic plasticity has been described in many traits but examples of developmental plasticity in physiological traits, in particular, remain scarce. We examined developmental plasticity and acclimatization in pheromone production in the butterfly Bicyclus anynana in response to rearing temperature. B. anynana lives in the African tropics where warm rearing temperatures of the wet season produce active males that court and females that choose, whereas cooler temperatures of the dry season lead to choosy less active males and courting females. We hypothesized that if male pheromone production is costly, it should be reduced in the dry season form. After describing the ultrastructure of pheromone producing cells, we showed that dry season males produced significantly less sex pheromones than wet season males, partly due to acclimatization and partly due to developmental plasticity. Variation in levels of one of the compounds is associated with differential regulation of a pheromone biosynthetic enzyme gene. This plasticity might be an adaptation to minimize pheromone production costs during the stressful dry season. PMID:27966579
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Heterogeneous Stock Rat: A Unique Animal Model for Mapping Genes Influencing Bone Fragility
Alam, Imranul; Koller, Daniel L.; Sun, Qiwei; Roeder, Ryan K.; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J.; Turner, Charles H.; Foroud, Tatiana
2011-01-01
Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in 4 inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high-resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from 5 of the 8 progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. PMID:21334473
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Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.
Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana
2011-05-01
Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright © 2010 Elsevier Inc. All rights reserved.
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USDA-ARS?s Scientific Manuscript database
A new species of eriophyoid mite, Metaculus diplotaxi n.sp. inhabiting Diplotaxis tenuifolia (L.) DC., has been described from Serbia. To investigate interspecific variability between Metaculus spp., on three different host plants of Brassicaceae we analyzed phenotypic variability of morphological t...
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Advanced phenotyping and phenotype data analysis for the study of plant growth and development
Rahaman, Md. Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming
2015-01-01
Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060
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Picker-Minh, Sylvie; Mignot, Cyril; Doummar, Diane; Hashem, Mais; Faqeih, Eissa; Josset, Patrice; Dubern, Béatrice; Alkuraya, Fowzan S; Kraemer, Nadine; Kaindl, Angela M
2016-04-29
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.
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Presentation and Treatment of Poland Anomaly.
Buckwalter V, Joseph A; Shah, Apurva S
2016-12-01
Background: Poland anomaly is a sporadic, phenotypically variable congenital condition usually characterized by unilateral pectoral muscle agenesis and ipsilateral hand deformity. Methods: A comprehensive review of the medical literature on Poland anomaly was performed using a Medline search. Results: Poland anomaly is a sporadic, phenotypically variable congenital condition usually characterized by unilateral, simple syndactyly with ipsilateral limb hypoplasia and pectoralis muscle agenesis. Operative management of syndactyly in Poland anomaly is determined by the severity of hand involvement and the resulting anatomical dysfunction. Syndactyly reconstruction is recommended in all but the mildest cases because most patients with Poland anomaly have notable brachydactyly, and digital separation can improve functional length. Conclusions: Improved understanding the etiology and presentation of Poland anomaly can improve clinician recognition and management of this rare congenital condition.
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Abdullah, Wan Zawiah Wan; Mackey, Bernard M; Karatzas, Kimon Andreas G
2018-01-01
Salmonella is an important foodborne pathogen, whose ability to resist stress and survive can vary among strains. This variability is normally not taken into account when predictions are made about survival in foods with negative consequences. Therefore, we examined the contribution of variable phenotypic properties to survival under stress in 10 Salmonella serovars. One strain (Typhimurium 10) was intentionally RpoS-negative; however, another strain (Heidelberg) showed an rpoS mutation, rendering it inactive. We assessed an array of characteristics (motility, biofilm formation, bile resistance, acid resistance, and colony morphology) that show major variability among strains associated with a 10- to 19-fold difference between the highest and the lowest strain for most characteristics. The RpoS status of isolates did not affect variability in the characteristics, with the exception of resistance to NaCl, acetic acid, lactic acid, and the combination of acetic acid and salt, where the variability between the highest and the lowest strain was reduced to 3.1-fold, 1.7-fold, 2-fold, and 1.7-fold, respectively, showing that variability was significant among RpoS-positive strains. Furthermore, we also found a good correlation between acid resistance and lysine decarboxylase activity, showing its importance for acid resistance, and demonstrated a possible role of RpoS in the lysine decarboxylase activity in Salmonella.
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Verweij, Karin J.H.; Creemers, H.E.; Korhonen, T.; Latvala, A.; Dick, D.M.; Rose, R. J.; Huizink, A.C.; Kaprio, J.
2016-01-01
Aims To determine 1) the prospective associations of conduct problems during early adolescence with tobacco, alcohol and cannabis use in young adulthood and 2) to what extent these associations are due to overlapping genetic versus environmental influences. Design A prospective twin study using biometric twin modelling. Setting Finland. Participants 1847 Finnish twins (943 males and 904 females) were interviewed in early adolescence, of which 73% (N=1353, 640 males and 713 females) were retained in young adulthood. Measurements Symptom counts of conduct disorder (CD) criteria were obtained from a semi-structured clinical interview in early adolescence (age 14–15 years, M=14.2, SD=0.15). Frequency of alcohol, tobacco, and cannabis use was obtained from a semi-structured clinical interview in young adulthood (age 19.9–26.6 years, M=22.4, SD=0.7). Findings We found modest to moderate phenotypic correlations (r=0.16 to 0.35) between early adolescent CD symptoms and substance use in young adulthood. In males, the phenotypic correlations of CD symptoms with all three substance use variables are largely explained by overlapping genetic influences. In females, overlapping shared environmental influences predominantly explain the phenotypic correlation between CD symptoms and tobacco and cannabis use. Conclusions Conduct disorder symptoms in early adolescence appear to moderately predict substance use in early adulthood. In males, genetic influences seem to be most important in explaining the relationship between conduct disorder symptoms and substance use whereas in females, shared environmental influences seem to be most important. PMID:26748618
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Wasson, Anton P; Chiu, Grace S; Zwart, Alexander B; Binns, Timothy R
2017-01-01
Ensuring future food security for a growing population while climate change and urban sprawl put pressure on agricultural land will require sustainable intensification of current farming practices. For the crop breeder this means producing higher crop yields with less resources due to greater environmental stresses. While easy gains in crop yield have been made mostly "above ground," little progress has been made "below ground"; and yet it is these root system traits that can improve productivity and resistance to drought stress. Wheat pre-breeders use soil coring and core-break counts to phenotype root architecture traits, with data collected on rooting density for hundreds of genotypes in small increments of depth. The measured densities are both large datasets and highly variable even within the same genotype, hence, any rigorous, comprehensive statistical analysis of such complex field data would be technically challenging. Traditionally, most attributes of the field data are therefore discarded in favor of simple numerical summary descriptors which retain much of the high variability exhibited by the raw data. This poses practical challenges: although plant scientists have established that root traits do drive resource capture in crops, traits that are more randomly (rather than genetically) determined are difficult to breed for. In this paper we develop a hierarchical nonlinear mixed modeling approach that utilizes the complete field data for wheat genotypes to fit, under the Bayesian paradigm, an "idealized" relative intensity function for the root distribution over depth. Our approach was used to determine heritability : how much of the variation between field samples was purely random vs. being mechanistically driven by the plant genetics? Based on the genotypic intensity functions, the overall heritability estimate was 0.62 (95% Bayesian confidence interval was 0.52 to 0.71). Despite root count profiles that were statistically very noisy, our approach led to denoised profiles which exhibited rigorously discernible phenotypic traits. Profile-specific traits could be representative of a genotype, and thus, used as a quantitative tool to associate phenotypic traits with specific genotypes. This would allow breeders to select for whole root system distributions appropriate for sustainable intensification, and inform policy for mitigating crop yield risk and food insecurity.
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Good Epidemiologic Practice in Retinitis Pigmentosa: From Phenotyping to Biobanking
Chizzolini, Marzio; Galan, Alessandro; Milan, Elisabeth; Sebastiani, Adolfo; Costagliola, Ciro; Parmeggiani, Francesco
2011-01-01
Inherited retinal dystrophies, such as retinitis pigmentosa (RP), include a group of relatively rare hereditary diseases caused by mutations in genes that code for proteins involved in the maintenance and function of the photoreceptor cells (cones and rods). The different forms of RP consist of progressive neurodegenerative disorders which are generally related to various and severe limitations of visual performances. In the course of typical RP (rod-cone dystrophy), the affected individuals first experience night-blindness and/or visual field constriction (secondary to rod dysfunctions), followed by variable alterations of the central vision (due to cone damages). On the other hand, during the atypical form of RP (cone-rod dystrophy), the cone’s functionalities are prevalently disrupted in comparison with the rod’s ones. The basic diagnosis of RP relies upon the documentation of unremitting loss in photoreceptor activity by electroretinogram and/or visual field testing. The prevalence of all RP typologies is variably reported in about one case for each 3000-5000 individuals, with a total of about two millions of affected persons worldwide. The inherited retinal dystrophies are sometimes the epiphenomenon of a complex framework (syndromic RP), but more often they represent an isolated disorder (about 85-90 % of cases). Although 200 causative RP mutations have been hitherto detected in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the analyzed patients with RP. Not only the RP genotypes are very heterogeneous, but also the patients with the same mutation can be affected by different phenotypic manifestations. RP can be inherited as autosomal dominant, autosomal recessive or X-linked trait, and many sporadic forms are diagnosed in patients with no affected relatives. Dissecting the clinico-genetic complexity of RP has become an attainable objective by means of large-scale research projects, in which the collaboration between ophthalmologists, geneticists, and epidemiologists becomes a crucial aspect. In the present review, the main issues regarding clinical phenotyping and epidemiologic criticisms of RP are focused, especially highlighting the importance of both standardization of the diagnostic protocols and appropriateness of the disease’s registration systems. PMID:22131871
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Messai, Habib; Farman, Muhammad; Sarraj-Laabidi, Abir; Hammami-Semmar, Asma; Semmar, Nabil
2016-01-01
Background. Olive oils (OOs) show high chemical variability due to several factors of genetic, environmental and anthropic types. Genetic and environmental factors are responsible for natural compositions and polymorphic diversification resulting in different varietal patterns and phenotypes. Anthropic factors, however, are at the origin of different blends’ preparation leading to normative, labelled or adulterated commercial products. Control of complex OO samples requires their (i) characterization by specific markers; (ii) authentication by fingerprint patterns; and (iii) monitoring by traceability analysis. Methods. These quality control and management aims require the use of several multivariate statistical tools: specificity highlighting requires ordination methods; authentication checking calls for classification and pattern recognition methods; traceability analysis implies the use of network-based approaches able to separate or extract mixed information and memorized signals from complex matrices. Results. This chapter presents a review of different chemometrics methods applied for the control of OO variability from metabolic and physical-chemical measured characteristics. The different chemometrics methods are illustrated by different study cases on monovarietal and blended OO originated from different countries. Conclusion. Chemometrics tools offer multiple ways for quantitative evaluations and qualitative control of complex chemical variability of OO in relation to several intrinsic and extrinsic factors. PMID:28231172
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Termites promote resistance of decomposition to spatiotemporal variability in rainfall.
Veldhuis, Michiel P; Laso, Francisco J; Olff, Han; Berg, Matty P
2017-02-01
The ecological impact of rapid environmental change will depend on the resistance of key ecosystems processes, which may be promoted by species that exert strong control over local environmental conditions. Recent theoretical work suggests that macrodetritivores increase the resistance of African savanna ecosystems to changing climatic conditions, but experimental evidence is lacking. We examined the effect of large fungus-growing termites and other non-fungus-growing macrodetritivores on decomposition rates empirically with strong spatiotemporal variability in rainfall and temperature. Non-fungus-growing larger macrodetritivores (earthworms, woodlice, millipedes) promoted decomposition rates relative to microbes and small soil fauna (+34%) but both groups reduced their activities with decreasing rainfall. However, fungus-growing termites increased decomposition rates strongest (+123%) under the most water-limited conditions, making overall decomposition rates mostly independent from rainfall. We conclude that fungus-growing termites are of special importance in decoupling decomposition rates from spatiotemporal variability in rainfall due to the buffered environment they create within their extended phenotype (mounds), that allows decomposition to continue when abiotic conditions outside are less favorable. This points at a wider class of possibly important ecological processes, where soil-plant-animal interactions decouple ecosystem processes from large-scale climatic gradients. This may strongly alter predictions from current climate change models. © 2016 by the Ecological Society of America.
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Andrews, Katrina A; Ascher, David B; Pires, Douglas Eduardo Valente; Barnes, Daniel R; Vialard, Lindsey; Casey, Ruth T; Bradshaw, Nicola; Adlard, Julian; Aylwin, Simon; Brennan, Paul; Brewer, Carole; Cole, Trevor; Cook, Jackie A; Davidson, Rosemarie; Donaldson, Alan; Fryer, Alan; Greenhalgh, Lynn; Hodgson, Shirley V; Irving, Richard; Lalloo, Fiona; McConachie, Michelle; McConnell, Vivienne P M; Morrison, Patrick J; Murday, Victoria; Park, Soo-Mi; Simpson, Helen L; Snape, Katie; Stewart, Susan; Tomkins, Susan E; Wallis, Yvonne; Izatt, Louise; Goudie, David; Lindsay, Robert S; Perry, Colin G; Woodward, Emma R; Antoniou, Antonis C; Maher, Eamonn R
2018-06-01
Germline pathogenic variants in SDHB/SDHC / SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC / SDHD mutation carriers. A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC / SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD: p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC / SDHD mutation carriers. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Transgenerational Epigenetics: The Role of Maternal Effects in Cardiovascular Development
Ho, Dao H.
