Voluntary participation and comprehension of informed consent in a genetic epidemiological study of breast cancer in Nigeria

PubMed Central

2014-01-01

Background Studies on informed consent to medical research conducted in low or middle-income settings have increased, including empirical investigations of consent to genetic research. We investigated voluntary participation and comprehension of informed consent among women involved in a genetic epidemiological study on breast cancer in an urban setting of Nigeria comparing women in the case and control groups. Methods Surveys were administered in face-to-face interviews with 215 participants following their enrollment in the genetic study (106 patients, 109 controls). Audio-taped in-depth interviews were conducted with a sub-sample of 17 (8%) women who completed the survey. Results The majority of all participants reported being told that participation in the genetic study was voluntary (97%), that they did not feel pressured to participate in the study (99%), and that they could withdraw from the study (81%). The majority of the breast cancer patients (83%) compared to 58% of women in the control group reported that the study purpose was to learn about the genetic inheritance of breast cancer (OR 3.44; 95% CI =1.66, 7.14, p value = 0.001). Most participants reported being told about study procedures (95%) and study benefits (98%). Sixty-eight percent of the patients, compared to 47% of the control group reported being told about study risks (p-value <0.001). Of the 165 married women, 19% reported asking permission from their husbands to enroll in the breast cancer study; no one sought permission from local elders. In-depth interviews highlight the use of persuasion and negotiation between a wife and her husband regarding study participation. Conclusions The global expansion of genetic and genomic research highlights our need to understand informed consent practices for studies in ethnically diverse cultural environments such as Africa. Quantitative and qualitative empirical investigations of the informed consent process for genetic and genomic research will further our knowledge of complex issues associated with communication of information, comprehension, decisional authority and voluntary participation. In the future, the development and testing of innovative strategies to promote voluntary participation and comprehension of the goals of genomic research will contribute to our understanding of strategies that enhance the consent process. PMID:24885380

Cross-study differences in the etiology of reading comprehension: A meta-analytical review of twin studies

PubMed Central

Little, Callie W; Haughbrook, Rasheda; Hart, Sara A

2016-01-01

Numerous twin studies have been published examining the genetic and environmental etiology of reading comprehension, though the etiological estimates may be influenced currently unidentified sample conditions (e.g., Tucker-Drob & Bates, 2015). The purpose of the current meta-analysis was to average the etiological influences of reading comprehension and to explore the potential moderators that may be influencing these estimates. Results revealed an average heritability estimate of h2 = .59, with significant variation in estimates across studies, suggesting potential moderation. Heritability was moderated by publication year, grade level, project, zygosity determination method, and response type. The average shared environmental estimate was c2 = .16, with publication year, grade and zygosity determination method acting as significant moderators. These findings support the large role of genetic influences on reading comprehension, and a small but significant role of shared environmental influences. The significant moderators of etiological influences within the current synthesis suggest our interpretation of how genes and environment influence reading comprehension should reflect aspects of study and sample. PMID:27630039

An introduction to genetic quality in the context of sexual selection.

PubMed

Pitcher, Trevor E; Mays, Herman L

2008-09-01

This special issue of Genetica brings together empirical researchers and theoreticians to present the latest on the evolutionary ecology of genetic quality in the context of sexual selection. The work comes from different fields of study including behavioral ecology, quantitative genetics and molecular genetics on a diversity of organisms using different approaches from comparative studies, mathematical modeling, field studies and laboratory experiments. The papers presented in this special issue primarily focus on genetic quality in relation to (1) sources of genetic variation, (2) polyandry, (3) new theoretical developments and (4) comprehensive reviews.

Do Knowledge Arrangements Affect Student Reading Comprehension of Genetics?

ERIC Educational Resources Information Center

Wu, Jen-Yi; Tung, Yu-Neng; Hwang, Bi-Chi; Lin, Chen-Yung; Che-Di, Lee; Chang, Yung-Ta

2014-01-01

Various sequences for teaching genetics have been proposed. Three seventh-grade biology textbooks in Taiwan share similar key knowledge assemblages but have different knowledge arrangements. To investigate the influence of knowledge arrangements on student understanding of genetics, we compared students' reading comprehension of the three texts…

'RetinoGenetics': a comprehensive mutation database for genes related to inherited retinal degeneration.

PubMed

Ran, Xia; Cai, Wei-Jun; Huang, Xiu-Feng; Liu, Qi; Lu, Fan; Qu, Jia; Wu, Jinyu; Jin, Zi-Bing

2014-01-01

Inherited retinal degeneration (IRD), a leading cause of human blindness worldwide, is exceptionally heterogeneous with clinical heterogeneity and genetic variety. During the past decades, tremendous efforts have been made to explore the complex heterogeneity, and massive mutations have been identified in different genes underlying IRD with the significant advancement of sequencing technology. In this study, we developed a comprehensive database, 'RetinoGenetics', which contains informative knowledge about all known IRD-related genes and mutations for IRD. 'RetinoGenetics' currently contains 4270 mutations in 186 genes, with detailed information associated with 164 phenotypes from 934 publications and various types of functional annotations. Then extensive annotations were performed to each gene using various resources, including Gene Ontology, KEGG pathways, protein-protein interaction, mutational annotations and gene-disease network. Furthermore, by using the search functions, convenient browsing ways and intuitive graphical displays, 'RetinoGenetics' could serve as a valuable resource for unveiling the genetic basis of IRD. Taken together, 'RetinoGenetics' is an integrative, informative and updatable resource for IRD-related genetic predispositions. Database URL: http://www.retinogenetics.org/. © The Author(s) 2014. Published by Oxford University Press.

Genetic Distinctiveness of Rye In situ Accessions from Portugal Unveils a New Hotspot of Unexplored Genetic Resources

PubMed Central

Monteiro, Filipa; Vidigal, Patrícia; Barros, André B.; Monteiro, Ana; Oliveira, Hugo R.; Viegas, Wanda

2016-01-01

Rye (Secale cereale L.) is a cereal crop of major importance in many parts of Europe and rye breeders are presently very concerned with the restrict pool of rye genetic resources available. Such narrowing of rye genetic diversity results from the presence of “Petkus” pool in most modern rye varieties as well as “Petkus” × “Carsten” heterotic pool in hybrid rye breeding programs. Previous studies on rye's genetic diversity revealed moreover a common genetic background on landraces (ex situ) and cultivars, regardless of breeding level or geographical origin. Thus evaluation of in situ populations is of utmost importance to unveil “on farm” diversity, which is largely undervalued. Here, we perform the first comprehensive assessment of rye's genetic diversity and population structuring using cultivars, ex situ landraces along a comprehensive sampling of in situ accessions from Portugal, through a molecular-directed analysis using SSRs markers. Rye genetic diversity and population structure analysis does not present any geographical trend but disclosed marked differences between genetic backgrounds of in situ accessions and those of cultivars/ex situ collections. Such genetic distinctiveness of in situ accessions highlights their unexplored potential as new genetic resources, which can be used to boost rye breeding strategies and the production of new varieties. Overall, our study successfully demonstrates the high prospective impact of comparing genetic diversity and structure of cultivars, ex situ, and in situ samples in ascertaining the status of plant genetic resources (PGR). PMID:27630658

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

PubMed Central

Moreno-Moral, Aida

2016-01-01

ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes.

PubMed

Moreno-Moral, Aida; Petretto, Enrico

2016-10-01

Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. © 2016. Published by The Company of Biologists Ltd.

The Genetic and Environmental Etiologies of the Relations between Cognitive Skills and Components of Reading Ability

PubMed Central

Christopher, Micaela E.; Keenan, Janice M.; Hulslander, Jacqueline; DeFries, John C.; Miyake, Akira; Wadsworth, Sally J.; Willcutt, Erik; Pennington, Bruce; Olson, Richard K.

2016-01-01

While previous research has shown cognitive skills to be important predictors of reading ability in children, the respective roles for genetic and environmental influences on these relations is an open question. The present study explored the genetic and environmental etiologies underlying the relations between selected executive functions and cognitive abilities (working memory, inhibition, processing speed, and naming speed) with three components of reading ability (word reading, reading comprehension, and listening comprehension). Twin pairs drawn from the Colorado Front Range (n = 676; 224 monozygotic pairs; 452 dizygotic pairs) between the ages of eight and 16 (M = 11.11) were assessed on multiple measures of each cognitive and reading-related skill. Each cognitive and reading-related skill was modeled as a latent variable, and behavioral genetic analyses estimated the portions of phenotypic variance on each latent variable due to genetic, shared environmental, and nonshared environmental influences. The covariance between the cognitive skills and reading-related skills was driven primarily by genetic influences. The cognitive skills also shared large amounts of genetic variance, as did the reading-related skills. The common cognitive genetic variance was highly correlated with the common reading genetic variance, suggesting that genetic influences involved in general cognitive processing are also important for reading ability. Skill-specific genetic variance in working memory and processing speed also predicted components of reading ability. Taken together, the present study supports a genetic association between children’s cognitive ability and reading ability. PMID:26974208

Test anxiety and a high-stakes standardized reading comprehension test: A behavioral genetics perspective.

PubMed

Wood, Sarah G; Hart, Sara A; Little, Callie W; Phillips, Beth M

2016-07-01

Past research suggests that reading comprehension test performance does not rely solely on targeted cognitive processes such as word reading, but also on other non-target aspects such as test anxiety. Using a genetically sensitive design, we sought to understand the genetic and environmental etiology of the association between test anxiety and reading comprehension as measured by a high-stakes test. Mirroring the behavioral literature of test anxiety, three different dimensions of test anxiety were examined in relation to reading comprehension, namely intrusive thoughts, autonomic reactions, and off-task behaviors. Participants included 426 sets of twins from the Florida Twin Project on Reading. The results indicated test anxiety was negatively associated with reading comprehension test performance, specifically through common shared environmental influences. The significant contribution of test anxiety to reading comprehension on a high-stakes test supports the notion that non-targeted factors may be interfering with accurately assessing students' reading abilities.

Present status of understanding on the genetic etiology of polycystic ovary syndrome.

PubMed

Dasgupta, S; Reddy, B Mohan

2008-01-01

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age with a prevalence of approximately 7-10% worldwide. PCOS reflects multiple potential aetiologies and variable clinical manifestations. This syndrome is characterized by serious health implications such as diabetes, coronary heart diseases and cancer and also leads to infertility. PCOS can be viewed as a heterogeneous androgen excess disorder with varying degrees of reproductive and metabolic abnormalities determined by the interaction of multiple genetic and environmental factors. In this paper, we have attempted a comprehensive review of primarily molecular genetic studies done so far on PCOS. We have also covered the studies focusing on the environmental factors and impact of ethnicity on the presentation of this syndrome. A large number of studies have been attempted to understand the aetiological mechanisms behind PCOS both at the clinical and molecular genetic levels. In the Indian context, majority of the PCOS studies have been confined to the clinical dimensions. However, a concrete genetic mechanism behind the manifestation of PCOS is yet to be ascertained. Understanding of this complex disorder requires comprehensive studies incorporating relatively larger homogenous samples for genetic analysis and taking into account the ethnicity and the environmental conditions of the population/cohort under study. Research focused on these aspects may provide better understanding on the genetic etiology and the interaction between genes and environment, which may help develop new treatment methods and possible prevention of the syndrome.

MetaGenyo: a web tool for meta-analysis of genetic association studies.

PubMed

Martorell-Marugan, Jordi; Toro-Dominguez, Daniel; Alarcon-Riquelme, Marta E; Carmona-Saez, Pedro

2017-12-16

Genetic association studies (GAS) aims to evaluate the association between genetic variants and phenotypes. In the last few years, the number of this type of study has increased exponentially, but the results are not always reproducible due to experimental designs, low sample sizes and other methodological errors. In this field, meta-analysis techniques are becoming very popular tools to combine results across studies to increase statistical power and to resolve discrepancies in genetic association studies. A meta-analysis summarizes research findings, increases statistical power and enables the identification of genuine associations between genotypes and phenotypes. Meta-analysis techniques are increasingly used in GAS, but it is also increasing the amount of published meta-analysis containing different errors. Although there are several software packages that implement meta-analysis, none of them are specifically designed for genetic association studies and in most cases their use requires advanced programming or scripting expertise. We have developed MetaGenyo, a web tool for meta-analysis in GAS. MetaGenyo implements a complete and comprehensive workflow that can be executed in an easy-to-use environment without programming knowledge. MetaGenyo has been developed to guide users through the main steps of a GAS meta-analysis, covering Hardy-Weinberg test, statistical association for different genetic models, analysis of heterogeneity, testing for publication bias, subgroup analysis and robustness testing of the results. MetaGenyo is a useful tool to conduct comprehensive genetic association meta-analysis. The application is freely available at http://bioinfo.genyo.es/metagenyo/ .

Comprehensive molecular diagnosis of Epstein-Barr virus-associated lymphoproliferative diseases using next-generation sequencing.

PubMed

Ono, Shintaro; Nakayama, Manabu; Kanegane, Hirokazu; Hoshino, Akihiro; Shimodera, Saeko; Shibata, Hirofumi; Fujino, Hisanori; Fujino, Takahiro; Yunomae, Yuta; Okano, Tsubasa; Yamashita, Motoi; Yasumi, Takahiro; Izawa, Kazushi; Takagi, Masatoshi; Imai, Kohsuke; Zhang, Kejian; Marsh, Rebecca; Picard, Capucine; Latour, Sylvain; Ohara, Osamu; Morio, Tomohiro

2018-05-18

Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD were used in this comprehensive molecular diagnosis. Causative gene mutations (involving PRF1 and SH2D1A) were detected in two of the 19 patients studied. This comprehensive diagnosis method effectively detected mutations in all coding exons of 23 genes with sufficient read numbers for each amplicon. This comprehensive molecular diagnostic method using PCR and NGS provides a rapid, accurate, low-cost diagnosis for patients with XLP or XLP-like diseases.

Generalizing genetical genomics: getting added value from environmental perturbation.

PubMed

Li, Yang; Breitling, Rainer; Jansen, Ritsert C

2008-10-01

Genetical genomics is a useful approach for studying the effect of genetic perturbations on biological systems at the molecular level. However, molecular networks depend on the environmental conditions and, thus, a comprehensive understanding of biological systems requires studying them across multiple environments. We propose a generalization of genetical genomics, which combines genetic and sensibly chosen environmental perturbations, to study the plasticity of molecular networks. This strategy forms a crucial step toward understanding why individuals respond differently to drugs, toxins, pathogens, nutrients and other environmental influences. Here we outline a strategy for selecting and allocating individuals to particular treatments, and we discuss the promises and pitfalls of the generalized genetical genomics approach.

Test Anxiety and a High-Stakes Standardized Reading Comprehension Test: A Behavioral Genetics Perspective

ERIC Educational Resources Information Center

Wood, Sarah G.; Hart, Sara A.; Little, Callie W.; Phillips, Beth M.

2016-01-01

Past research suggests that reading comprehension test performance does not rely solely on targeted cognitive processes such as word reading, but also on other nontarget aspects such as test anxiety. Using a genetically sensitive design, we sought to understand the genetic and environmental etiology of the association between test anxiety and…

Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value.