2014-01-01
Transgenerational epigenetics, the study of non-genetic transfer of information from one generation to the next, has gained much attention in the past few decades due to the fact that, in many instances, epigenetic processes outweigh direct genetic processes in the manifestation of aberrant phenotypes across several generations. Maternal effects, or the influences of maternal environment, phenotype, and/or genotype on offsprings’ phenotypes, independently of the offsprings’ genotypes, are a subcategory of transgenerational epigenetics. Due to the intimate role of the mother during early development in animals, there is much interest in investigating the means by which maternal effects can shape the individual. Maternal effects are responsible for cellular organization, determination of the body axis, initiation and maturation of organ systems, and physiological performance of a wide variety of species and biological systems. The cardiovascular system is the first to become functional and can significantly influence the development of other organ systems. Thus, it is important to elucidate the role of maternal effects in cardiovascular development, and to understand its impact on adult cardiovascular health. Topics to be addressed include: (1) how and when do maternal effects change the developmental trajectory of the cardiovascular system to permanently alter the adult’s cardiovascular phenotype, (2) what molecular mechanisms have been associated with maternally induced cardiovascular phenotypes, and (3) what are the evolutionary implications of maternally mediated changes in cardiovascular phenotype? PMID:24813463
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Torres-Dowdall, Julián; Handelsman, Corey A; Reznick, David N; Ghalambor, Cameron K
2012-11-01
Divergent selection pressures across environments can result in phenotypic differentiation that is due to local adaptation, phenotypic plasticity, or both. Trinidadian guppies exhibit local adaptation to the presence or absence of predators, but the degree to which predator-induced plasticity contributes to population differentiation is less clear. We conducted common garden experiments on guppies obtained from two drainages containing populations adapted to high- and low-predation environments. We reared full-siblings from all populations in treatments simulating the presumed ancestral (predator cues present) and derived (predator cues absent) conditions and measured water column use, head morphology, and size at maturity. When reared in presence of predator cues, all populations had phenotypes that were typical of a high-predation ecotype. However, when reared in the absence of predator cues, guppies from high- and low-predation regimes differed in head morphology and size at maturity; the qualitative nature of these differences corresponded to those that characterize adaptive phenotypes in high- versus low-predation environments. Thus, divergence in plasticity is due to phenotypic differences between high- and low-predation populations when reared in the absence of predator cues. These results suggest that plasticity might initially play an important role during colonization of novel environments, and then evolve as a by-product of adaptation to the derived environment. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.
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Passot, Sixtine; Moreno-Ortega, Beatriz; Moukouanga, Daniel; Balsera, Crispulo; Guyomarc'h, Soazig; Lucas, Mikael; Lobet, Guillaume; Laplaze, Laurent; Muller, Bertrand; Guédon, Yann
2018-05-11
Recent progress in root phenotyping has focused mainly on increasing throughput for genetic studies while identifying root developmental patterns has been comparatively underexplored. We introduce a new phenotyping pipeline for producing high-quality spatio-temporal root system development data and identifying developmental patterns within these data. The SmartRoot image analysis system and temporal and spatial statistical models were applied to two cereals, pearl millet (Pennisetum glaucum) and maize (Zea mays). Semi-Markov switching linear models were used to cluster lateral roots based on their growth rate profiles. These models revealed three types of lateral roots with similar characteristics in both species. The first type corresponds to fast and accelerating roots, the second to rapidly arrested roots, and the third to an intermediate type where roots cease elongation after a few days. These types of lateral roots were retrieved in different proportions in a maize mutant affected in auxin signaling, while the first most vigorous type was absent in maize plants exposed to severe shading. Moreover, the classification of growth rate profiles was mirrored by a ranking of anatomical traits in pearl millet. Potential dependencies in the succession of lateral root types along the primary root were then analyzed using variable-order Markov chains. The lateral root type was not influenced by the shootward neighbor root type or by the distance from this root. This random branching pattern of primary roots was remarkably conserved, despite the high variability of root systems in both species. Our phenotyping pipeline opens the door to exploring the genetic variability of lateral root developmental patterns. {copyright, serif} 2018 American Society of Plant Biologists. All rights reserved.
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van den Broek, M; Bolat, I; Nijkamp, J F; Ramos, E; Luttik, M A H; Koopman, F; Geertman, J M; de Ridder, D; Pronk, J T; Daran, J-M
2015-09-01
Lager brewing strains of Saccharomyces pastorianus are natural interspecific hybrids originating from the spontaneous hybridization of Saccharomyces cerevisiae and Saccharomyces eubayanus. Over the past 500 years, S. pastorianus has been domesticated to become one of the most important industrial microorganisms. Production of lager-type beers requires a set of essential phenotypes, including the ability to ferment maltose and maltotriose at low temperature, the production of flavors and aromas, and the ability to flocculate. Understanding of the molecular basis of complex brewing-related phenotypic traits is a prerequisite for rational strain improvement. While genome sequences have been reported, the variability and dynamics of S. pastorianus genomes have not been investigated in detail. Here, using deep sequencing and chromosome copy number analysis, we showed that S. pastorianus strain CBS1483 exhibited extensive aneuploidy. This was confirmed by quantitative PCR and by flow cytometry. As a direct consequence of this aneuploidy, a massive number of sequence variants was identified, leading to at least 1,800 additional protein variants in S. pastorianus CBS1483. Analysis of eight additional S. pastorianus strains revealed that the previously defined group I strains showed comparable karyotypes, while group II strains showed large interstrain karyotypic variability. Comparison of three strains with nearly identical genome sequences revealed substantial chromosome copy number variation, which may contribute to strain-specific phenotypic traits. The observed variability of lager yeast genomes demonstrates that systematic linking of genotype to phenotype requires a three-dimensional genome analysis encompassing physical chromosomal structures, the copy number of individual chromosomes or chromosomal regions, and the allelic variation of copies of individual genes. Copyright © 2015, van den Broek et al.
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van den Broek, M.; Bolat, I.; Nijkamp, J. F.; Ramos, E.; Luttik, M. A. H.; Koopman, F.; Geertman, J. M.; de Ridder, D.; Pronk, J. T.
2015-01-01
Lager brewing strains of Saccharomyces pastorianus are natural interspecific hybrids originating from the spontaneous hybridization of Saccharomyces cerevisiae and Saccharomyces eubayanus. Over the past 500 years, S. pastorianus has been domesticated to become one of the most important industrial microorganisms. Production of lager-type beers requires a set of essential phenotypes, including the ability to ferment maltose and maltotriose at low temperature, the production of flavors and aromas, and the ability to flocculate. Understanding of the molecular basis of complex brewing-related phenotypic traits is a prerequisite for rational strain improvement. While genome sequences have been reported, the variability and dynamics of S. pastorianus genomes have not been investigated in detail. Here, using deep sequencing and chromosome copy number analysis, we showed that S. pastorianus strain CBS1483 exhibited extensive aneuploidy. This was confirmed by quantitative PCR and by flow cytometry. As a direct consequence of this aneuploidy, a massive number of sequence variants was identified, leading to at least 1,800 additional protein variants in S. pastorianus CBS1483. Analysis of eight additional S. pastorianus strains revealed that the previously defined group I strains showed comparable karyotypes, while group II strains showed large interstrain karyotypic variability. Comparison of three strains with nearly identical genome sequences revealed substantial chromosome copy number variation, which may contribute to strain-specific phenotypic traits. The observed variability of lager yeast genomes demonstrates that systematic linking of genotype to phenotype requires a three-dimensional genome analysis encompassing physical chromosomal structures, the copy number of individual chromosomes or chromosomal regions, and the allelic variation of copies of individual genes. PMID:26150454
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Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes
Mefford, Heather C.; Sharp, Andrew J.; Baker, Carl; Itsara, Andy; Jiang, Zhaoshi; Buysse, Karen; Huang, Shuwen; Maloney, Viv K.; Crolla, John A.; Baralle, Diana; Collins, Amanda; Mercer, Catherine; Norga, Koen; de Ravel, Thomy; Devriendt, Koen; Bongers, Ernie M.H.F.; de Leeuw, Nicole; Reardon, William; Gimelli, Stefania; Bena, Frederique; Hennekam, Raoul C.; Male, Alison; Gaunt, Lorraine; Clayton-Smith, Jill; Simonic, Ingrid; Park, Soo Mi; Mehta, Sarju G.; Nik-Zainal, Serena; Woods, C. Geoffrey; Firth, Helen V.; Parkin, Georgina; Fichera, Marco; Reitano, Santina; Giudice, Mariangela Lo; Li, Kelly E.; Casuga, Iris; Broomer, Adam; Conrad, Bernard; Schwerzmann, Markus; Räber, Lorenz; Gallati, Sabina; Striano, Pasquale; Coppola, Antonietta; Tolmie, John L.; Tobias, Edward S.; Lilley, Chris; Armengol, Lluis; Spysschaert, Yves; Verloo, Patrick; De Coene, Anja; Goossens, Linde; Mortier, Geert; Speleman, Frank; van Binsbergen, Ellen; Nelen, Marcel R.; Hochstenbach, Ron; Poot, Martin; Gallagher, Louise; Gill, Michael; McClellan, Jon; King, Mary-Claire; Regan, Regina; Skinner, Cindy; Stevenson, Roger E.; Antonarakis, Stylianos E.; Chen, Caifu; Estivill, Xavier; Menten, Björn; Gimelli, Giorgio; Gribble, Susan; Schwartz, Stuart; Sutcliffe, James S.; Walsh, Tom; Knight, Samantha J.L.; Sebat, Jonathan; Romano, Corrado; Schwartz, Charles E.; Veltman, Joris A.; de Vries, Bert B.A.; Vermeesch, Joris R.; Barber, John C.K.; Willatt, Lionel; Tassabehji, May; Eichler, Evan E.
2009-01-01
BACKGROUND Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10−7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in the nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype. PMID:18784092
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The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong, Jessica X.; Buckingham, Kati J.; Jhangiani, Shalini N.; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D.; Harrell, Tanya M.; McMillin, Margaret J.; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H.; Doheny, Kimberly; Scott, Alan F.; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P. Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E.; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V. Reid; Tabor, Holly K.; Leal, Suzanne M.; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A.; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R.; Lifton, Richard P.; Valle, David; Nickerson, Deborah A.; Bamshad, Michael J.
2015-01-01
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families. PMID:26166479
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Ramírez-Prado, Dolores; Cortés, Ernesto; Aguilar-Segura, María Soledad; Gil-Guillén, Vicente Francisco
2016-01-01
In January 2012, a review of the cases of chromosome 15q24 microdeletion syndrome was published. However, this study did not include inferential statistics. The aims of the present study were to update the literature search and calculate confidence intervals for the prevalence of each phenotype using bootstrap methodology. Published case reports of patients with the syndrome that included detailed information about breakpoints and phenotype were sought and 36 were included. Deletions in megabase (Mb) pairs were determined to calculate the size of the interstitial deletion of the phenotypes studied in 2012. To determine confidence intervals for the prevalence of the phenotype and the interstitial loss, we used bootstrap methodology. Using the bootstrap percentiles method, we found wide variability in the prevalence of the different phenotypes (3–100%). The mean interstitial deletion size was 2.72 Mb (95% CI [2.35–3.10 Mb]). In comparison with our work, which expanded the literature search by 45 months, there were differences in the prevalence of 17% of the phenotypes, indicating that more studies are needed to analyze this rare disease. PMID:26925314
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Systematic Association of Genes to Phenotypes by Genome and Literature Mining
Jensen, Lars J; Perez-Iratxeta, Carolina; Kaczanowski, Szymon; Hooper, Sean D; Andrade, Miguel A
2005-01-01
One of the major challenges of functional genomics is to unravel the connection between genotype and phenotype. So far no global analysis has attempted to explore those connections in the light of the large phenotypic variability seen in nature. Here, we use an unsupervised, systematic approach for associating genes and phenotypic characteristics that combines literature mining with comparative genome analysis. We first mine the MEDLINE literature database for terms that reflect phenotypic similarities of species. Subsequently we predict the likely genomic determinants: genes specifically present in the respective genomes. In a global analysis involving 92 prokaryotic genomes we retrieve 323 clusters containing a total of 2,700 significant gene–phenotype associations. Some clusters contain mostly known relationships, such as genes involved in motility or plant degradation, often with additional hypothetical proteins associated with those phenotypes. Other clusters comprise unexpected associations; for example, a group of terms related to food and spoilage is linked to genes predicted to be involved in bacterial food poisoning. Among the clusters, we observe an enrichment of pathogenicity-related associations, suggesting that the approach reveals many novel genes likely to play a role in infectious diseases. PMID:15799710
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Circadian Phenotype Composition is a Major Predictor of Diurnal Physical Performance in Teams.
Facer-Childs, Elise; Brandstaetter, Roland
2015-01-01
Team performance is a complex phenomenon involving numerous influencing factors including physiology, psychology, and management. Biological rhythms and the impact of circadian phenotype have not been studied for their contribution to this array of factors so far despite our knowledge of the circadian regulation of key physiological processes involved in physical and mental performance. This study involved 216 individuals from 12 different teams who were categorized into circadian phenotypes using the novel RBUB chronometric test. The composition of circadian phenotypes within each team was used to model predicted daily team performance profiles based on physical performance tests. Our results show that the composition of circadian phenotypes within teams is variable and unpredictable. Predicted physical peak performance ranged from 1:52 to 8:59 p.m. with performance levels fluctuating by up to 14.88% over the course of the day. The major predictor for peak performance time in the course of a day in a team is the occurrence of late circadian phenotypes. We conclude that circadian phenotype is a performance indicator in teams that allows new insight and a better understanding of team performance variation in the course of a day as often observed in different groupings of individuals.
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Circadian Phenotype Composition is a Major Predictor of Diurnal Physical Performance in Teams
Facer-Childs, Elise; Brandstaetter, Roland
2015-01-01
Team performance is a complex phenomenon involving numerous influencing factors including physiology, psychology, and management. Biological rhythms and the impact of circadian phenotype have not been studied for their contribution to this array of factors so far despite our knowledge of the circadian regulation of key physiological processes involved in physical and mental performance. This study involved 216 individuals from 12 different teams who were categorized into circadian phenotypes using the novel RBUB chronometric test. The composition of circadian phenotypes within each team was used to model predicted daily team performance profiles based on physical performance tests. Our results show that the composition of circadian phenotypes within teams is variable and unpredictable. Predicted physical peak performance ranged from 1:52 to 8:59 p.m. with performance levels fluctuating by up to 14.88% over the course of the day. The major predictor for peak performance time in the course of a day in a team is the occurrence of late circadian phenotypes. We conclude that circadian phenotype is a performance indicator in teams that allows new insight and a better understanding of team performance variation in the course of a day as often observed in different groupings of individuals. PMID:26483754
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Bryan, Angela D; Jakicic, John M; Hunter, Christine M; Evans, Mary E; Yanovski, Susan Z; Epstein, Leonard H
2017-10-01
Risk for obesity is determined by a complex mix of genetics and lifetime exposures at multiple levels, from the metabolic milieu to psychosocial and environmental influences. These phenotypic differences underlie the variability in risk for obesity and response to weight management interventions, including differences in physical activity and sedentary behavior. As part of a broader effort focused on behavioral and psychological phenotyping in obesity research, the National Institutes of Health convened a multidisciplinary workshop to explore the state of the science in behavioral and psychological phenotyping in humans to explain individual differences in physical activity, both as a risk factor for obesity development and in response to activity-enhancing interventions. Understanding the behavioral and psychological phenotypes that contribute to differences in physical activity and sedentary behavior could allow for improved treatment matching and inform new targets for tailored, innovative, and effective weight management interventions. This summary provides the rationale for identifying psychological and behavioral phenotypes relevant to physical activity and identifies opportunities for future research to better understand, define, measure, and validate putative phenotypic factors and characterize emerging phenotypes that are empirically associated with initiation of physical activity, response to intervention, and sustained changes in physical activity. © 2017 The Obesity Society.
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Nonlinear Epigenetic Variance: Review and Simulations
ERIC Educational Resources Information Center
Kan, Kees-Jan; Ploeger, Annemie; Raijmakers, Maartje E. J.; Dolan, Conor V.; van Der Maas, Han L. J.
2010-01-01
We present a review of empirical evidence that suggests that a substantial portion of phenotypic variance is due to nonlinear (epigenetic) processes during ontogenesis. The role of such processes as a source of phenotypic variance in human behaviour genetic studies is not fully appreciated. In addition to our review, we present simulation studies…
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Nochomovitz, Yigal D; Li, Hao
2006-03-14
Deciphering the design principles for regulatory networks is fundamental to an understanding of biological systems. We have explored the mapping from the space of network topologies to the space of dynamical phenotypes for small networks. Using exhaustive enumeration of a simple model of three- and four-node networks, we demonstrate that certain dynamical phenotypes can be generated by an atypically broad spectrum of network topologies. Such dynamical outputs are highly designable, much like certain protein structures can be designed by an unusually broad spectrum of sequences. The network topologies that encode a highly designable dynamical phenotype possess two classes of connections: a fully conserved core of dedicated connections that encodes the stable dynamical phenotype and a partially conserved set of variable connections that controls the transient dynamical flow. By comparing the topologies and dynamics of the three- and four-node network ensembles, we observe a large number of instances of the phenomenon of "mutational buffering," whereby addition of a fourth node suppresses phenotypic variation amongst a set of three-node networks.
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Organelles – understanding noise and heterogeneity in cell biology at an intermediate scale
Chang, Amy Y.
2017-01-01
ABSTRACT Many studies over the years have shown that non-genetic mechanisms for producing cell-to-cell variation can lead to highly variable behaviors across genetically identical populations of cells. Most work to date has focused on gene expression noise as the primary source of phenotypic heterogeneity, yet other sources may also contribute. In this Commentary, we explore organelle-level heterogeneity as a potential secondary source of cellular ‘noise’ that contributes to phenotypic heterogeneity. We explore mechanisms for generating organelle heterogeneity and present evidence of functional links between organelle morphology and cellular behavior. Given the many instances in which molecular-level heterogeneity has been linked to phenotypic heterogeneity, we posit that organelle heterogeneity may similarly contribute to overall phenotypic heterogeneity and underline the importance of studying organelle heterogeneity to develop a more comprehensive understanding of phenotypic heterogeneity. Finally, we conclude with a discussion of the medical challenges associated with phenotypic heterogeneity and outline how improved methods for characterizing and controlling this heterogeneity may lead to improved therapeutic strategies and outcomes for patients. PMID:28183729
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Johnson, M T J
2007-01-01
Monocarpic plant species, where reproduction is fatal, frequently exhibit variation in the length of their prereproductive period prior to flowering. If this life-history variation in flowering strategy has a genetic basis, genotype-by-environment interactions (G x E) may maintain phenotypic diversity in flowering strategy. The native monocarpic plant Common Evening Primrose (Oenothera biennis L., Onagraceae) exhibits phenotypic variation for annual vs. biennial flowering strategies. I tested whether there was a genetic basis to variation in flowering strategy in O. biennis, and whether environmental variation causes G x E that imposes variable selection on flowering strategy. In a field experiment, I randomized more than 900 plants from 14 clonal families (genotypes) into five distinct habitats that represented a natural productivity gradient. G x E strongly affected the lifetime fruit production of O. biennis, with the rank-order in relative fitness of genotypes changing substantially between habitats. I detected genetic variation in annual vs. biennial strategies in most habitats, as well as a G x E effect on flowering strategy. This variation in flowering strategy was correlated with genetic variation in relative fitness, and phenotypic and genotypic selection analyses revealed that environmental variation resulted in variable directional selection on annual vs. biennial strategies. Specifically, a biennial strategy was favoured in moderately productive environments, whereas an annual strategy was favoured in low-productivity environments. These results highlight the importance of variable selection for the maintenance of genetic variation in the life-history strategy of a monocarpic plant.
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The case-fatality rate of meningococcal disease in Catalonia, 1990-1997.
Domínguez, Angela; Cardeñosa, Neus; Pañella, Helena; Orcau, Angels; Companys, Maria; Alseda, Miquel; Oviedo, Manuel; Carmona, Glòria; Minguell, Sofia; Salleras, Lluis
2004-01-01
The objective was to analyse the case-fatality rate (CFR) of meningococcal disease (MD) in Catalonia, Spain. A retrospective study was carried out. Clinical histories of cases of MD reported for the period 1990-1997 in Catalonia were reviewed. For all cases, the variables gender, age, clinical type, y of presentation, province, phenotype and death by meningococcal disease were collected. The association between death and the other variables was studied by bivariate and unconditional logistic regression analysis. In the 2343 cases studied there were 146 deaths (6.2%) due to meningococcal disease. The CFR was higher in females (OR: 1.5, 95%CI: 1.1-2.1), in the 20 to 49 y (OR: 2.4, 95%CI: 1.2-4.9) and > or = 50 y (OR: 5.3, 95%CI: 2.8-10.1) age groups, in cases with septicaemia (OR: 2.4, 95%CI: 1.6-3.5), in the cases produced by serogroup A (OR: 4.7, 95%CI: 1.0-23.4) and in cases occurring during 1993 (OR: 2.1, 95%CI: 1.1-4.1) or in the province of Lleida (OR: 2.9, 95%CI: 1.2-7.2). In the multivariate analysis, death was associated with the 20-49 y age group (OR: 3.9, 95%CI: 1.8-8.4), the > or = 50 y age group (OR: 7.3, 95%CI: 3.6-14.7), septicaemia (OR: 3.1; 95%CI: 2.0-4.7) and residing in the province of Lleida (OR: 3.2; 95%CI: 1.2-8.5). The CFR of meningococcal disease in Catalonia was not associated with the emergent phenotype C:2b:P1.2,5 strain, which caused an outbreak in other regions of Spain.
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Noonan like appearance and familial deletion of the 22q11 Shprintzen-DiGeorge critical region
DOE Office of Scientific and Technical Information (OSTI.GOV)
Piussan, C.; Mathieu, M.; Boudailliez, B.
1994-09-01
Shprintzen velocardiofacial syndrome (VCFS) and reported cases of autosomal dominant DiGeorge sequence (DGS) both belong to a heterogeneous developmental field defect due to the familial segregation of a 22q11 deletion. Two sisters present with mental retardation, dysmorphia and multiple congenital anomalies. The eldest has a Noonan-like appearance; short stature, short webbed neck, low posterior hairline, widely spaced nipples, hemivertebrae, speech disability and mild hypoparathyroidism. Her younger sister has prominent eyes, floppy ears, pulmonary valvular stenosis, hypoplastic right kidney, left multicystic kidney, hypoparathyroidism and renal failure causing death at age 3. Their retarded mother has a typical Shprintzen phenotype and nomore » hypoparathyroidism. A deletion of the critical DiGeorge-Shprintzen conotruncal malformation region was found by FISH in the mother and her Noonan-like daughter. In the mother`s family exist 3 cleft palates, an imperforate anus, a stillbirth and one infant died at age 3 months because of heart malformation. To our knowledge, another case of Noonan-like appearance in a DG patient affected with monosomy 22q11 has been reported in 1992 by Wilson et al. Whether resulting from the hemizygosity of a gene or from the deletion of contiguous genes, the wide DGS-VCFS spectrum encompasses quite variable phenotypes, discordant for palatal and conotruncal defects as well as for hypoparathyroidism, dysmorphic features and multiple congenital anomalies. Physical mapping of both the large 22q11 region commonly lost and the smallest deletion sufficient to produce DGS has been done and may account for the broadening spectrum, the variable expression and the frequently delayed diagnosis of this syndrome.« less
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Taguchi-Shiobara, Fumio; Ota, Tatsuya; Ebana, Kaworu; Ookawa, Taiichiro; Yamasaki, Masanori; Tanabata, Takanari; Yamanouchi, Utako; Wu, Jianzhong; Ono, Nozomi; Nonoue, Yasunori; Nagata, Kazufumi; Fukuoka, Shuichi; Hirabayashi, Hideyuki; Yamamoto, Toshio; Yano, Masahiro
2015-10-01
We investigated the natural variations in the flag leaf morphology of rice. We conducted a principal component analysis based on nine flag leaf morphology traits using 103 accessions from the National Institute of Agrobiological Sciences Core Collection. The first component explained 39% of total variance, and the variable with highest loading was the width of the flag leaf (WFL). A genome-wide association analysis of 102 diverse Japanese accessions revealed that marker RM6992 on chromosome 4 was highly associated with WFL. In analyses of progenies derived from a cross between Takanari and Akenohoshi, the most significant quantitative trait locus (QTL) for WFL was in a 10.3-kb region containing the NARROW LEAF 1 (NAL1) gene, located 0.4 Mb downstream of RM6992. Analyses of chromosomal segment substitution lines indicated that a mutation (G1509A single-nucleotide mutation, causing an R233H amino acid substitution in NAL1) was present at the QTL. This explained 13 and 20% of total variability in WFL and the distance between small vascular bundles, respectively. The mutation apparently occurred during rice domestication and spread into japonica, tropical japonica, and indica subgroups. Notably, one accession, Phulba, had a NAL1 allele encoding only the N-terminal, or one-fourth, of the wild-type peptide. Given that the Phulba allele and the histidine-type allele showed essentially the same phenotype, the histidine-type allele was regarded as malfunctional. The phenotypes of transgenic plants varied depending on the ratio of histidine-type alleles to arginine-type alleles, raising the possibility that H(233)-type products function differently from and compete with R(233)-type products. Copyright © 2015 by the Genetics Society of America.
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Life History Traits of an Extended Longevity Phenotype of Drosophila melanogaster.
Deepashree, S; Shivanandappa, T; Ramesh, S R
2017-01-01
Aging or senescence is a complex biological phenomenon. Artificially selected Drosophila for extended longevity is one of the experimental models used to understand the mechanisms involved in aging and to test various theories. To examine the life history traits and biochemical defenses in relation to aging in an extended longevity phenotype of Drosophila melanogaster. Life history traits viz., survivability, fecundity, development time, dry weight, wing size, lipid content, starvation, desiccation and cold resistances, locomotory ability, antioxidant enzyme activities and reactive oxygen species level between control and selected lines of D. melanogaster were investigated. In our model of Drosophila, extended longevity is associated with no trade-off in fecundity and shows variable resistance to environmental stress such as starvation, cold and desiccation. Enhanced biochemical defense involving the antioxidant enzymes was positively correlated with longevity. Extended longevity phenotypes of Drosophila represent genomic plasticity associated with variable life history traits attributed to the genetic background of the progenitor population and the environment of selection. Oxidative stress resistance seems to be a significant factor in longevity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Genetic and epigenetic contributions to the cortical phenotype in mammals☆
Larsen, DeLaine D.; Krubitzer, Leah
2008-01-01
One aspect of cortical organization, cortical field size, is variable both within and across species. The observed variability arises from a variety of sources, including genes intrinsic to the neocortex and a number of extrinsic and epigenetic factors. Genes intrinsic to the cortex are directly involved in the development and specification of cortical fields and are regulated from both signaling centers located outside of the neocortex, which secrete diffusible molecules, and the expression of transcription factors within the neocortex. In addition, extrinsic factors such as the type, location and density of sensory receptor arrays and how these receptor arrays are utilized, are also strongly related to cortical field size. Epigenetic factors including the relative activity patterns generated by the different types of physical stimuli in a given environment also contribute to differences in cortical organization, including cortical field size. Since both genetic and epigenetic factors contribute to cortical organization, some aspects of the cortical phenotype evolve, while other aspects of the cortical phenotype persist only if the environment in which an individual develops is relatively stable. PMID:18331904
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Evaluation and integration of disparate classification systems for clefts of the lip
Wang, Kathie H.; Heike, Carrie L.; Clarkson, Melissa D.; Mejino, Jose L. V.; Brinkley, James F.; Tse, Raymond W.; Birgfeld, Craig B.; Fitzsimons, David A.; Cox, Timothy C.
2014-01-01
Orofacial clefting is a common birth defect with wide phenotypic variability. Many systems have been developed to classify cleft patterns to facilitate diagnosis, management, surgical treatment, and research. In this review, we examine the rationale for different existing classification schemes and determine their inter-relationships, as well as strengths and deficiencies for subclassification of clefts of the lip. The various systems differ in how they describe and define attributes of cleft lip (CL) phenotypes. Application and analysis of the CL classifications reveal discrepancies that may result in errors when comparing studies that use different systems. These inconsistencies in terminology, variable levels of subclassification, and ambiguity in some descriptions may confound analyses and impede further research aimed at understanding the genetics and etiology of clefts, development of effective treatment options for patients, as well as cross-institutional comparisons of outcome measures. Identification and reconciliation of discrepancies among existing systems is the first step toward creating a common standard to allow for a more explicit interpretation that will ultimately lead to a better understanding of the causes and manifestations of phenotypic variations in clefting. PMID:24860508
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Dynamical predictors of an imminent phenotypic switch in bacteria
NASA Astrophysics Data System (ADS)
Wang, Huijing; Ray, J. Christian J.