PubMed

Pacheco-Villalobos, David; Hardtke, Christian S

2012-06-05

Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics.

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

DTIC Science & Technology

2013-03-14

SUPPLEMENTARY NOTES 14. ABSTRACT Autism is an extremely common and heterogeneous neurodevelopmental disorder. While genetic factors are known to play...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population.

PubMed

Lin, X Y; Wang, J; Xiao, X; Xu, Y W; Yan, Q J; Jiang, W Y

2018-04-01

To reduce the incidence of hemophilia B (HB) which with no complete cure currently, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are effective and feasible means. However, previous studies about genetic diagnosis in HB mostly just focused on the detection of patients and carriers. Here, we established a comprehensive genetic diagnosis strategy for HB and worked it out in Chinese population. The strategy includes the detection of patients and carriers, prenatal diagnosis, and PGD. Seven unrelated HB families from Chinese population involved in this study. Firstly, probands and available members were carried out coagulation laboratory assays, and the clinical information has been recorded. Secondly, we used DNA direct sequencing to screen the whole FIX gene of them. The pathogenicity of novel mutations was verified according to 2015 ACMG-AM guidelines. For prenatal diagnosis, a mix of DNA direct sequencing and STR linkage analysis was employed. To explore a better PGD protocol, Karyomapping was first applied in PGD of HB, comparing with conventional PCR-based methods. Six different pathogenic mutations including 1 novel duplication (c.660_661dup ATCA) were identified. The results of prenatal diagnosis were consistent with birth outcomes. In the PGD case, 4 of 11 embryos were confirmed to be normal and one of them was transferred and led to a healthy birth. The established genetic diagnosis strategy for HB in our study was comprehensive and well applied in clinic practice. Besides, we recommended that DNA direct sequencing combined with Karyomapping was a better PGD protocol. © 2017 John Wiley & Sons Ltd.

Exploring the Co-development of Reading Fluency and Reading Comprehension: A Twin Study

PubMed Central

Little, Callie W.; Hart, Sara A.; Quinn, Jamie M.; Tucker-Drob, Elliot M.; Taylor, Jeanette; Schatschneider, Chris

2016-01-01

The present study explores the co-development of two related but separate reading skills, reading fluency and reading comprehension, across grades 1–4. A bivariate biometric dual change score model was applied to longitudinal data collected from 1784 twin pairs between the ages of 6 and 10 years. Grade 1 skills were influenced by highly overlapping genetic and environmental factors. Growth in both skills was influenced by highly overlapping shared environmental factors. Cross-lagged parameters indicated bidirectional effects, with stronger effects from fluency to comprehension change than from comprehension to fluency change. PMID:27859016

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

PubMed Central

Zwingerman, Nora; Medina-Rivera, Alejandra; Kassam, Irfahan; Wilson, Michael D.; Morange, Pierre-Emmanuel; Trégouët, David-Alexandre; Gagnon, France

2017-01-01

Background Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. Methods A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. Results A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96–1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71–0.97, p = 0.021) for venous thrombosis. Conclusions A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models. PMID:28552956

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis.

PubMed

Zwingerman, Nora; Medina-Rivera, Alejandra; Kassam, Irfahan; Wilson, Michael D; Morange, Pierre-Emmanuel; Trégouët, David-Alexandre; Gagnon, France

2017-01-01

Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96-1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71-0.97, p = 0.021) for venous thrombosis. A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.

Finding Patterns of Emergence in Science and Technology

DTIC Science & Technology

2012-09-24

formal evaluation scheduled – Case Studies, Eight Examples: Tissue Engineering, Cold Fusion, RF Metamaterials, DNA Microarrays, Genetic Algorithms, RNAi...emerging capabilities Case Studies, Eight Examples: • Tissue Engineering, Cold Fusion, RF Metamaterials, DNA Microarrays, Genetic Algorithms...Evidence Quality (i.e., the rubric ) and deliver comprehensible evidential support for nomination • Demonstrate proof-of-concept nomination for Chinese

The Genetic Architecture of Oral Language, Reading Fluency, and Reading Comprehension: A Twin Study from 7 to 16 Years

ERIC Educational Resources Information Center

Tosto, Maria G.; Hayiou-Thomas, Marianna E.; Harlaar, Nicole; Prom-Wormley, Elizabeth; Dale, Philip S.; Plomin, Robert

2017-01-01

This study examines the genetic and environmental etiology underlying the development of oral language and reading skills, and the relationship between them, over a long period of developmental time spanning middle childhood and adolescence. It focuses particularly on the differential relationship between language and two different aspects of…

Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations.

PubMed

Tsangaris, E; Klaassen, R; Fernandez, C V; Yanofsky, R; Shereck, E; Champagne, J; Silva, M; Lipton, J H; Brossard, J; Michon, B; Abish, S; Steele, M; Ali, K; Dower, N; Athale, U; Jardine, L; Hand, J P; Odame, I; Canning, P; Allen, C; Carcao, M; Beyene, J; Roifman, C M; Dror, Y

2011-09-01

Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond-Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman-Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 10(6) births, with Fanconi anaemia having the highest incidence (11.4 cases per 10(6) births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Genetic and Proteomic Interrogation of Lower Confidence Candidate Genes Reveals Signaling Networks in beta-Catenin-Active Cancers | Office of Cancer Genomics

Cancer.gov

Genome-scale expression studies and comprehensive loss-of-function genetic screens have focused almost exclusively on the highest confidence candidate genes. Here, we describe a strategy for characterizing the lower confidence candidates identified by such approaches.

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

PubMed Central

Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

2015-01-01

In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

Genetics in primary health care and the National Policy on Comprehensive Care for People with Rare Diseases in Brazil: opportunities and challenges for professional education.

PubMed

Melo, Débora Gusmão; de Paula, Pamela Karen; de Araujo Rodrigues, Stephania; da Silva de Avó, Lucimar Retto; Germano, Carla Maria Ramos; Demarzo, Marcelo Marcos Piva

2015-07-01

As discoveries regarding the genetic contribution to disease have grown rapidly, health care professionals are expected to incorporate genetic and genomic perspectives into health education and practice. Genetic competencies common to all health professionals have been identified by the US National Coalition for Health Professional Education in Genetics (NCHPEG), which defined the knowledge, skills, and attitudes required to achieve these competencies. The aim of this study is to analyze genetic competencies of primary health care professionals in Brazil. It is a descriptive survey study, whereby doctors, nurses, and dentists were invited to participate by answering a questionnaire including 11 issues based on competencies established by the NCHPEG. Data were presented as percentages. Differences between groups of participants were assessed by the Fisher exact test, with the level of significance set at p < 0.05. Results showed that concerning knowledge, about 80 % of the participants recognized basic genetics terminology, but practitioners had difficulty in identifying patterns of inheritance. Regarding clinical skills, practitioners were able to recognize facial dysmorphias and identify situations where referral of patients to specialists was necessary. Nevertheless, there were challenges in the process of valuing and gathering information about family history. Regarding attitudes, 68.9 % of the participants thought about the comprehensiveness of care but faced challenges in counselling parents. The results of this study may contribute to developing an ongoing education program for primary health care professionals, leading to a strategy to overcome the challenges of including genetics in the Brazilian Unified Health System.