2017-08-01
Single cells can stochastically switch across thresholds imposed by regulatory networks. Such thresholds can act as a tipping point, drastically changing global phenotypic states. In ecology and economics, imminent transitions across such tipping points can be predicted using dynamical early warning indicators. A typical example is ‘flickering’ of a fast variable, predicting a longer-lasting switch from a low to a high state or vice versa. Considering the different timescales between metabolite and protein fluctuations in bacteria, we hypothesized that metabolic early warning indicators predict imminent transitions across a network threshold caused by enzyme saturation. We used stochastic simulations to determine if flickering predicts phenotypic transitions, accounting for a variety of molecular physiological parameters, including enzyme affinity, burstiness of enzyme gene expression, homeostatic feedback, and rates of metabolic precursor influx. In most cases, we found that metabolic flickering rates are robustly peaked near the enzyme saturation threshold. The degree of fluctuation was amplified by product inhibition of the enzyme. We conclude that sensitivity to flickering in fast variables may be a possible natural or synthetic strategy to prepare physiological states for an imminent transition.
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Say-Meyer syndrome: additional manifestations in a new patient and phenotypic assessment.
Salinas-Torres, Victor M
2015-07-01
In 1981, Say and Meyer described a seemingly X-linked recessive syndrome of trigonocephaly, short stature, and developmental delay. Here, I present a new patient and review eight patients from the literature examining the nature and phenotypic differences. A Mexican 10-year-old boy with Say-Meyer syndrome is described. Additionally, he had C6 vertebral right pedicle agenesis, brachymesophalangy of the fifth fingers, bilateral widening of Sylvian fissure, and white matter amplitude as novel observed findings of the syndrome. This appears to be the first Say-Meyer syndrome patient with extracranial skeletal anomalies. In light of these manifestations, a detailed comparative phenotypic analysis of published patients revealed a heterogeneous syndrome with a significant clinical variability. Moreover, increasing evidence points to a variable expressivity of the same autosomal dominant mutation. Accordingly, it is proposed that Say-Meyer syndrome should be considered in those patients with the combination of trigonocephaly/metopic synostosis, short stature, developmental delay including prenatal and postnatal growth disorders, craniofacial dysmorphic features (especially hypotelorism), structural CNS anomalies (mainly white matter involvement), conductive hearing loss, seizures, and cardiovascular abnormalities.
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Mitochondrial threshold effects.
Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry
2003-01-01
The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the 'phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the 'biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a 'translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases. PMID:12467494
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Molar intercuspal dimensions: genetic input to phenotypic variation.
Townsend, G; Richards, L; Hughes, T
2003-05-01
Molecular studies indicate that epigenetic events are important in determining how the internal enamel epithelium folds during odontogenesis. Since this process of folding leads to the subsequent arrangement of cusps on molar teeth, we hypothesized that intercuspal distances of human molar teeth would display greater phenotypic variation but lower heritabilities than overall crown diameters. Intercuspal distances and maximum crown diameters were recorded from digitized images of dental casts in 100 monozygotic and 74 dizygotic twin pairs. Intercuspal distances displayed less sexual dimorphism in mean values but greater relative variability and fluctuating asymmetry than overall crown measures. Correlations between intercuspal distances and overall crown measures were low. Models incorporating only environmental effects accounted for observed variation in several intercuspal measures. For those intercuspal variables displaying significant additive genetic variance, estimates of heritability ranged from 43 to 79%, whereas those for overall crown size were higher generally, ranging from 60 to 82%. Our finding of high phenotypic variation in intercuspal distances with only moderate genetic contribution is consistent with substantial epigenetic influence on the progressive folding of the internal enamel epithelium, following formation of the primary and secondary enamel knots.
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Phenotypic and immunohistochemical characterization of sarcoglycanopathies
Ferreira, Ana F. B.; Carvalho, Mary S.; Resende, Maria Bernadete D.; Wakamatsu, Alda; Reed, Umbertina Conti; Marie, Suely Kazue Nagahashi
2011-01-01
INTRODUCTION: Limb-girdle muscular dystrophy presents with heterogeneous clinical and molecular features. The primary characteristic of this disorder is proximal muscular weakness with variable age of onset, speed of progression, and intensity of symptoms. Sarcoglycanopathies, which are a subgroup of the limb-girdle muscular dystrophies, are caused by mutations in sarcoglycan genes. Mutations in these genes cause secondary deficiencies in other proteins, due to the instability of the dystrophin-glycoprotein complex. Therefore, determining the etiology of a given sarcoglycanopathy requires costly and occasionally inaccessible molecular methods. OBJECTIVE: The aim of this study was to identify phenotypic differences among limb-girdle muscular dystrophy patients who were grouped according to the immunohistochemical phenotypes for the four sarcoglycans. METHODS: To identify phenotypic differences among patients with different types of sarcoglycanopathies, a questionnaire was used and the muscle strength and range of motion of nine joints in 45 patients recruited from the Department of Neurology – HC-FMUSP (Clinics Hospital of the Faculty of Medicine of the University of São Paulo) were evaluated. The findings obtained from these analyses were compared with the results of the immunohistochemical findings. RESULTS: The patients were divided into the following groups based on the immunohistochemical findings: α-sarcoglycanopathies (16 patients), β-sarcoglycanopathies (1 patient), γ-sarcoglycanopathies (5 patients), and non-sarcoglycanopathies (23 patients). The muscle strength analysis revealed significant differences for both upper and lower limb muscles, particularly the shoulder and hip muscles, as expected. No pattern of joint contractures was found among the four groups analyzed, even within the same family. However, a high frequency of tiptoe gait was observed in patients with α-sarcoglycanopathies, while calf pseudo-hypertrophy was most common in patients with non-sarcoglycanopathies. The α-sarcoglycanopathy patients presented with more severe muscle weakness than did γ-sarcoglycanopathy patients. CONCLUSION: The clinical differences observed in this study, which were associated with the immunohistochemical findings, may help to prioritize the mutational investigation of sarcoglycan genes. PMID:22012042
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PEZZANI, FABIANA; MONTAÑA, CARLOS
2006-01-01
• Background and Aims In many locations, plants are faced with adjacent, contrasting environments, and the between-species differential evolution of life history traits can be interpreted as an evolutionary response to this environmental heterogeneity. However, there has been little research on the intraspecific variability in these attributes as a possible evolutionary response of plants. • Methods In the two-phase mosaic of the Chihuahuan Desert (adjacent patches with contrasting resource availability), analyses were carried out of the germination response to the scarification and light quality to which grass seeds growing on these patches are exposed (open and closed habitats). • Key Results Species that grow in open habitats exhibited a higher germination success than those from closed habitats after scarification. At both the inter- and intraspecific level, there were differences in the germination percentage and in the germination speed in response to light quality. Intraspecific variation in the species from the closed habitat (Pleuraphis mutica and Trichloris crinita) and in Chloris virgata (which grows in both habitats) was due to genetic variation (the family factor was significant), but there was no genetic variation in phenotypic plasticity (non-significant interaction between family and light quality). In contrast, for the species that grows only in the open habitat (Dasyochloa pulchella), the family did not have a significant effect, but there was genetic variation in the phenotypic plasticity (significant interaction between family and light quality). • Conclusions In C. virgata, P. mutica and T. crinita, natural selection could be favouring those genotypes that responded better in each light environment, but it is not possible that the natural selection resulted in different optimal phenotypes in each habitat. On the contrary, in D. pulchella, selection could have reduced the genetic variation, but there is the possibility of the evolution of reaction norms, resulting in the selection of alternative phenotypes for each habitat. PMID:16621861
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Pezzani, Fabiana; Montaña, Carlos
2006-06-01
In many locations, plants are faced with adjacent, contrasting environments, and the between-species differential evolution of life history traits can be interpreted as an evolutionary response to this environmental heterogeneity. However, there has been little research on the intraspecific variability in these attributes as a possible evolutionary response of plants. In the two-phase mosaic of the Chihuahuan Desert (adjacent patches with contrasting resource availability), analyses were carried out of the germination response to the scarification and light quality to which grass seeds growing on these patches are exposed (open and closed habitats). Species that grow in open habitats exhibited a higher germination success than those from closed habitats after scarification. At both the inter- and intraspecific level, there were differences in the germination percentage and in the germination speed in response to light quality. Intraspecific variation in the species from the closed habitat (Pleuraphis mutica and Trichloris crinita) and in Chloris virgata (which grows in both habitats) was due to genetic variation (the family factor was significant), but there was no genetic variation in phenotypic plasticity (non-significant interaction between family and light quality). In contrast, for the species that grows only in the open habitat (Dasyochloa pulchella), the family did not have a significant effect, but there was genetic variation in the phenotypic plasticity (significant interaction between family and light quality). In C. virgata, P. mutica and T. crinita, natural selection could be favouring those genotypes that responded better in each light environment, but it is not possible that the natural selection resulted in different optimal phenotypes in each habitat. On the contrary, in D. pulchella, selection could have reduced the genetic variation, but there is the possibility of the evolution of reaction norms, resulting in the selection of alternative phenotypes for each habitat.
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Gobin-Limballe, S; Djouadi, F; Aubey, F; Olpin, S; Andresen, B S; Yamaguchi, S; Mandel, H; Fukao, T; Ruiter, J P N; Wanders, R J A; McAndrew, R; Kim, J J; Bastin, J
2007-12-01
Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an inborn mitochondrial fatty-acid beta-oxidation (FAO) defect associated with a broad mutational spectrum, with phenotypes ranging from fatal cardiopathy in infancy to adolescent-onset myopathy, and for which there is no established treatment. Recent data suggest that bezafibrate could improve the FAO capacities in beta-oxidation-deficient cells, by enhancing the residual level of mutant enzyme activity via gene-expression stimulation. Since VLCAD-deficient patients frequently harbor missense mutations with unpredictable effects on enzyme activity, we investigated the response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblasts representing 45 different mutations. Treatment with bezafibrate (400 microM for 48 h) resulted in a marked increase in FAO capacities, often leading to restoration of normal values, for 21 genotypes that mainly corresponded to patients with the myopathic phenotype. In contrast, bezafibrate induced no changes in FAO for 11 genotypes corresponding to severe neonatal or infantile phenotypes. This pattern of response was not due to differential inductions of VLCAD messenger RNA, as shown by quantitative real-time polymerase chain reaction, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacological profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. Altogether, the responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype, thus providing a new approach for analysis of genetic heterogeneity. Finally, this study emphasizes the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD deficiency and exemplifies the integration of molecular information in a therapeutic strategy.
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2013-01-01
Background The genus Limonium Miller comprises annual and perennial halophytes that can produce sexual and/or asexual seeds (apomixis). Genetic and epigenetic (DNA methylation) variation patterns were investigated in populations of three phenotypically similar putative sexual diploid species (L. nydeggeri, L. ovalifolium, L. lanceolatum), one sexual tetraploid species (L. vulgare) and two apomict tetraploid species thought to be related (L. dodartii, L. multiflorum). The extent of morphological differentiation between these species was assessed using ten diagnostic morphometric characters. Results A discriminant analysis using the morphometric variables reliably assigns individuals into their respective species groups. We found that only modest genetic and epigenetic differentiation was revealed between species by Methylation Sensitive Amplification Polymorphism (MSAP). However, whilst there was little separation possible between ploidy levels on the basis of genetic profiles, there was clear and pronounced interploidy discrimination on the basis of epigenetic profiles. Here we investigate the relative contribution of genetic and epigenetic factors in explaining the complex phenotypic variability seen in problematic taxonomic groups such as Limonium that operate both apomixis and sexual modes of reproduction. Conclusions Our results suggest that epigenetic variation might be one of the drivers of the phenotypic divergence between diploid and tetraploid taxa and discuss that intergenome silencing offers a plausible mechanistic explanation for the observed phenotypic divergence between these microspecies. These results also suggest that epigenetic profiling offer an additional tool to infer ploidy level in stored specimens and that stable epigenetic change may play an important role in apomict evolution and species recognition. PMID:24314092
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Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K.; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M.M.; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E.; Yntema, Helger G.; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L.; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C.; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D.; Cavé, Hélène; Ahmadian, Mohammad R.; Tartaglia, Marco
2014-01-01
RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. PMID:24705357
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Mallick, Pijush; Sikdar, Samir Ranjan
2014-08-01
Nine inter-generic somatic hybrids named as pfle were produced through PEG-mediated protoplast fusion between Pleurotus florida and Lentinula edodes using double selection method. Hybridity of the newly developed strains was established on the basis of colony morphology, mycelial growth, hyphal traits, fruit-body productivity and inter single sequence repeat (ISSR) marker profiling. Hybrid population was assessed with different phenotypic variables by one-way analysis of variance. Principal component matrices were analyzed for the six phenotypic variables in scatter plot showing maximum positive correlation between each variable for all strains examined. Six ISSR primers generated 66 reproducible fragments with 98.48 % polymorphism. The dendrogram thus created based on unweighted pair-group method with mathematic averages method of clustering and Euclidean distance which exhibited three major groups between the parents and pfle hybrids. Though P. florida parent remained in one group but it showed different degrees of genetic distance with all the hybrid lines belonging to the other two groups while L. edodes was most distantly related to all the hybrid lines. L. edodes specific sequence-rich ISSR amplicon was recorded in all the hybrid lines and in L. edodes but not in P. florida. All the fruit body generating pfle hybrid lines could produce basidiocarp on paddy straw in sub-tropical climate and showed phenotypic resemblance to the P. florida parent.
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Pre-disposition and epigenetics govern variation in bacterial survival upon stress.
Ni, Ming; Decrulle, Antoine L; Fontaine, Fanette; Demarez, Alice; Taddei, Francois; Lindner, Ariel B
2012-01-01
Bacteria suffer various stresses in their unpredictable environment. In response, clonal populations may exhibit cell-to-cell variation, hypothetically to maximize their survival. The origins, propagation, and consequences of this variability remain poorly understood. Variability persists through cell division events, yet detailed lineage information for individual stress-response phenotypes is scarce. This work combines time-lapse microscopy and microfluidics to uniformly manipulate the environmental changes experienced by clonal bacteria. We quantify the growth rates and RpoH-driven heat-shock responses of individual Escherichia coli within their lineage context, stressed by low streptomycin concentrations. We observe an increased variation in phenotypes, as different as survival from death, that can be traced to asymmetric division events occurring prior to stress induction. Epigenetic inheritance contributes to the propagation of the observed phenotypic variation, resulting in three-fold increase of the RpoH-driven expression autocorrelation time following stress induction. We propose that the increased permeability of streptomycin-stressed cells serves as a positive feedback loop underlying this epigenetic effect. Our results suggest that stochasticity, pre-disposition, and epigenetic effects are at the source of stress-induced variability. Unlike in a bet-hedging strategy, we observe that cells with a higher investment in maintenance, measured as the basal RpoH transcriptional activity prior to antibiotic treatment, are more likely to give rise to stressed, frail progeny.
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Rustioni, Laura; De Lorenzis, Gabriella; Hârţa, Monica; Failla, Osvaldo
2016-01-01
Color has a fundamental role for the qualitative evaluation and cultivar characterization of fruits. In grape, a normally functional pigment biosynthesis leads to the accumulation of a high quantity of anthocyanins. In this work, 28 Vitis vinifera L. cultivars accumulating low anthocyanins in berries were studied to characterize the biosynthetic dysfunctions in both a phenotypic and genotypic point of view. Reflectance spectroscopy, HPLC profiles and molecular markers related to VvMybA1 and VvMybA2 genes allowed a detailed description of the pigment-related characteristics of these cultivars. Data were consistent concerning the heterozygosity of the non-functional allele in both investigated genes, resulting in a low colored phenotype as described by reflectance. However, the variability in berry colour among our samples was not fully explained by MybA locus, probably due to specific interferences among the biosynthetic pathways, as suggested by the anthocyanin profile variations detected among our samples. The results presented in this work confirmed the importance of the genetic background: grapes accumulating high levels of cyanidin-3-O-glucosides (di-substituted anthocyanin) are generally originated by white cultivar retro-mutations and they seem to preserve the anomalies in the flavonoid hydroxylases enzymes which negatively affect the synthesis of tri-substituted anthocyanins. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
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Basu, D; Nguyen, T-T K; Montone, K T; Zhang, G; Wang, L-P; Diehl, J A; Rustgi, A K; Lee, J T; Weinstein, G S; Herlyn, M
2010-07-22
Variable drug responses among malignant cells within individual tumors may represent a barrier to their eradication using chemotherapy. Carcinoma cells expressing mesenchymal markers resist conventional and epidermal growth factor receptor (EGFR)-targeted chemotherapy. In this study, we evaluated whether mesenchymal-like sub-populations within human squamous cell carcinomas (SCCs) with predominantly epithelial features contribute to overall therapy resistance. We identified a mesenchymal-like subset expressing low E-cadherin (Ecad-lo) and high vimentin within the upper aerodigestive tract SCCs. This subset was both isolated from the cell lines and was identified in xenografts and primary clinical specimens. The Ecad-lo subset contained more low-turnover cells, correlating with resistance to the conventional chemotherapeutic paclitaxel in vitro. Epidermal growth factor induced less stimulation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways in Ecad-lo cells, which was likely due to lower EGFR expression in this subset and correlated with in vivo resistance to the EGFR-targeted antibody, cetuximab. The Ecad-lo and high E-cadherin subsets were dynamic in phenotype, showing the capacity to repopulate each other from single-cell clones. Taken together, these results provide evidence for a low-turnover, mesenchymal-like sub-population in SCCs with diminished EGFR pathway function and intrinsic resistance to conventional and EGFR-targeted chemotherapies.
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Nagashima-type palmoplantar keratosis in a Chinese Han population
Zhang, Jia; Zhang, Guolong; Ni, Cheng; Cheng, Ruhong; Liang, Jianying; Li, Ming; Yao, Zhirong
2016-01-01
Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive form of palmoplantar keratoderma (PPK), which is caused by mutations in the SERPINB7 gene. NPPK has only been reported in Japanese and Chinese populations. The present study was conducted on 12 unrelated Chinese patients who were clinically predicted to suffer from NPPK. Mutation screening was performed by direct sequencing of the entire coding regions of SERPINB7, SLURP1, AQP5, CSTA, KRT1 and KRT9 genes. Direct sequencing of SERPINB7 revealed five homozygous founder mutations (c.796C>T) and four compound heterozygous mutations in nine patients, including one novel mutation (c.122_127delTGGTCC). Nine out of the 12 patients were diagnosed with NPPK due to SERPINB7 pathogenic mutations, and the results expanded the known mutation spectrum of NPPK. Taking the other seven reported Chinese patients, who had been definitively diagnosed with NPPK by genetic testing, into account, the present study further demonstrated that NPPK is a common entity in Mainland China, and c.796C>T is the most prevalent mutation and exerts a founder effect. Furthermore, the NPPK cases described in the current study presented a consistently mild phenotype, as compared with the degrees of phenotypic variability associated with other types of relatively severe PPK, including Mal de Meleda and Olmsted syndrome. PMID:27666198
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McGregor, Bonnie A; Murphy, Karly M; Albano, Denise L; Ceballos, Rachel M
2016-01-01
Animal and human in vitro models suggest that stress-related B lymphocyte decrements are due to high levels of glucocorticoids which cause apoptosis of pre-B-cells as they emerge from the bone marrow. The present study sought to explore the relationships among distress, salivary cortisol, and human B lymphocytes in vivo. Distress (perceived stress, negative affect, depressive symptoms), lymphocyte phenotype, and salivary cortisol were assessed among first-year graduate students (n = 22) and a community control sample (n = 30) at the start of classes in the fall and the week immediately before spring preliminary exams. Compared to controls, students reported greater distress on all measures at each time point except baseline perceived stress. Hierarchical linear regression with necessary control variables was used to assess the effect of student status on the three measures of distress, the four measures of lymphocyte phenotype, and cortisol AUC and CAR over time (T1-T2). Student status was associated with a significant decrease in CD19 + B lymphocytes and flattened cortisol awakening response (CAR). Change in CAR was associated with the decrease in CD19 + B lymphocytes. Results indicated that there are significant associations among student status, flattening of CAR, and decrements in CD19 + lymphocytes.
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Phenological plasticity will not help all species adapt to climate change.
Duputié, Anne; Rutschmann, Alexis; Ronce, Ophélie; Chuine, Isabelle
2015-08-01
Concerns are rising about the capacity of species to adapt quickly enough to climate change. In long-lived organisms such as trees, genetic adaptation is slow, and how much phenotypic plasticity can help them cope with climate change remains largely unknown. Here, we assess whether, where and when phenological plasticity is and will be adaptive in three major European tree species. We use a process-based species distribution model, parameterized with extensive ecological data, and manipulate plasticity to suppress phenological variations due to interannual, geographical and trend climate variability, under current and projected climatic conditions. We show that phenological plasticity is not always adaptive and mostly affects fitness at the margins of the species' distribution and climatic niche. Under current climatic conditions, phenological plasticity constrains the northern range limit of oak and beech and the southern range limit of pine. Under future climatic conditions, phenological plasticity becomes strongly adaptive towards the trailing edges of beech and oak, but severely constrains the range and niche of pine. Our results call for caution when interpreting geographical variation in trait means as adaptive, and strongly point towards species distribution models explicitly taking phenotypic plasticity into account when forecasting species distribution under climate change scenarios. © 2015 John Wiley & Sons Ltd.
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Drug-resistant tuberculosis: An update on disease burden, diagnosis and treatment.
Lange, Christoph; Chesov, Dumitru; Heyckendorf, Jan; Leung, Chi C; Udwadia, Zarir; Dheda, Keertan
2018-04-11
The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure. © 2018 Asian Pacific Society of Respirology.
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Belangero, S I; Pacanaro, A N X; Bellucco, F T; Christofolini, D M; Kulikowski, L D; Guilherme, R S; Bortolai, A; Dutra, A R N; Piazzon, F B; Cernach, M C; Melaragno, M I
2012-01-01
A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter→q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling. Copyright © 2012 S. Karger AG, Basel.
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Platform for combined analysis of functional and biomolecular phenotypes of the same cell
Kelbauskas, L.; Ashili, S.; Zeng, J.; Rezaie, A.; Lee, K.; Derkach, D.; Ueberroth, B.; Gao, W.; Paulson, T.; Wang, H.; Tian, Y.; Smith, D.; Reid, B.; Meldrum, Deirdre R.
2017-01-01
Functional and molecular cell-to-cell variability is pivotal at the cellular, tissue and whole-organism levels. Yet, the ultimate goal of directly correlating the function of the individual cell with its biomolecular profile remains elusive. We present a platform for integrated analysis of functional and transcriptional phenotypes in the same single cells. We investigated changes in the cellular respiration and gene expression diversity resulting from adaptation to repeated episodes of acute hypoxia in a premalignant progression model. We find differential, progression stage-specific alterations in phenotypic heterogeneity and identify cells with aberrant phenotypes. To our knowledge, this study is the first demonstration of an integrated approach to elucidate how heterogeneity at the transcriptional level manifests in the physiologic profile of individual cells in the context of disease progression. PMID:28300162
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Phenotype-Driven Therapeutics in Severe Asthma.
Opina, Maria Theresa D; Moore, Wendy C
2017-02-01
Inhaled corticosteroids are the mainstay of asthma treatment using a step-up approach with incremental dosing and additional controller medications in order to achieve symptom control and prevent exacerbations. While most patients respond well to this treatment approach, some patients remain refractory despite high doses of inhaled corticosteroids and a long-acting β-agonist. The problem lies in the heterogeneity of severe asthma, which is further supported by the emergence of severe asthma phenotypes. This heterogeneity contributes to the variability in treatment response. Randomized controlled trials involving add-on therapies in poorly controlled asthma have challenged the idea of a "one size fits all" approach targeting specific phenotypes in their subject selection. This review discusses severe asthma phenotypes from unbiased clustering approaches and the most recent scientific evidence on novel treatments to provide a guide in personalizing severe asthma treatment.
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Morphological and niche divergence of pinyon pines.
Ortiz-Medrano, Alejandra; Scantlebury, Daniel Patrick; Vázquez-Lobo, Alejandra; Mastretta-Yanes, Alicia; Piñero, Daniel
2016-05-01
The environmental variables that define a species ecological niche should be associated with the evolutionary patterns present in the adaptations that resulted from living in these conditions. Thus, when comparing across species, we can expect to find an association between phylogenetically independent phenotypic characters and ecological niche evolution. Few studies have evaluated how organismal phenotypes might mirror patterns of niche evolution if these phenotypes reflect adaptations. Doing so could contribute on the understanding of the origin and maintenance of phenotypic diversity observed in nature. Here, we show the pattern of niche evolution of the pinyon pine lineage (Pinus subsection Cembroides); then, we suggest morphological adaptations possibly related to niche divergence, and finally, we test for correlation between ecological niche and morphology. We demonstrate that niche divergence is the general pattern within the clade and that it is positively correlated with adaptation.
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Shrivastava, Manisha; Navaid, Seema; Peethambarakshan, A; Agrawal, Kalpana; Khan, Athar
2015-01-01
Due to lack of correct blood grouping practices, the rare Bombay Oh phenotype may be missed, subjecting patients to the risk of severe hemolytic transfusion reaction. In the absence of blood donor registry, transfusion management of patients needing immediate surgery is a challenge. This study presents detection of rare Bombay Oh phenotype patients and their management by acute peri-operative acute normovolemic hemodilution (ANH) in a hospital from central India. Blood grouping of patients and blood donors with a standard tube method was carried out and samples identified as rare Bombay phenotype were confirmed by saliva inhibition test. Surgical management of cases needing transfusion was done by ANH, as per the British Committee for Standards in Hematology guidelines. The incidence of Bombay phenotype was 0.002% or 1 in 51,924 in the study. Amongst three cases (patients) identified as Bombay phenotype, one was Bombay Oh, Rh negative. Two cases were missed in the first instance and one case actually did not require transfusion. In the absence of a blood donor registry for Bombay phenotype, the cases needing transfusion were successfully managed with ANH in the operation theatre. A simple test like blood grouping should be done with serious intention with incorporation of both forward and reverse grouping, so that no patient receives wrong blood leading to fatal hemolysis due to transfusion. ANH is a cost-effective transfusion option for suitable patients. Appropriate clinical decision making, use of strategies to decrease peri-operative blood losses and cost-effective country based planning could be more widely applied to improve clinical transfusion practice.
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USDA-ARS?s Scientific Manuscript database
Weight loss (WL) induced by energy restriction is highly variable even in controlled clinical trials. An integrative analysis of the plasma metabolome coupled to traditional clinical variables may reveal a WL “responder” phenotype. Therfore, we predicted WL in overweight and obese individuals on a...
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USDA-ARS?s Scientific Manuscript database
Weight loss (WL) induced by energy restriction is highly variable even in controlled clinical trials. An integrative analysis of the plasma metabolome coupled to traditional clinical variables may reveal a WL “responder” phenotype. Therfore, we predicted WL in overweight and obese individuals on a...
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Estella Gilbert; James A. Powell; Jesse A. Logan; Barbara J. Bentz
2004-01-01
In all organisms, phenotypic variability is an evolutionary stipulation. Because the development of poikilothermic organisms depends directly on the temperature of their habitat, environmental variability is also an integral factor in models of their phenology. In this paper we present two existing phenology models, the distributed delay model and the Sharpe and...
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Common genetic variation drives molecular heterogeneity in human iPSCs.
Kilpinen, Helena; Goncalves, Angela; Leha, Andreas; Afzal, Vackar; Alasoo, Kaur; Ashford, Sofie; Bala, Sendu; Bensaddek, Dalila; Casale, Francesco Paolo; Culley, Oliver J; Danecek, Petr; Faulconbridge, Adam; Harrison, Peter W; Kathuria, Annie; McCarthy, Davis; McCarthy, Shane A; Meleckyte, Ruta; Memari, Yasin; Moens, Nathalie; Soares, Filipa; Mann, Alice; Streeter, Ian; Agu, Chukwuma A; Alderton, Alex; Nelson, Rachel; Harper, Sarah; Patel, Minal; White, Alistair; Patel, Sharad R; Clarke, Laura; Halai, Reena; Kirton, Christopher M; Kolb-Kokocinski, Anja; Beales, Philip; Birney, Ewan; Danovi, Davide; Lamond, Angus I; Ouwehand, Willem H; Vallier, Ludovic; Watt, Fiona M; Durbin, Richard; Stegle, Oliver; Gaffney, Daniel J
2017-06-15
Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.