SZDB: A Database for Schizophrenia Genetic Research

PubMed Central

Wu, Yong; Yao, Yong-Gang

2017-01-01

Abstract Schizophrenia (SZ) is a debilitating brain disorder with a complex genetic architecture. Genetic studies, especially recent genome-wide association studies (GWAS), have identified multiple variants (loci) conferring risk to SZ. However, how to efficiently extract meaningful biological information from bulk genetic findings of SZ remains a major challenge. There is a pressing need to integrate multiple layers of data from various sources, eg, genetic findings from GWAS, copy number variations (CNVs), association and linkage studies, gene expression, protein–protein interaction (PPI), co-expression, expression quantitative trait loci (eQTL), and Encyclopedia of DNA Elements (ENCODE) data, to provide a comprehensive resource to facilitate the translation of genetic findings into SZ molecular diagnosis and mechanism study. Here we developed the SZDB database (http://www.szdb.org/), a comprehensive resource for SZ research. SZ genetic data, gene expression data, network-based data, brain eQTL data, and SNP function annotation information were systematically extracted, curated and deposited in SZDB. In-depth analyses and systematic integration were performed to identify top prioritized SZ genes and enriched pathways. Multiple types of data from various layers of SZ research were systematically integrated and deposited in SZDB. In-depth data analyses and integration identified top prioritized SZ genes and enriched pathways. We further showed that genes implicated in SZ are highly co-expressed in human brain and proteins encoded by the prioritized SZ risk genes are significantly interacted. The user-friendly SZDB provides high-confidence candidate variants and genes for further functional characterization. More important, SZDB provides convenient online tools for data search and browse, data integration, and customized data analyses. PMID:27451428

Novel SSR Markers from BAC-End Sequences, DArT Arrays and a Comprehensive Genetic Map with 1,291 Marker Loci for Chickpea (Cicer arietinum L.)

PubMed Central

Nayak, Spurthi N.; Varghese, Nicy; Shah, Trushar M.; Penmetsa, R. Varma; Thirunavukkarasu, Nepolean; Gudipati, Srivani; Gaur, Pooran M.; Kulwal, Pawan L.; Upadhyaya, Hari D.; KaviKishor, Polavarapu B.; Winter, Peter; Kahl, Günter; Town, Christopher D.; Kilian, Andrzej; Cook, Douglas R.; Varshney, Rajeev K.

2011-01-01

Chickpea (Cicer arietinum L.) is the third most important cool season food legume, cultivated in arid and semi-arid regions of the world. The goal of this study was to develop novel molecular markers such as microsatellite or simple sequence repeat (SSR) markers from bacterial artificial chromosome (BAC)-end sequences (BESs) and diversity arrays technology (DArT) markers, and to construct a high-density genetic map based on recombinant inbred line (RIL) population ICC 4958 (C. arietinum)×PI 489777 (C. reticulatum). A BAC-library comprising 55,680 clones was constructed and 46,270 BESs were generated. Mining of these BESs provided 6,845 SSRs, and primer pairs were designed for 1,344 SSRs. In parallel, DArT arrays with ca. 15,000 clones were developed, and 5,397 clones were found polymorphic among 94 genotypes tested. Screening of newly developed BES-SSR markers and DArT arrays on the parental genotypes of the RIL mapping population showed polymorphism with 253 BES-SSR markers and 675 DArT markers. Segregation data obtained for these polymorphic markers and 494 markers data compiled from published reports or collaborators were used for constructing the genetic map. As a result, a comprehensive genetic map comprising 1,291 markers on eight linkage groups (LGs) spanning a total of 845.56 cM distance was developed (http://cmap.icrisat.ac.in/cmap/sm/cp/thudi/). The number of markers per linkage group ranged from 68 (LG 8) to 218 (LG 3) with an average inter-marker distance of 0.65 cM. While the developed resource of molecular markers will be useful for genetic diversity, genetic mapping and molecular breeding applications, the comprehensive genetic map with integrated BES-SSR markers will facilitate its anchoring to the physical map (under construction) to accelerate map-based cloning of genes in chickpea and comparative genome evolution studies in legumes. PMID:22102885

The Association between Pediatric NAFLD and Common Genetic Variants

PubMed Central

Umano, Giuseppina Rosaria; Martino, Mariangela; Santoro, Nicola

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease. PMID:28629152

[The discussion of the infiltrative model of mathematical knowledge to genetics teaching].

PubMed

Liu, Jun; Luo, Pei-Gao

2011-11-01

Genetics, the core course of biological field, is an importance major-basic course in curriculum of many majors related with biology. Due to strong theoretical and practical as well as abstract of genetics, it is too difficult to study on genetics for many students. At the same time, mathematics is one of the basic courses in curriculum of the major related natural science, which has close relationship with the establishment, development and modification of genetics. In this paper, to establish the intrinsic logistic relationship and construct the integral knowledge network and to help students improving the analytic, comprehensive and logistic abilities, we applied some mathematical infiltrative model genetic knowledge in genetics teaching, which could help students more deeply learn and understand genetic knowledge.

Genome-wide single nucleotide polymorphisms (SNPs) for a model invasive ascidian Botryllus schlosseri.

PubMed

Gao, Yangchun; Li, Shiguo; Zhan, Aibin

2018-04-01

Invasive species cause huge damages to ecology, environment and economy globally. The comprehensive understanding of invasion mechanisms, particularly genetic bases of micro-evolutionary processes responsible for invasion success, is essential for reducing potential damages caused by invasive species. The golden star tunicate, Botryllus schlosseri, has become a model species in invasion biology, mainly owing to its high invasiveness nature and small well-sequenced genome. However, the genome-wide genetic markers have not been well developed in this highly invasive species, thus limiting the comprehensive understanding of genetic mechanisms of invasion success. Using restriction site-associated DNA (RAD) tag sequencing, here we developed a high-quality resource of 14,119 out of 158,821 SNPs for B. schlosseri. These SNPs were relatively evenly distributed at each chromosome. SNP annotations showed that the majority of SNPs (63.20%) were located at intergenic regions, and 21.51% and 14.58% were located at introns and exons, respectively. In addition, the potential use of the developed SNPs for population genomics studies was primarily assessed, such as the estimate of observed heterozygosity (H O ), expected heterozygosity (H E ), nucleotide diversity (π), Wright's inbreeding coefficient (F IS ) and effective population size (Ne). Our developed SNP resource would provide future studies the genome-wide genetic markers for genetic and genomic investigations, such as genetic bases of micro-evolutionary processes responsible for invasion success.

Longitudinal Stability in Reading Comprehension Is Largely Heritable from Grades 1 to 6

PubMed Central

Soden, Brooke; Christopher, Micaela E.; Hulslander, Jacqueline; Olson, Richard K.; Cutting, Laurie; Keenan, Janice M.; Thompson, Lee A.; Wadsworth, Sally J.; Willcutt, Erik G.; Petrill, Stephen A.

2015-01-01

Reading comprehension is a foundational academic skill and significant attention has focused on reading development. This report is the first to examine the stability and change in genetic and environmental influences on reading comprehension across Grades 1 to 6. This developmental range is particularly important because it encompasses the timespan in which most children move from learning how to read to using reading for learning. Longitudinal simplex models were fitted separately for two independent twin samples (N = 706; N = 976). Results suggested that the shared environment contributed to variance in early but not later reading. Instead, stability in reading development was largely mediated by continuous genetic influences. Thus, although reading is clearly a learned skill and the environment remains important for reading development, individual differences in reading comprehension appear to be also influenced by a core of genetic stability that persists through the developmental course of reading. PMID:25602760

The humankind genome: from genetic diversity to the origin of human diseases.

PubMed

Belizário, Jose E

2013-12-01

Genome-wide association studies have failed to establish common variant risk for the majority of common human diseases. The underlying reasons for this failure are explained by recent studies of resequencing and comparison of over 1200 human genomes and 10 000 exomes, together with the delineation of DNA methylation patterns (epigenome) and full characterization of coding and noncoding RNAs (transcriptome) being transcribed. These studies have provided the most comprehensive catalogues of functional elements and genetic variants that are now available for global integrative analysis and experimental validation in prospective cohort studies. With these datasets, researchers will have unparalleled opportunities for the alignment, mining, and testing of hypotheses for the roles of specific genetic variants, including copy number variations, single nucleotide polymorphisms, and indels as the cause of specific phenotypes and diseases. Through the use of next-generation sequencing technologies for genotyping and standardized ontological annotation to systematically analyze the effects of genomic variation on humans and model organism phenotypes, we will be able to find candidate genes and new clues for disease's etiology and treatment. This article describes essential concepts in genetics and genomic technologies as well as the emerging computational framework to comprehensively search websites and platforms available for the analysis and interpretation of genomic data.

NCI Dictionary of Genetics Terms

Cancer.gov

A dictionary of more than 150 genetics-related terms written for healthcare professionals. This resource was developed to support the comprehensive, evidence-based, peer-reviewed PDQ cancer genetics information summaries.

Impact of genetic counseling and Connexin-26 and Connexin-30 testing on deaf identity and comprehension of genetic test results in a sample of deaf adults: a prospective, longitudinal study.

PubMed

Palmer, Christina G S; Boudreault, Patrick; Baldwin, Erin E; Sinsheimer, Janet S

2014-01-01

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results.

A comprehensive global genotype-phenotype database for rare diseases.

PubMed

Trujillano, Daniel; Oprea, Gabriela-Elena; Schmitz, Yvonne; Bertoli-Avella, Aida M; Abou Jamra, Rami; Rolfs, Arndt

2017-01-01

The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ® ) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool for identifying new disease genes through the correlation of novel genetic variants with specific, well-defined phenotypes.

[A new teaching mode improves the effect of comprehensive experimental teaching of genetics].

PubMed

Fenghua, He; Jieqiang, Li; Biyan, Zhu; Feng, Gao

2015-04-01

To improve the research atmosphere in genetics experimental teaching and develop students' creativity in research, we carried out a reform in comprehensive experimental teaching which is one of important modules for genetics practice. In our new student-centered teaching mode, they chose research topics, performed experiments and took innovative approaches independently. With the open laboratory and technical platform in our experimental teaching center, students finished their experiments and were required to write a mini-research article. Comprehensive experimental teaching is a scientific research practice before they complete their thesis. Through this teaching practice, students' research skills in experimental design and operation, data analysis and results presentation, as well as their collaboration spirit and innovation consciousness are strengthened.

Genetics Home Reference: Leber congenital amaurosis

MedlinePlus

... FP, van den Hurk JA, den Hollander AI. Molecular genetics of Leber congenital amaurosis. Hum Mol Genet. 2002 ... J. Leber congenital amaurosis: comprehensive survey of the genetic ... as a strategy for molecular diagnosis. Hum Mutat. 2004 Apr;23(4):306- ...

Study Sheds Light on Role of Inherited Mutations in Childhood Cancer

Cancer.gov

In the most comprehensive study of its kind conducted to date, more than 8 percent of children with cancer were found to have inherited genetic mutations associated with a predisposition to the disease.

Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants.

PubMed

Tada, Hayato; Kawashiri, Masa-Aki; Yamagishi, Masakazu

2017-04-01

Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.

A genomic perspective on the generation and maintenance of genetic diversity in herbivorous insects

PubMed Central

Gloss, Andrew D.; Groen, Simon C.; Whiteman, Noah K.

2017-01-01

Understanding the processes that generate and maintain genetic variation within populations is a central goal in evolutionary biology. Theory predicts that some of this variation is maintained as a consequence of adapting to variable habitats. Studies in herbivorous insects have played a key role in confirming this prediction. Here, we highlight theoretical and conceptual models for the maintenance of genetic diversity in herbivorous insects, empirical genomic studies testing these models, and pressing questions within the realm of evolutionary and functional genomic studies. To address key gaps, we propose an integrative approach combining population genomic scans for adaptation, genome-wide characterization of targets of selection through experimental manipulations, mapping the genetic architecture of traits influencing fitness, and functional studies. We also stress the importance of studying the maintenance of genetic variation across biological scales—from variation within populations to divergence among populations—to form a comprehensive view of adaptation in herbivorous insects. PMID:28736510

[Genetic diseases in pediatric patients hospitalised in the town of Ubaté, Colombia].

PubMed

Páez, Paola; Suárez-Obando, Fernando; Zarante, Ignacio

2008-01-01

Describing genetic disease frequency in a second-level hospital's in-patient paediatric service The hospital's statistical department's records for 2005 were comprehensively reviewed; the study was carried out in the town of Ubaté during 2006. Complex diseases led to nearly 25% of all hospitalisations, including multifactor diseases and congenital malformations. However, an aetiological study and/or geneticist consultation or referral took place on a few occasions. Primary care hospitals should become more relevant reference centres for detecting genetic diseases amongst the paediatric population. New mechanisms are needed for implementing this to allow patients access to a geneticist and for an aetiological diagnosis to be made and providing suitable genetic counselling.

Comprehensive Genetic Analysis of Early Host Body Reactions to the Bioactive and Bio-Inert Porous Scaffolds

PubMed Central

Ehashi, Tomo; Takemura, Taro; Hanagata, Nobutaka; Minowa, Takashi; Kobayashi, Hisatoshi; Ishihara, Kazuhiko; Yamaoka, Tetsuji

2014-01-01

To design scaffolds for tissue regeneration, details of the host body reaction to the scaffolds must be studied. Host body reactions have been investigated mainly by immunohistological observations for a long time. Despite of recent dramatic development in genetic analysis technologies, genetically comprehensive changes in host body reactions are hardly studied. There is no information about host body reactions that can predict successful tissue regeneration in the future. In the present study, porous polyethylene scaffolds were coated with bioactive collagen or bio-inert poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) and were implanted subcutaneously and compared the host body reaction to those substrates by normalizing the result using control non-coat polyethylene scaffold. The comprehensive analyses of early host body reactions to the scaffolds were carried out using a DNA microarray assay. Within numerous genes which were expressed differently among these scaffolds, particular genes related to inflammation, wound healing, and angiogenesis were focused upon. Interleukin (IL)-1β and IL-10 are important cytokines in tissue responses to biomaterials because IL-1β promotes both inflammation and wound healing and IL-10 suppresses both of them. IL-1β was up-regulated in the collagen-coated scaffold. Collagen-specifically up-regulated genes contained both M1- and M2-macrophage-related genes. Marked vessel formation in the collagen-coated scaffold was occurred in accordance with the up-regulation of many angiogenesis-inducible factors. The DNA microarray assay provided global information regarding the host body reaction. Interestingly, several up-regulated genes were detected even on the very bio-inert PMB-coated surfaces and those genes include inflammation-suppressive and wound healing-suppressive IL-10, suggesting that not only active tissue response but also the inert response may relates to these genetic regulations. PMID:24454803

Genetic variants in Alzheimer disease – molecular and brain network approaches

PubMed Central

Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher; De Jager, Philip L.; Bennett, David A.

2016-01-01

Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care for AD. However, due to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extracting actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effect of LOAD-associated genetic variants. We then discuss emerging combinations of omic data types in multiscale models, which provide a more comprehensive representation of the effect of LOAD-associated genetic variants at multiple biophysical scales. Further, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models. PMID:27282653

Molecular inversion probe assay.