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Common genetic variation drives molecular heterogeneity in human iPSCs
Leha, Andreas; Afzal, Vackar; Alasoo, Kaur; Ashford, Sofie; Bala, Sendu; Bensaddek, Dalila; Casale, Francesco Paolo; Culley, Oliver J; Danecek, Petr; Faulconbridge, Adam; Harrison, Peter W; Kathuria, Annie; McCarthy, Davis; McCarthy, Shane A; Meleckyte, Ruta; Memari, Yasin; Moens, Nathalie; Soares, Filipa; Mann, Alice; Streeter, Ian; Agu, Chukwuma A; Alderton, Alex; Nelson, Rachel; Harper, Sarah; Patel, Minal; White, Alistair; Patel, Sharad R; Clarke, Laura; Halai, Reena; Kirton, Christopher M; Kolb-Kokocinski, Anja; Beales, Philip; Birney, Ewan; Danovi, Davide; Lamond, Angus I; Ouwehand, Willem H; Vallier, Ludovic; Watt, Fiona M; Durbin, Richard
2017-01-01
Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells. PMID:28489815
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Desiderata for computable representations of electronic health records-driven phenotype algorithms
Mo, Huan; Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Jiang, Guoqian; Kiefer, Richard; Zhu, Qian; Xu, Jie; Montague, Enid; Carrell, David S; Lingren, Todd; Mentch, Frank D; Ni, Yizhao; Wehbe, Firas H; Peissig, Peggy L; Tromp, Gerard; Larson, Eric B; Chute, Christopher G; Pathak, Jyotishman; Speltz, Peter; Kho, Abel N; Jarvik, Gail P; Bejan, Cosmin A; Williams, Marc S; Borthwick, Kenneth; Kitchner, Terrie E; Roden, Dan M; Harris, Paul A
2015-01-01
Background Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM). Methods A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms. Results We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility. Conclusion A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages. PMID:26342218
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Ben-Ari, Meital; Naor, Shulamit; Zeevi-Levin, Naama; Schick, Revital; Ben Jehuda, Ronen; Reiter, Irina; Raveh, Amit; Grijnevitch, Inna; Barak, Omri; Rosen, Michael R.; Weissman, Amir; Binah, Ofer
2016-01-01
Background Previous studies proposed that throughout differentiation of human induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) only 3 types of action potentials (AP) exist: nodal, atrial and ventricular-like. Objective To investigate whether there are precisely 3 phenotypes or a continuum exists among them, we tested 2 hypotheses: (1) during culture development a cardiac precursor cell is present that - depending on age - can evolve into the 3 phenotypes. (2) The predominant pattern is early prevalence of nodal phenotype, transient appearance of atrial phenotype, evolution to ventricular phenotype, and persistence of transitional phenotypes. Methods To test these hypotheses we: (1) performed FACS analysis of nodal, atrial and ventricular markers; (2) recorded AP from 280 7-to-95 day old iPSC-CMs; (3) analyzed AP characteristics. Results The major findings were: (1) FACS analysis of 30 and 60-day old cultures showed that an iPSC-CMs population shifts from nodal into atrial/ventricular phenotype, while including significant transitional populations.(2) The AP population did not consist of 3 distinct phenotypes; (3) Culture aging was associated with a shift from nodal to ventricular dominance, with a transient (57–70 days) appearance of atrial phenotype; (4) Beat Rate Variability was more prominent in nodal than ventricular cardiomyocytes while If density increased in older cultures. Conclusions From the onset of development the iPSC-CMs population includes nodal, atrial and ventricular AP and a broad spectrum of transitional phenotypes. The most readily distinguishable phenotype is atrial which appears only transiently, yet dominates at 57–70 days of evolution. PMID:27639456
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Federated Tensor Factorization for Computational Phenotyping
Kim, Yejin; Sun, Jimeng; Yu, Hwanjo; Jiang, Xiaoqian
2017-01-01
Tensor factorization models offer an effective approach to convert massive electronic health records into meaningful clinical concepts (phenotypes) for data analysis. These models need a large amount of diverse samples to avoid population bias. An open challenge is how to derive phenotypes jointly across multiple hospitals, in which direct patient-level data sharing is not possible (e.g., due to institutional policies). In this paper, we developed a novel solution to enable federated tensor factorization for computational phenotyping without sharing patient-level data. We developed secure data harmonization and federated computation procedures based on alternating direction method of multipliers (ADMM). Using this method, the multiple hospitals iteratively update tensors and transfer secure summarized information to a central server, and the server aggregates the information to generate phenotypes. We demonstrated with real medical datasets that our method resembles the centralized training model (based on combined datasets) in terms of accuracy and phenotypes discovery while respecting privacy. PMID:29071165
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Liu, Yanling; McDaniel, Jonathan R; Khan, Srijit; Campisi, Paolo; Propst, Evan J; Holler, Theresa; Grunebaum, Eyal; Georgiou, George; Ippolito, Gregory C; Ehrhardt, Götz R A
2018-06-15
FCRL4, a low-affinity IgA Ab receptor with strong immunoregulatory potential, is an identifying feature of a tissue-based population of memory B cells (Bmem). We used two independent approaches to perform a comparative analysis of the Ag receptor repertoires of FCRL4 + and FCRL4 - Bmem in human tonsils. We determined that FCRL4 + Bmem displayed lower levels of somatic mutations in their Ag receptors compared with FCRL4 - Bmem but had similar frequencies of variable gene family usage. Importantly, Abs with reactivity to commensal microbiota were enriched in FCRL4 + cells, a phenotype not due to polyreactive binding characteristics. Our study links expression of the immunoregulatory FCRL4 molecule with increased recognition of commensal microbial Ags. Copyright © 2018 by The American Association of Immunologists, Inc.
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[Myotonic dystrophy - a new insight into a well-known disease].
Lusakowska, Anna; Sułek-Piatkowska, Anna
2010-01-01
Myotonic dystrophy (DM), the most common dystrophy in adults, is an autosomal dominant disease characterized by a variety of multisystemic features. Two genetically distinct forms of DM are identified - type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is caused by trinucleotide expansion of CTG in the myotonic dystrophy protein kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in the zinc finger protein 9 gene was identified. Both mutations are dynamic and are located in non-coding parts of the genes. Phenotype variability of DM1 and DM2 is caused by a molecular mechanism due to mutated RNA toxicity. This paper reviews the clinical features of both types of myotonic dystrophies and summarizes current views on pathogenesis of myotonic dystrophy.
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Monogenic autoimmune diseases of the endocrine system.
Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E
2016-10-01
The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Cone opsins, colour blindness and cone dystrophy: Genotype-phenotype correlations.
Gardner, J C; Michaelides, M; Hardcastle, A J
2016-05-25
X-linked cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of cone opsin disorders.
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3D sorghum reconstructions from depth images identify QTL regulating shoot architecture
DOE Office of Scientific and Technical Information (OSTI.GOV)
Mccormick, Ryan F.; Truong, Sandra K.; Mullet, John E.
Dissecting the genetic basis of complex traits is aided by frequent and nondestructive measurements. Advances in range imaging technologies enable the rapid acquisition of three-dimensional (3D) data from an imaged scene. A depth camera was used to acquire images of sorghum (Sorghum bicolor), an important grain, forage, and bioenergy crop, at multiple developmental time points from a greenhouse-grown recombinant inbred line population. A semiautomated software pipeline was developed and used to generate segmented, 3D plant reconstructions from the images. Automated measurements made from 3D plant reconstructions identified quantitative trait loci for standard measures of shoot architecture, such as shoot height,more » leaf angle, and leaf length, and for novel composite traits, such as shoot compactness. The phenotypic variability associated with some of the quantitative trait loci displayed differences in temporal prevalence; for example, alleles closely linked with the sorghum Dwarf3 gene, an auxin transporter and pleiotropic regulator of both leaf inclination angle and shoot height, influence leaf angle prior to an effect on shoot height. Furthermore, variability in composite phenotypes that measure overall shoot architecture, such as shoot compactness, is regulated by loci underlying component phenotypes like leaf angle. As such, depth imaging is an economical and rapid method to acquire shoot architecture phenotypes in agriculturally important plants like sorghum to study the genetic basis of complex traits.« less
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3D sorghum reconstructions from depth images identify QTL regulating shoot architecture
Mccormick, Ryan F.; Truong, Sandra K.; Mullet, John E.
2016-08-15
Dissecting the genetic basis of complex traits is aided by frequent and nondestructive measurements. Advances in range imaging technologies enable the rapid acquisition of three-dimensional (3D) data from an imaged scene. A depth camera was used to acquire images of sorghum (Sorghum bicolor), an important grain, forage, and bioenergy crop, at multiple developmental time points from a greenhouse-grown recombinant inbred line population. A semiautomated software pipeline was developed and used to generate segmented, 3D plant reconstructions from the images. Automated measurements made from 3D plant reconstructions identified quantitative trait loci for standard measures of shoot architecture, such as shoot height,more » leaf angle, and leaf length, and for novel composite traits, such as shoot compactness. The phenotypic variability associated with some of the quantitative trait loci displayed differences in temporal prevalence; for example, alleles closely linked with the sorghum Dwarf3 gene, an auxin transporter and pleiotropic regulator of both leaf inclination angle and shoot height, influence leaf angle prior to an effect on shoot height. Furthermore, variability in composite phenotypes that measure overall shoot architecture, such as shoot compactness, is regulated by loci underlying component phenotypes like leaf angle. As such, depth imaging is an economical and rapid method to acquire shoot architecture phenotypes in agriculturally important plants like sorghum to study the genetic basis of complex traits.« less
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Robustness to Faults Promotes Evolvability: Insights from Evolving Digital Circuits
Nolfi, Stefano
2016-01-01
We demonstrate how the need to cope with operational faults enables evolving circuits to find more fit solutions. The analysis of the results obtained in different experimental conditions indicates that, in absence of faults, evolution tends to select circuits that are small and have low phenotypic variability and evolvability. The need to face operation faults, instead, drives evolution toward the selection of larger circuits that are truly robust with respect to genetic variations and that have a greater level of phenotypic variability and evolvability. Overall our results indicate that the need to cope with operation faults leads to the selection of circuits that have a greater probability to generate better circuits as a result of genetic variation with respect to a control condition in which circuits are not subjected to faults. PMID:27409589
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Presentation and Treatment of Poland Anomaly
Buckwalter V, Joseph A.; Shah, Apurva S.
2016-01-01
Background: Poland anomaly is a sporadic, phenotypically variable congenital condition usually characterized by unilateral pectoral muscle agenesis and ipsilateral hand deformity. Methods: A comprehensive review of the medical literature on Poland anomaly was performed using a Medline search. Results: Poland anomaly is a sporadic, phenotypically variable congenital condition usually characterized by unilateral, simple syndactyly with ipsilateral limb hypoplasia and pectoralis muscle agenesis. Operative management of syndactyly in Poland anomaly is determined by the severity of hand involvement and the resulting anatomical dysfunction. Syndactyly reconstruction is recommended in all but the mildest cases because most patients with Poland anomaly have notable brachydactyly, and digital separation can improve functional length. Conclusions: Improved understanding the etiology and presentation of Poland anomaly can improve clinician recognition and management of this rare congenital condition. PMID:28149203
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Nelson, Lindsay D.; Patrick, Christopher J.; Bernat, Edward M.
2010-01-01
The externalizing dimension is viewed as a broad dispositional factor underlying risk for numerous disinhibitory disorders. Prior work has documented deficits in event-related brain potential (ERP) responses in individuals prone to externalizing problems. Here, we constructed a direct physiological index of externalizing vulnerability from three ERP indicators and evaluated its validity in relation to criterion measures in two distinct domains: psychometric and physiological. The index was derived from three ERP measures that covaried in their relations with externalizing proneness the error-related negativity and two variants of the P3. Scores on this ERP composite predicted psychometric criterion variables and accounted for externalizing-related variance in P3 response from a separate task. These findings illustrate how a diagnostic construct can be operationalized as a composite (multivariate) psychophysiological variable (phenotype). PMID:20573054
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Franco, M M; Santos, J B F; Mendonça, A S; Silva, T C F; Antunes, R C; Melo, E O
2016-09-23
The domestication of the Equus genus 5000-6000 years ago has influenced the history of human civilization. As soon as horse and donkey species had been domesticated, they were crossbred, producing humanity's first documented attempt at animal genome manipulation. Since then, the mule (male donkey x female horse) and the reciprocal cross (the hinny, male horse x female donkey) have been the most common equine hybrids in the world. Due to their hybrid vigor, mules and hinnies have been intensively used for carrying loads and people and for tilling the land. Despite their importance, visual distinction of mules and hinnies is difficult due to high phenotypic resemblance. However, the distinction between these two hybrids is of pivotal importance for equid breeders and ranchers. In this study, an easy, low-cost, effective, and fast multiplex-polymerase chain reaction method was developed to distinguish the maternal origin of mules and hinnies, targeting the hyper-variable mitochondrial DNA D-loop region. This methodology can help breeders, ranchers, animal science professionals, and researchers manage their equine herds with more confidence and precision.
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Phenotype comparison confirms ZMYND11 as a critical gene for 10p15.3 microdeletion syndrome.
Tumiene, Birute; Čiuladaitė, Ž; Preikšaitienė, E; Mameniškienė, R; Utkus, A; Kučinskas, V
2017-11-01
Proper epigenetic regulation processes are crucial in the normal development of the human brain. An ever-increasing group of neurodevelopmental disorders due to derangements of epigenetic regulation involve both microdeletion and monogenic syndromes. Some of these syndromes have overlapping clinical phenotypes due to haploinsufficiency-sensitive genes involved in microdeletions. It was shown recently that the ZMYND11 gene has important functions in epigenetic regulation as an unconventional transcription co-repressor of highly expressed genes, possibly acting in the repression of cryptic transcription from gene bodies. The aim of our study was to compare the clinical phenotypes of patients with 10p15.3 deletions with the phenotypes of patients with loss-of-function ZMYND11 mutations. The results of our study further confirm that the ZMYND11 gene is the critical gene for the clinical phenotype of 10p15.3 microdeletion involving the terminal ~4 Mb of chromosome 10p. In addition, accumulating clinical data allow for further characterisation of this syndrome, including neurodevelopmental disorder, characteristic dysmorphic features and some other more frequent symptoms, such as behavioural disturbances, hypotonia, seizures, low birth weight, short stature in those older than 10 years of age, genitourinary malformations and recurrent infections.