PubMed

Absalan, Farnaz; Ronaghi, Mostafa

2007-01-01

We have described molecular inversion probe technologies for large-scale genetic analyses. This technique provides a comprehensive and powerful tool for the analysis of genetic variation and enables affordable, large-scale studies that will help uncover the genetic basis of complex disease and explain the individual variation in response to therapeutics. Major applications of the molecular inversion probes (MIP) technologies include targeted genotyping from focused regions to whole-genome studies, and allele quantification of genomic rearrangements. The MIP technology (used in the HapMap project) provides an efficient, scalable, and affordable way to score polymorphisms in case/control populations for genetic studies. The MIP technology provides the highest commercially available multiplexing levels and assay conversion rates for targeted genotyping. This enables more informative, genome-wide studies with either the functional (direct detection) approach or the indirect detection approach.

TCGA study of genetic drivers of melanoma

Cancer.gov

A comprehensive analysis of the genome of cutaneous melanoma has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive the development of this disease.

The Genomic and Genetic Toolbox of the Teleost Medaka (Oryzias latipes)

PubMed Central

Kirchmaier, Stephan; Naruse, Kiyoshi; Wittbrodt, Joachim; Loosli, Felix

2015-01-01

The Japanese medaka, Oryzias latipes, is a vertebrate teleost model with a long history of genetic research. A number of unique features and established resources distinguish medaka from other vertebrate model systems. A large number of laboratory strains from different locations are available. Due to a high tolerance to inbreeding, many highly inbred strains have been established, thus providing a rich resource for genetic studies. Furthermore, closely related species native to different habitats in Southeast Asia permit comparative evolutionary studies. The transparency of embryos, larvae, and juveniles allows a detailed in vivo analysis of development. New tools to study diverse aspects of medaka biology are constantly being generated. Thus, medaka has become an important vertebrate model organism to study development, behavior, and physiology. In this review, we provide a comprehensive overview of established genetic and molecular-genetic tools that render medaka fish a full-fledged vertebrate system. PMID:25855651

Comprehensive Genetic Characterization of Intraprostatic Chronic Inflammation and Prostate Cancer in African American Men

DTIC Science & Technology

2017-09-01

with new methodologies of intratumoral phylogenetic analyses, will yield pivotal information in elucidating the key genes involved evolution of PCa...combined with both clinical and experimental genetic data produced by this study may empower patients and doctors to make personalized treatment decisions...sequencing, paired with new methodologies of intratumoral phylogenetic analyses, will yield pivotal information in elucidating the key genes involved

Impact of Genetic Counseling and Connexin-26 and Connexin-30 Testing on Deaf Identity and Comprehension of Genetic Test Results in a Sample of Deaf Adults: A Prospective, Longitudinal Study

PubMed Central

Palmer, Christina G. S.; Boudreault, Patrick; Baldwin, Erin E.; Sinsheimer, Janet S.

2014-01-01

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results. PMID:25375116

Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis.

PubMed

Jezernik, Gregor; Potočnik, Uroš

2018-03-01

Fatty acids and their derivatives play an important role in inflammation. Diet and genetics influence fatty acid profiles. Abnormalities of fatty acid profiles have been observed in inflammatory bowel diseases (IBD), a group of complex diseases defined by chronic gastrointestinal inflammation. IBD associated fatty acid profile abnormalities were observed independently of nutritional status or disease activity, suggesting a common genetic background. However, no study so far has attempted to look for overlap between IBD loci and fatty acid associated loci or investigate the genetics of fatty acid profiles in IBD. To this end, we conducted a comprehensive genetic study of fatty acid profiles in IBD using iCHIP, a custom microarray platform designed for deep sequencing of immune-mediated disease associated loci. This study identifies 10 loci associated with fatty acid profiles in IBD. The most significant associations were a locus near CBS (p = 7.62 × 10 -8 ) and a locus in LRRK2 (p = 1.4 × 10 -7 ). Of note, this study replicates the FADS gene cluster locus, previously associated with both fatty acid profiles and IBD pathogenesis. Furthermore, we identify 18 carbon chain trans-fatty acids (p = 1.12 × 10 -3 ), total trans-fatty acids (p = 4.49 × 10 -3 ), palmitic acid (p = 5.85 × 10 -3 ) and arachidonic acid (p = 8.58 × 10 -3 ) as significantly associated with IBD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy of a Web-based Intelligent Tutoring System for Communicating Genetic Risk of Breast Cancer: A Fuzzy-Trace Theory Approach

PubMed Central

Wolfe, Christopher R.; Reyna, Valerie F.; Widmer, Colin L.; Cedillos, Elizabeth M.; Fisher, Christopher R.; Brust-Renck, Priscila G.; Weil, Audrey M.

2014-01-01

Background Many healthy women consider genetic testing for breast cancer risk, yet BRCA testing issues are complex. Objective Determining whether an intelligent tutor, BRCA Gist, grounded in fuzzy-trace theory (FTT), increases gist comprehension and knowledge about genetic testing for breast cancer risk, improving decision-making. Design In two experiments, 410 healthy undergraduate women were randomly assigned to one of three groups: an online module using a web-based tutoring system (BRCA Gist) that uses artificial intelligence technology, a second group read highly similar content from the NCI web site, and a third completed an unrelated tutorial. Intervention BRCA Gist applied fuzzy trace theory and was designed to help participants develop gist comprehension of topics relevant to decisions about BRCA genetic testing, including how breast cancer spreads, inherited genetic mutations, and base rates. Measures We measured content knowledge, gist comprehension of decision-relevant information, interest in testing, and genetic risk and testing judgments. Results Control knowledge scores ranged from 54% to 56%, NCI improved significantly to 65% and 70%, and BRCA Gist improved significantly more to 75% and 77%, p<.0001. BRCA Gist scored higher on gist comprehension than NCI and control, p<.0001. Control genetic risk-assessment mean was 48% correct; BRCA Gist (61%), and NCI (56%) were significantly higher, p<.0001. BRCA Gist participants recommended less testing for women without risk factors (not good candidates), (24% and 19%) than controls (50%, both experiments) and NCI, (32%) Experiment 2, p<.0001. BRCA Gist testing interest was lower than controls, p<.0001. Limitations BRCA Gist has not been tested with older women from diverse groups. Conclusions Intelligent tutors, such as BRCA Gist, are scalable, cost effective ways of helping people understand complex issues, improving decision-making. PMID:24829276

SoyBase, The USDA-ARS Soybean Genetics and Genomics Database

USDA-ARS?s Scientific Manuscript database

SoyBase, the USDA-ARS soybean genetic database, is a comprehensive repository for professionally curated genetics, genomics and related data resources for soybean. SoyBase contains the most current genetic, physical and genomic sequence maps integrated with qualitative and quantitative traits. The...

[The discussion of the infiltrative model of chemical knowledge stepping into genetics teaching in agricultural institute or university].

PubMed

Zou, Ping; Luo, Pei-Gao

2010-05-01

Chemistry is an important group of basic courses, while genetics is one of the important major-basic courses in curriculum of many majors in agricultural institutes or universities. In order to establish the linkage between the major course and the basic course, the ability of application of the chemical knowledge previously learned in understanding genetic knowledge in genetics teaching is worthy of discussion for genetics teachers. In this paper, the authors advocate to apply some chemical knowledge previously learned to understand genetic knowledge in genetics teaching with infiltrative model, which could help students learn and understand genetic knowledge more deeply. Analysis of the intrinsic logistic relationship among the knowledge of different courses and construction of the integral knowledge network are useful for students to improve their analytic, comprehensive and logistic abilities. By this way, we could explore a new teaching model to develop the talents with new ideas and comprehensive competence in agricultural fields.

TCGA study of genetic drivers of melanoma - TCGA

Cancer.gov

A comprehensive analysis of the genome of cutaneous melanoma has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive the development of this disease.

TCGA study improves understanding of thyroid cancer genetics - TCGA

Cancer.gov

A comprehensive analysis of the genomes of nearly 500 papillary thyroid carcinomas has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive disease development.

Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes

DTIC Science & Technology

2012-12-05

Bisgaier J, Levinson D, Cutts DB, & Rhodes KV., (2011) Access to autism evaluation appointments with developmental-behavioral and neurodevelopmental ...W403 Columbus, OH 43205 Final Report Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes...QFOXGHDUHDFRGH 1.0 Summary In 2006, the Central Ohio Registry for Autism (CORA) was initiated as a collaboration between Wright-Patterson Air

The Life Course Perspective: a Guide for Genetic Counselors.

PubMed

Hamilton, Rebekah J; Innella, Nancy A; Bounds, Dawn T

2016-02-01

This is the first article in a two part series about utilizing the life course perspective (LCP) in genetic counseling. LCP can be a useful tool for genetic counselors when counseling people with a known genetic mutation. Previous theories such as Protection Motivation Theory (PMT) and Common Sense Model of Self-Regulation (CSMSR) examine current reactions to a positive genetic test result. LCP extends beyond the current time to explore temporal and contextual elements of the experience. A review of research revealed, LCP has been used to study the perspective of caregivers of people with Alzheimer's disease, referral for a family history of breast cancer, Mexican American caregivers of older adult, social class and cancer incidence and cancer and the sense of mastery. Incorporating LCP into a study explaining the experiences of people living with a positive test result for a genetic mutation such as the BRCA mutation provides a comprehensive exploration of this experience.

Promiscuity, sexual selection, and genetic diversity: a reply to Spurgin.

PubMed

Lifjeld, Jan T; Gohli, Jostein; Johnsen, Arild

2013-10-01

We recently reported a positive association between female promiscuity and genetic diversity across passerine birds, and launched the hypothesis that female promiscuity acts as a balancing selection, pressure maintaining genetic diversity in populations (Gohli et al.2013). Spurgin (2013) questions both our analyses and interpretations. While we agree that the hypothesis needs more comprehensive empirical testing, we find his specific points of criticism unjustified. In a more general perspective, we call for a more explicit recognition of female mating preferences as mechanisms of selection in population genetics theory. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Genetics of Skin Cancer (PDQ®)—Health Professional Version

Cancer.gov

Genetics of Skin Cancer includes information about genes and hereditary syndromes associated with basal cell, squamous cell, and melanoma skin cancer. Get comprehensive information about the genetics of skin cancer and interventions in this summary for clinicians.

Transitioning from Targeted to Comprehensive Mass Spectrometry Using Genetic Algorithms.

PubMed

Jaffe, Jacob D; Feeney, Caitlin M; Patel, Jinal; Lu, Xiaodong; Mani, D R

2016-11-01

Targeted proteomic assays are becoming increasingly popular because of their robust quantitative applications enabled by internal standardization, and they can be routinely executed on high performance mass spectrometry instrumentation. However, these assays are typically limited to 100s of analytes per experiment. Considerable time and effort are often expended in obtaining and preparing samples prior to targeted analyses. It would be highly desirable to detect and quantify 1000s of analytes in such samples using comprehensive mass spectrometry techniques (e.g., SWATH and DIA) while retaining a high degree of quantitative rigor for analytes with matched internal standards. Experimentally, it is facile to port a targeted assay to a comprehensive data acquisition technique. However, data analysis challenges arise from this strategy concerning agreement of results from the targeted and comprehensive approaches. Here, we present the use of genetic algorithms to overcome these challenges in order to configure hybrid targeted/comprehensive MS assays. The genetic algorithms are used to select precursor-to-fragment transitions that maximize the agreement in quantification between the targeted and the comprehensive methods. We find that the algorithm we used provided across-the-board improvement in the quantitative agreement between the targeted assay data and the hybrid comprehensive/targeted assay that we developed, as measured by parameters of linear models fitted to the results. We also found that the algorithm could perform at least as well as an independently-trained mass spectrometrist in accomplishing this task. We hope that this approach will be a useful tool in the development of quantitative approaches for comprehensive proteomics techniques. Graphical Abstract ᅟ.

Transitioning from Targeted to Comprehensive Mass Spectrometry Using Genetic Algorithms

NASA Astrophysics Data System (ADS)

Jaffe, Jacob D.; Feeney, Caitlin M.; Patel, Jinal; Lu, Xiaodong; Mani, D. R.

2016-11-01

Targeted proteomic assays are becoming increasingly popular because of their robust quantitative applications enabled by internal standardization, and they can be routinely executed on high performance mass spectrometry instrumentation. However, these assays are typically limited to 100s of analytes per experiment. Considerable time and effort are often expended in obtaining and preparing samples prior to targeted analyses. It would be highly desirable to detect and quantify 1000s of analytes in such samples using comprehensive mass spectrometry techniques (e.g., SWATH and DIA) while retaining a high degree of quantitative rigor for analytes with matched internal standards. Experimentally, it is facile to port a targeted assay to a comprehensive data acquisition technique. However, data analysis challenges arise from this strategy concerning agreement of results from the targeted and comprehensive approaches. Here, we present the use of genetic algorithms to overcome these challenges in order to configure hybrid targeted/comprehensive MS assays. The genetic algorithms are used to select precursor-to-fragment transitions that maximize the agreement in quantification between the targeted and the comprehensive methods. We find that the algorithm we used provided across-the-board improvement in the quantitative agreement between the targeted assay data and the hybrid comprehensive/targeted assay that we developed, as measured by parameters of linear models fitted to the results. We also found that the algorithm could perform at least as well as an independently-trained mass spectrometrist in accomplishing this task. We hope that this approach will be a useful tool in the development of quantitative approaches for comprehensive proteomics techniques.

Lexical decision as an endophenotype for reading comprehension: An exploration of an association

PubMed Central

NAPLES, ADAM; KATZ, LEN; GRIGORENKO, ELENA L.

2012-01-01

Based on numerous suggestions in the literature, we evaluated lexical decision (LD) as a putative endophenotype for reading comprehension by investigating heritability estimates and segregation analyses parameter estimates for both of these phenotypes. Specifically, in a segregation analysis of a large sample of families, we established that there is little to no overlap between genes contributing to LD and reading comprehension and that the genetic mechanism behind LD derived from this analysis appears to be more complex than that for reading comprehension. We conclude that in our sample, LD is not a good candidate as an endophenotype for reading comprehension, despite previous suggestions from the literature. Based on this conclusion, we discuss the role and benefit of the endophenotype approach in studies of complex human cognitive functions. PMID:23062302

CURRENT CONCEPTS ON THE GENETIC FACTORS IN ROTATOR CUFF PATHOLOGY AND FUTURE IMPLICATIONS FOR SPORTS PHYSICAL THERAPISTS

PubMed Central

Paré, Jessica; Froehlich, John E

2017-01-01

Context Recent advances within the field of genetics are currently changing many of the methodologies in which medicine is practiced. These advances are also beginning to influence the manner in which physical therapy services are rendered. Rotator cuff pathology is one of the most common diagnoses treated by the sports physical therapist. The purpose of this commentary is to educate sports physical therapists on the recent advances regarding how genetics influences rotator cuff pathology, including rotator cuff tears, and provide a perspective on how this information will likely influence post-operative shoulder rehabilitation in the near future. Evidence Acquisition A comprehensive review of the literature was completed using the Medline database along with individual searches of relevant physical therapy, surgical, cell biology, and sports medicine journals. Search terms included: shoulder, rotator cuff pathology, genetics, apoptosis, and physical therapy. Search results were compiled and evaluated; relevant primary studies and review articles were gathered; the results from this comprehensive review are summarized here. Study Design Clinical Commentary, Review of the Literature Results Recent advances within the understanding of rotator cuff pathology have further elucidated the cellular and molecular mechanisms associated with rotator cuff tears. There appears to be a hypoxic-induced apoptotic cellular pathway that contributes to rotator cuff tears. Activation of specific proteins termed matrix metalloproteinases appear to be involved in not only primary rotator cuff tears, but also may influence the re-tear rate after surgical intervention. Further advancements in the understanding of the cellular mechanisms contributing to rotator cuff tears and postoperative techniques to help prevent re-tears, may soon influence the methodology in which physical therapy services are provided to patients sustaining a rotator cuff injury. Conclusions At this time continued research is required to more fully develop a comprehensive understanding of the role of genetic variables both within primary rotator cuff tears and their influences on post-operative rehabilitation from rotator cuff repair surgery. Level of Evidence Level 5 PMID:28515982