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Comparison of phenotyping methods for resistance to stem rot and aggregated sheath spot in rice
USDA-ARS?s Scientific Manuscript database
Stem and sheath diseases caused by Sclerotium oryzae Cattaneo (SCL) and Rhizoctonia oryzae-sativae Sawada Mordue (ROS) can severely reduce rice (Oryza sativa L.) yield and grain quality. Genetic resistance is the best strategy to control them. Phenotypic selection for resistance is hampered due to a...
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Angelman syndrome due to paternal uniparental disomy of chromosome 15: A milder phenotype?
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bottani, A.; Robinson, W.P.; DeLoizer-Blanchet, C.D.
1994-05-15
The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal uniparental disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isodisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; bothmore » patients had late-onset mild seizures; as they grow older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal uniparental disomy will have to be confirmed by detailed clinical descriptions of further patients. 25 refs., 2 figs., 1 tab.« less
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Hall, F. Scott; Perona, Maria T. G.
2012-01-01
This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that are determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. PMID:22643448
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Sexual dimorphism in Ramphastos toco and Ramphastos dicolorus (Piciformes, Aves).
Castro, Márcio S; Recco-Pimentel, Shirlei M; Rocha, Guaracy T
2003-03-01
Phenotypic sexual dimorphism seems to be rare in the Ramphastidae family, except in Pteroglossus viridis and in the genus Selenidera. Many breeders of wild birds believe that specimens of Ramphastos toco can be sexed using bill characteristics. In this study, various discriminant phenotypic variables were analyzed in birds which were sexed cytogenetically. Fifty-one specimens of R. toco and 20 R. dicolorus were studied. The statistically significant parameters which served to distinguish the sex in these species were the length of the culmen and tomium, length of the lower corneous beak and the cloaca. Using these parameters, captive bird breeders can determine sex of R. toco specimens by phenotypic analysis and form breeding couples more quickly.
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Mycological studies housed in the Apollo 16 microbial ecology evaluation device
NASA Technical Reports Server (NTRS)
Volz, P. A.
1973-01-01
Survival, death, and phenotype count have yielded variation in the number of fungi recovered from the controls and the flight exposed cuvettes during preliminary analysis of postflight first phase data. Also the preliminary analysis was indicative that fungi exposed to specific space flight conditions demonstrated variable survival rates and phenotype counts. Specific space flight conditions included full light space exposure for Chaetomium globosum, exposure at 300- and 254-nanometer wavelengths for Rhodotorula rubra, full light and 280-nanometer wavelength exposure for Trichophyton terrestre, and 254-nanometer wavelength exposure for Saccharomyces cerevisiae. In general, phenotype counts for flight cuvettes and survival rates for control cuvettes were higher compared with the remaining cuvettes.
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Partial epilepsy and 47,XXX karyotype: report of four cases.
Roubertie, Agathe; Humbertclaude, Véronique; Leydet, Julie; Lefort, Geneviève; Echenne, Bernard
2006-07-01
Epilepsy is a common finding in chromosomal imbalances, but only a few chromosome abnormalities have a characteristic electro-clinical pattern. Trisomy X is one of the most common sex chromosome abnormalities in females, and is associated with considerable phenotypic variability. This report describes four 47,XXX females with mental deficiency and epilepsy. Although a specific electro-clinical pattern could not be defined, the epileptic phenotypes of these patients share many features; we suggest that the association 47,XXX/epilepsy/mental retardation may not be coincidental. This report also enlarges the clinical spectrum of the 47,XXX phenotype. Moreover, these observations highlight the critical role of chromosome X in epilepsy and mental retardation.
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Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian and Afrikaner families.
De Paepe, A; Viljoen, D; Matton, M; Beighton, P; Lenaerts, V; Vossaert, K; De Bie, S; Voet, D; De Laey, J J; Kint, A
1991-01-01
A multidisciplinary survey of the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with biopsy-proven pseudoxanthoma elasticum (PXE) was undertaken. The major PXE phenotype emerging from this study is very similar in both patient groups and is characterized by severe ophthalmologic manifestations with variable, mild cutaneous and vascular symptoms. In the families with more than one affected relative, segregation analysis is compatible with autosomal recessive inheritance in both groups. It is suggested that the PXE phenotype of these Belgian and Afrikaner patients is distinct from the other recognized PXE subtypes. The phenotypic resemblance in both patient groups raises the question whether a similar genetic mechanism is involved.
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Wu, Mon-Ju; Mwangi, Benson; Bauer, Isabelle E; Passos, Ives C; Sanches, Marsal; Zunta-Soares, Giovana B; Meyer, Thomas D; Hasan, Khader M; Soares, Jair C
2017-01-15
Diagnosis, clinical management and research of psychiatric disorders remain subjective - largely guided by historically developed categories which may not effectively capture underlying pathophysiological mechanisms of dysfunction. Here, we report a novel approach of identifying and validating distinct and biologically meaningful clinical phenotypes of bipolar disorders using both unsupervised and supervised machine learning techniques. First, neurocognitive data were analyzed using an unsupervised machine learning approach and two distinct clinical phenotypes identified namely; phenotype I and phenotype II. Second, diffusion weighted imaging scans were pre-processed using the tract-based spatial statistics (TBSS) method and 'skeletonized' white matter fractional anisotropy (FA) and mean diffusivity (MD) maps extracted. The 'skeletonized' white matter FA and MD maps were entered into the Elastic Net machine learning algorithm to distinguish individual subjects' phenotypic labels (e.g. phenotype I vs. phenotype II). This calculation was performed to ascertain whether the identified clinical phenotypes were biologically distinct. Original neurocognitive measurements distinguished individual subjects' phenotypic labels with 94% accuracy (sensitivity=92%, specificity=97%). TBSS derived FA and MD measurements predicted individual subjects' phenotypic labels with 76% and 65% accuracy respectively. In addition, individual subjects belonging to phenotypes I and II were distinguished from healthy controls with 57% and 92% accuracy respectively. Neurocognitive task variables identified as most relevant in distinguishing phenotypic labels included; Affective Go/No-Go (AGN), Cambridge Gambling Task (CGT) coupled with inferior fronto-occipital fasciculus and callosal white matter pathways. These results suggest that there may exist two biologically distinct clinical phenotypes in bipolar disorders which can be identified from healthy controls with high accuracy and at an individual subject level. We suggest a strong clinical utility of the proposed approach in defining and validating biologically meaningful and less heterogeneous clinical sub-phenotypes of major psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.
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Anderson, Jill T; Eckhart, Vincent M; Geber, Monica A
2015-09-01
Sister taxa with distinct phenotypes often occupy contrasting environments in parapatric ranges, yet we generally do not know whether trait divergence reflects spatially varying selection. We conducted a reciprocal transplant experiment to test whether selection favors "native phenotypes" in two subspecies of Clarkia xantiana (Onagraceae), an annual plant in California. For four quantitative traits that differ between subspecies, we estimated phenotypic selection in subspecies' exclusive ranges and their contact zone in two consecutive years. We predicted that in the arid, pollinator-scarce eastern region, selection favors phenotypes of the native subspecies parviflora: small leaves, slow leaf growth, early flowering, and diminutive flowers. In the wetter, pollinator-rich, western range of subspecies xantiana, we expected selection for opposite phenotypes. We investigated pollinator contributions to selection by comparing naturally pollinated and pollen-supplemented individuals. For reproductive traits and for subspecies xantiana, selection generally matched expectations. The contact zone sometimes showed distinctive selection, and in ssp. parviflora selection sometimes favored nonnative phenotypes. Pollinators influenced selection on flowering time but not on flower size. Little temporal variation in selection occurred, possibly because of plastic trait responses across years. Though there were exceptions and some causes of selection remain obscure, phenotypic differentiation between subspecies appears to reflect spatially variable selection. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.
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Metabolomic phenotyping of a cloned pig model
2011-01-01
Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6) by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals. PMID:21859467
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Deletions of VCX-A and NLGN4: A Variable Phenotype Including Normal Intellect
ERIC Educational Resources Information Center
Macarov, M.; Zeigler, M.; Newman, J. P.; Strich, D.; Sury, V.; Tennenbaum, A.; Meiner, V.
2007-01-01
Background: Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, "VCX-A" (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports…
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Hellenbroich, Y; Tzivras, G; Neppert, B; Schwinger, E; Zühlke, C
2001-01-01
Five autosomal dominantly inherited corneal dystrophies are caused by missense mutations in the betaIGH3 gene on chromosome 5q31. Here we describe the clinical features and the analysis of the betaIGH3 gene in a Greek four-generation family with lattice corneal dystrophy type 1 (CDL1). Sequencing of the betaIGH3 cDNA from an affected family member revealed the R124C mutation. More recent data indicate that this is probably a mutation hot spot in CDL1. We could not find a common haplotype with another CDL1 family with the R124C mutation demonstrating that this mutation occurs independently in different families. The clinical course of the disease showed a remarkable variability between the affected family members. To investigate a possible role between the phenotypic variability and apolipoprotein E (ApoE), which co-localises with amyloid deposits in CDL1, we determined the ApoE genotype of all family members. The resulting data revealed no association with the variable clinical course. Copyright 2001 S. Karger AG, Basel
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sarkar, Mohamadi; Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298; Stabbert, Regina
Some aromatic amines are considered to be putative bladder carcinogens. Hemoglobin (Hb) adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) have been used as biomarkers of exposure to aromatic amines from cigarette smoke. One of the goals of this study was to determine intra- and inter-individual variability in 3-ABP and 4-ABP Hb adducts and to explore the predictability of ABP Hb adduct levels based on caffeine phenotyping. The study was conducted in adult smokers (S, n = 65) and non-smokers (NS, n 65). The subjects were phenotyped for CYP1A2 and NAT2 using urinary caffeine metabolites. Blood samples were collected twice withinmore » 6 weeks and adducts measured by GC/MS. The levels of 4-ABP Hb adducts were significantly (p < 0.0001) greater in S (34.5 {+-} 21.06 pg/g Hb) compared to NS (6.3 {+-} 3.02 pg/g Hb). The levels of 3-ABP Hb adducts were below the limit of quantification (BLOQ) in most (82%) of the NS and about 10-fold lower in S (3.6 {+-} 3.29 pg/g Hb) compared to 4-ABP Hb adducts. No differences were observed in the adduct levels between weeks 1 and 6 in the smokers, suggesting that a single sample would be adequate to monitor cigarette smoke exposure. The regression model developed with CYP1A2, NAT2 phenotype and number of cigarettes smoked (NCIG) accounted for 47% of the variability in 3-ABP adducts, whereas 32% variability in 4-ABP adducts was accounted by CYP1A2 and NCIG. The ratio of 4-ABP Hb adducts in adult S:NS was {approx} 5:1, whereas 3-ABP Hb adducts levels were BLOQ in some S, exhibited large interindividual variability ({approx} 91% compared to 57% for 4-ABP Hb) and poor dose response relationship. Therefore, 4-ABP Hb adduct levels may be a more useful biomarker of aminobiphenyl exposure from cigarette smoke.« less
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Zhou, Chaomin; Li, Yongqiang; Shao, Xiaofei; Zou, Hequn
2018-01-25
Assessing and comparing the ability of the hypertriglyceridemic waist (HW) phenotype and anthropometric obesity indexes to identify subjects at high risk of chronic kidney disease (CKD) in a relatively lean population in South China. Using data from a community-based, cross-sectional study conducted in Zhuhai City, Southern China, we examined associations between the HW phenotype, anthropometric obesity indexes, and incident CKD risk in a relatively lean population. Multiple logistic regression analyses were used to evaluate the associations. The HW phenotype associated with CKD significantly in the unadjusted analysis (OR 3.53, 95% CI 1.65-7.52, P = 0.001). Further adjustment for gender, age, and other potential confounding variables had an impact on the odd ratios (OR); the OR decreased but still existed (OR 2.91, 95% 1.23-6.87, P = 0.016). The association of the HW phenotype with CKD remained significant after further adjustment for hypertension and diabetes. No significant association between the anthropometric indexes and incident CKD was found. The HW phenotype, but not the anthropometric indexes, is associated with an elevated risk of CKD in relatively lean subjects. The HW phenotype appears to be a better predictor of CKD than the anthropometric indexes. Level V, descriptive study.
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Identification of novel mutations in Mexican patients with Aarskog-Scott syndrome.
Pérez-Coria, Mariana; Lugo-Trampe, José J; Zamudio-Osuna, Michell; Rodríguez-Sánchez, Iram P; Lugo-Trampe, Angel; de la Fuente-Cortez, Beatriz; Campos-Acevedo, Luis D; Martínez-de-Villarreal, Laura E
2015-05-01
Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X-linked disorder of recessive inheritance, characterized by short stature and facial, skeletal, and urogenital abnormalities. AAS is caused by mutations in the FGD1 gene (Xp11.22), with over 56 different mutations identified to date. We present the clinical and molecular analysis of four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop mutations not previously reported in the literature: p.Gln664* and p.Glu380*. Phenotypically, every male patient met the clinical criteria of the syndrome, whereas discrepancies were found between phenotypes in female patients. Our results identify two novel mutations in FGD1, broadening the spectrum of reported mutations; and provide further delineation of the phenotypic variability previously described in AAS.
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Identification of novel mutations in Mexican patients with Aarskog–Scott syndrome
Pérez-Coria, Mariana; Lugo-Trampe, José J; Zamudio-Osuna, Michell; Rodríguez-Sánchez, Iram P; Lugo-Trampe, Angel; de la Fuente-Cortez, Beatriz; Campos-Acevedo, Luis D; Martínez-de-Villarreal, Laura E
2015-01-01
Aarskog–Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X-linked disorder of recessive inheritance, characterized by short stature and facial, skeletal, and urogenital abnormalities. AAS is caused by mutations in the FGD1 gene (Xp11.22), with over 56 different mutations identified to date. We present the clinical and molecular analysis of four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop mutations not previously reported in the literature: p.Gln664* and p.Glu380*. Phenotypically, every male patient met the clinical criteria of the syndrome, whereas discrepancies were found between phenotypes in female patients. Our results identify two novel mutations in FGD1, broadening the spectrum of reported mutations; and provide further delineation of the phenotypic variability previously described in AAS. PMID:26029706
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Saccharomyces cerevisiae metabolism in ecological context.