A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

PubMed

Nikpay, Majid; Goel, Anuj; Won, Hong-Hee; Hall, Leanne M; Willenborg, Christina; Kanoni, Stavroula; Saleheen, Danish; Kyriakou, Theodosios; Nelson, Christopher P; Hopewell, Jemma C; Webb, Thomas R; Zeng, Lingyao; Dehghan, Abbas; Alver, Maris; Armasu, Sebastian M; Auro, Kirsi; Bjonnes, Andrew; Chasman, Daniel I; Chen, Shufeng; Ford, Ian; Franceschini, Nora; Gieger, Christian; Grace, Christopher; Gustafsson, Stefan; Huang, Jie; Hwang, Shih-Jen; Kim, Yun Kyoung; Kleber, Marcus E; Lau, King Wai; Lu, Xiangfeng; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Mihailov, Evelin; Morrison, Alanna C; Pervjakova, Natalia; Qu, Liming; Rose, Lynda M; Salfati, Elias; Saxena, Richa; Scholz, Markus; Smith, Albert V; Tikkanen, Emmi; Uitterlinden, Andre; Yang, Xueli; Zhang, Weihua; Zhao, Wei; de Andrade, Mariza; de Vries, Paul S; van Zuydam, Natalie R; Anand, Sonia S; Bertram, Lars; Beutner, Frank; Dedoussis, George; Frossard, Philippe; Gauguier, Dominique; Goodall, Alison H; Gottesman, Omri; Haber, Marc; Han, Bok-Ghee; Huang, Jianfeng; Jalilzadeh, Shapour; Kessler, Thorsten; König, Inke R; Lannfelt, Lars; Lieb, Wolfgang; Lind, Lars; Lindgren, Cecilia M; Lokki, Marja-Liisa; Magnusson, Patrik K; Mallick, Nadeem H; Mehra, Narinder; Meitinger, Thomas; Memon, Fazal-Ur-Rehman; Morris, Andrew P; Nieminen, Markku S; Pedersen, Nancy L; Peters, Annette; Rallidis, Loukianos S; Rasheed, Asif; Samuel, Maria; Shah, Svati H; Sinisalo, Juha; Stirrups, Kathleen E; Trompet, Stella; Wang, Laiyuan; Zaman, Khan S; Ardissino, Diego; Boerwinkle, Eric; Borecki, Ingrid B; Bottinger, Erwin P; Buring, Julie E; Chambers, John C; Collins, Rory; Cupples, L Adrienne; Danesh, John; Demuth, Ilja; Elosua, Roberto; Epstein, Stephen E; Esko, Tõnu; Feitosa, Mary F; Franco, Oscar H; Franzosi, Maria Grazia; Granger, Christopher B; Gu, Dongfeng; Gudnason, Vilmundur; Hall, Alistair S; Hamsten, Anders; Harris, Tamara B; Hazen, Stanley L; Hengstenberg, Christian; Hofman, Albert; Ingelsson, Erik; Iribarren, Carlos; Jukema, J Wouter; Karhunen, Pekka J; Kim, Bong-Jo; Kooner, Jaspal S; Kullo, Iftikhar J; Lehtimäki, Terho; Loos, Ruth J F; Melander, Olle; Metspalu, Andres; März, Winfried; Palmer, Colin N; Perola, Markus; Quertermous, Thomas; Rader, Daniel J; Ridker, Paul M; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Sanghera, Dharambir K; Schwartz, Stephen M; Seedorf, Udo; Stewart, Alexandre F; Stott, David J; Thiery, Joachim; Zalloua, Pierre A; O'Donnell, Christopher J; Reilly, Muredach P; Assimes, Themistocles L; Thompson, John R; Erdmann, Jeanette; Clarke, Robert; Watkins, Hugh; Kathiresan, Sekar; McPherson, Ruth; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J; Farrall, Martin

2015-10-01

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Crystal Genetics, Inc.

PubMed

Kermani, Bahram G

2016-07-01

Crystal Genetics, Inc. is an early-stage genetic test company, focused on achieving the highest possible clinical-grade accuracy and comprehensiveness for detecting germline (e.g., in hereditary cancer) and somatic (e.g., in early cancer detection) mutations. Crystal's mission is to significantly improve the health status of the population, by providing high accuracy, comprehensive, flexible and affordable genetic tests, primarily in cancer. Crystal's philosophy is that when it comes to detecting mutations that are strongly correlated with life-threatening diseases, the detection accuracy of every single mutation counts: a single false-positive error could cause severe anxiety for the patient. And, more importantly, a single false-negative error could potentially cost the patient's life. Crystal's objective is to eliminate both of these error types.

Consumers' views of direct-to-consumer genetic information.

PubMed

McBride, Colleen M; Wade, Christopher H; Kaphingst, Kimberly A

2010-01-01

In this report, we describe the evolution and types of genetic information provided directly to consumers, discuss potential advantages and disadvantages of these products, and review research evaluating consumer responses to direct-to-consumer (DTC) genetic testing. The available evidence to date has focused on predictive tests and does not suggest that individuals, health care providers, or health care systems have been harmed by a DTC provision of genetic information. An understanding of consumer responses to susceptibility tests has lagged behind. The Multiplex Initiative is presented as a case study of research to understand consumers' responses to DTC susceptibility tests. Three priority areas are recommended for accelerated research activities to inform public policy regarding DTC genetic information: (a) exploring consumer's long-term responses to DTC genetic testing on a comprehensive set of outcomes, (b) evaluating optimal services to support decision making about genetic testing, and (c) evaluating best practices in promoting genetic competencies among health providers.

Getting a head start: the importance of personal genetics education in high schools.

PubMed

Kung, Johnny T; Gelbart, Marnie E

2012-03-01

With advances in sequencing technology, widespread and affordable genome sequencing will soon be a reality. However, studies suggest that "genetic literacy" of the general public is inadequate to prepare our society for this unprecedented access to our genetic information. As the current generation of high school students will come of age in an era when personal genetic information is increasingly utilized in health care, it is of vital importance to ensure these students understand the genetic concepts necessary to make informed medical decisions. These concepts include not only basic scientific knowledge, but also considerations of the ethical, legal, and social issues that will arise in the age of personal genomics. In this article, we review the current state of genetics education, highlight issues that we believe need to be addressed in a comprehensive genetics education curriculum, and describe our education efforts at the Harvard Medical School-based Personal Genetics Education Project.

Genetic Predictors for Cardiovascular Disease in Hispanics

PubMed Central

Qi, Lu; Campos, Hannia

2012-01-01

A less favorable cardiovascular risk factor profile, but paradoxically lower cardiovascular morbidity and mortality have been observed in Hispanics, a pattern often referred to as the Hispanic Paradox. It was proposed the specific genetic susceptibility of this admixed population and gene-environment interactions may partly explain the paradox. The past few years have seen great advances in discovering genetic risk