Jouhten, Paula; Ponomarova, Olga; Gonzalez, Ramon; Patil, Kiran R
2016-11-01
The architecture and regulation of Saccharomyces cerevisiae metabolic network are among the best studied owing to its widespread use in both basic research and industry. Yet, several recent studies have revealed notable limitations in explaining genotype-metabolic phenotype relations in this yeast, especially when concerning multiple genetic/environmental perturbations. Apparently unexpected genotype-phenotype relations may originate in the evolutionarily shaped cellular operating principles being hidden in common laboratory conditions. Predecessors of laboratory S. cerevisiae strains, the wild and the domesticated yeasts, have been evolutionarily shaped by highly variable environments, very distinct from laboratory conditions, and most interestingly by social life within microbial communities. Here we present a brief review of the genotypic and phenotypic peculiarities of S. cerevisiae in the context of its social lifestyle beyond laboratory environments. Accounting for this ecological context and the origin of the laboratory strains in experimental design and data analysis would be essential in improving the understanding of genotype-environment-phenotype relationships. © FEMS 2016.
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Saccharomyces cerevisiae metabolism in ecological context
Jouhten, Paula; Ponomarova, Olga; Gonzalez, Ramon
2016-01-01
The architecture and regulation of Saccharomyces cerevisiae metabolic network are among the best studied owing to its widespread use in both basic research and industry. Yet, several recent studies have revealed notable limitations in explaining genotype–metabolic phenotype relations in this yeast, especially when concerning multiple genetic/environmental perturbations. Apparently unexpected genotype–phenotype relations may originate in the evolutionarily shaped cellular operating principles being hidden in common laboratory conditions. Predecessors of laboratory S. cerevisiae strains, the wild and the domesticated yeasts, have been evolutionarily shaped by highly variable environments, very distinct from laboratory conditions, and most interestingly by social life within microbial communities. Here we present a brief review of the genotypic and phenotypic peculiarities of S. cerevisiae in the context of its social lifestyle beyond laboratory environments. Accounting for this ecological context and the origin of the laboratory strains in experimental design and data analysis would be essential in improving the understanding of genotype–environment–phenotype relationships. PMID:27634775
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Natural Variation of Drug Susceptibility in Wild-Type Human Immunodeficiency Virus Type 1
Parkin, N. T.; Hellmann, N. S.; Whitcomb, J. M.; Kiss, L.; Chappey, C.; Petropoulos, C. J.
2004-01-01
Wild-type viruses from the ViroLogic phenotype-genotype database were evaluated to determine the upper confidence limit of the drug susceptibility distributions, or “biological cutoffs,” for the PhenoSense HIV phenotypic drug susceptibility assay. Definition of the natural variation in drug susceptibility in wild-type human immunodeficiency virus (HIV) type 1 isolates is necessary to determine the prevalence of innate drug resistance and to assess the capability of the PhenoSense assay to reliably measure subtle reductions in drug susceptibility. The biological cutoffs for each drug, defined by the 99th percentile of the fold change in the 50% inhibitory concentration distributions or the mean fold change plus 2 standard deviations, were lower than those previously reported for other phenotypic assays and lower than the clinically relevant cutoffs previously defined for the PhenoSense assay. The 99th percentile fold change values ranged from 1.2 (tenofovir) to 1.8 (zidovudine) for nucleoside reverse transcriptase RT inhibitors (RTIs), from 3.0 (efavirenz) to 6.2 (delavirdine) for nonnucleoside RTIs, and from 1.6 (lopinavir) to 3.6 (nelfinavir) for protease inhibitors. To evaluate the potential role of intrinsic assay variability in the observed variations in the drug susceptibilities of wild-type isolates, 10 reference viruses with different drug susceptibility patterns were tested 8 to 30 times each. The median coefficients of variation in fold change for the reference viruses ranged from 12 to 18% for all drugs except zidovudine (32%), strongly suggesting that the observed differences in wild-type virus susceptibility to the different drugs is related to intrinsic virus variability rather than assay variability. The low biological cutoffs and assay variability suggest that the PhenoSense HIV assay may assist in defining clinically relevant susceptibility cutoffs for resistance to antiretroviral drugs. PMID:14742192
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Newton, Katherine M; Peissig, Peggy L; Kho, Abel Ngo; Bielinski, Suzette J; Berg, Richard L; Choudhary, Vidhu; Basford, Melissa; Chute, Christopher G; Kullo, Iftikhar J; Li, Rongling; Pacheco, Jennifer A; Rasmussen, Luke V; Spangler, Leslie; Denny, Joshua C
2013-06-01
Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats. To present lessons learned about validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies. The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University. By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results. Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.
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Mather, Lisa; Blom, Victoria; Bergström, Gunnar; Svedberg, Pia
2016-12-01
Depression and anxiety are highly comorbid due to shared genetic risk factors, but less is known about whether burnout shares these risk factors. We aimed to examine whether the covariation between major depressive disorder (MDD), generalized anxiety disorder (GAD), and burnout is explained by common genetic and/or environmental factors. This cross-sectional study included 25,378 Swedish twins responding to a survey in 2005-2006. Structural equation models were used to analyze whether the trait variances and covariances were due to additive genetics, non-additive genetics, shared environment, and unique environment. Univariate analyses tested sex limitation models and multivariate analysis tested Cholesky, independent pathway, and common pathway models. The phenotypic correlations were 0.71 (0.69-0.74) between MDD and GAD, 0.58 (0.56-0.60) between MDD and burnout, and 0.53 (0.50-0.56) between GAD and burnout. Heritabilities were 45% for MDD, 49% for GAD, and 38% for burnout; no statistically significant sex differences were found. A common pathway model was chosen as the final model. The common factor was influenced by genetics (58%) and unique environment (42%), and explained 77% of the variation in MDD, 69% in GAD, and 44% in burnout. GAD and burnout had additive genetic factors unique to the phenotypes (11% each), while MDD did not. Unique environment explained 23% of the variability in MDD, 20% in GAD, and 45% in burnout. In conclusion, the covariation was explained by an underlying common factor, largely influenced by genetics. Burnout was to a large degree influenced by unique environmental factors not shared with MDD and GAD.
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McCracken, Allen; Locke, John
2014-01-01
Genes in multicellular organisms are expressed as part of a developmental program that is largely dependent on self-perpetuating higher-order chromatin states. The mechanism of establishing and maintaining these epigenetic events is well studied in Drosophila. The first known example of an epigenetic effect was that of (PEV) in Drosophila, which has been shown to be due to gene silencing via heterochromatin formation. We are investigating a process similar to Position Effect Variegation (PEV) using a mini-w transgene, called Pci, inserted in the upstream regulatory region of ci. The mini-white + transgene in Pci is expressed throughout the adult eye; however, when other P or KP elements are present, a variegated eye phenotype results indicating random w + silencing during development. This P element dependent silencing (PDS) can be modified by the haplo-suppressors/triplo-enhancers, Su(var)205 and Su(var)3–7, indicating that these heterochromatic modifiers also act dose dependently in PDS. Here we use a spontaneous derivative mutation of Pci called PciE1 (E1) that variegates like PDS in the absence of P elements, presumably due to an adjacent gypsy element insertion, to screen for second-site modifier mutations that enhance variable silencing of white + in E1. We isolated 7 mutations in CG8878, an essential gene, that enhance the E1 variegated phenotype. CG8878, a previously uncharacterized gene, potentially encodes a serine/threonine kinase whose closest Drosophila paralogue, ballchen (nhk-1), phosphorylates histones. These mutant alleles enhance both PDS at E1 and Position Effect Variegation (PEV) at wm4, indicating a previously unknown common silencing mechanism between the two. PMID:24614804
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2016-02-26
minimal to mild expansion of the white pulp by lymphoid hyperplasia with variable numbers of plasma cells within the white and red pulp (Figures 8G–I... Cell . Infect. Microbiol. 6:21. doi: 10.3389/fcimb.2016.00021 Phenotypic Characterization of a Novel Virulence-Factor Deletion Strain of Burkholderia...respect to intracellular growth, macrophage uptake and phagosomal escape, actin-based motility, and multinucleated giant cell formation. Based on observed
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Gregorio-Arenas, E; Ruiz-Cabello, P; Camiletti-Moirón, D; Moratalla-Cecilia, N; Aranda, P; López-Jurado, M; Llopis, J; Aparicio, V A
2016-10-01
To study the association between physical fitness and body-size phenotypes, and to test which aspects of physical fitness show the greatest independent association with cardiometabolic risk in perimenopausal women. This cross-sectional study involved 228 women aged 53±5years from southern Spain. Physical fitness was assessed by means of the Senior Fitness Test Battery (additionally including handgrip strength and timed up-and-go tests). Anthropometry, resting heart rate, blood pressure and plasma markers of lipid, glycaemic and inflammatory status were measured by standard procedures. The harmonized definition of the 'metabolically healthy but obese' (MHO) phenotype was employed to classify individuals. The overall prevalence of the MHO phenotype was 13% but was 43% among the obese women. Apart from traditional markers, metabolically healthy non-obese women had lower levels of C-reactive protein than women with the other phenotypes (p<0.001), and levels of glycosylated haemoglobin were lower in MHO women than in metabolically abnormal non-obese women (overall p=0.004). Most of the components of physical fitness differed with body-size phenotypes. The 6-min walk and the back-scratch tests presented the most robust differences (both p<0.001). Moreover, the women's performance on the back-scratch (β=0.32; p<0.001) and the 6-min walk (β=0.22; p=0.003) tests was independently associated with the clustered cardiometabolic risk. The back-scratch test explained 10% of the variability (step 1, p<0.001), and the final model, which also included the 6-min walk test (step 2, p=0.003), explained 14% of the variability. Low upper-body flexibility was the most important fitness indicator of cardiometabolic risk in perimenopausal women, but cardiorespiratory fitness also played an important role. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Embryonic environment and transgenerational effects in quail.
Leroux, Sophie; Gourichon, David; Leterrier, Christine; Labrune, Yann; Coustham, Vincent; Rivière, Sandrine; Zerjal, Tatiana; Coville, Jean-Luc; Morisson, Mireille; Minvielle, Francis; Pitel, Frédérique
2017-01-26
Environmental exposures, for instance to chemicals, are known to impact plant and animal phenotypes on the long term, sometimes across several generations. Such transgenerational phenotypes were shown to be promoted by epigenetic alterations such as DNA methylation, an epigenetic mark involved in the regulation of gene expression. However, it is yet unknown whether transgenerational epigenetic inheritance of altered phenotypes exists in birds. The purpose of this study was to develop an avian model to investigate whether changes to the embryonic environment had a transgenerational effect that could alter the phenotypes of third-generation offspring. Given its impact on the mammalian epigenome and the reproductive system in birds, genistein was used as an environment stressor. We compared several third-generation phenotypes of two quail "epilines", which were obtained from genistein-injected eggs (Epi+) or from untreated eggs (Epi-) from the same founders. A "mirrored" crossing strategy was used to minimize between-line genetic variability by maintaining similar ancestor contributions across generations in each line. Three generations after genistein treatment, a significant difference in the sexual maturity of the females, which, after three generations, could not be attributed to direct maternal effects, was observed between the lines, with Epi+ females starting to lay eggs later. Adult body weight was significantly affected by genistein treatment applied in a previous generation, and a significant interaction between line and sex was observed for body weight at 3 weeks. Behavioral traits, such as evaluating the birds' reaction to social isolation, were also significantly affected by genistein treatment. Yet, global methylation analyses revealed no significant difference between the epilines. These findings demonstrate that embryonic environment affects the phenotype of offspring three generations later in quail. While one cannot rule out the existence of some initial genetic variability between the lines, the mirrored animal design should have minimized its effects, and thus, the observed differences in animals of the third generation may be attributed, at least partly, to transgenerational epigenetic phenomena.
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López-Álvarez, Diana; Zubair, Hassan; Beckmann, Manfred; Draper, John
2017-01-01
Abstract Background and Aims Morphological traits in combination with metabolite fingerprinting were used to investigate inter- and intraspecies diversity within the model annual grasses Brachypodium distachyon, Brachypodium stacei and Brachypodium hybridum. Methods Phenotypic variation of 15 morphological characters and 2219 nominal mass (m/z) signals generated using flow infusion electrospray ionization–mass spectrometry (FIE–MS) were evaluated in individuals from a total of 174 wild populations and six inbred lines, and 12 lines, of the three species, respectively. Basic statistics and multivariate principal component analysis and discriminant analysis were used to differentiate inter- and intraspecific variability of the two types of variable, and their association was assayed with the rcorr function. Key Results Basic statistics and analysis of variance detected eight phenotypic characters [(stomata) leaf guard cell length, pollen grain length, (plant) height, second leaf width, inflorescence length, number of spikelets per inflorescence, lemma length, awn length] and 434 tentatively annotated metabolite signals that significantly discriminated the three species. Three phenotypic traits (pollen grain length, spikelet length, number of flowers per inflorescence) might be genetically fixed. The three species showed different metabolomic profiles. Discriminant analysis significantly discriminated the three taxa with both morphometric and metabolome traits and the intraspecific phenotypic diversity within B. distachyon and B. stacei. The populations of B. hybridum were considerably less differentiated. Conclusions Highly explanatory metabolite signals together with morphological characters revealed concordant patterns of differentiation of the three taxa. Intraspecific phenotypic diversity was observed between northern and southern Iberian populations of B. distachyon and between eastern Mediterranean/south-western Asian and western Mediterranean populations of B. stacei. Significant association was found for pollen grain length and lemma length and ten and six metabolomic signals, respectively. These results would guide the selection of new germplasm lines of the three model grasses in ongoing genome-wide association studies. PMID:28040672
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Clinical features associated with copy number variations of the 14q32 imprinted gene cluster.
Rosenfeld, Jill A; Fox, Joyce E; Descartes, Maria; Brewer, Fallon; Stroud, Tracy; Gorski, Jerome L; Upton, Sheila J; Moeschler, John B; Monteleone, Berrin; Neill, Nicholas J; Lamb, Allen N; Ballif, Blake C; Shaffer, Lisa G; Ravnan, J Britt
2015-02-01
Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes.
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Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L.
2013-01-01
Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays. PMID:23737753
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Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L
2013-05-01
Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays.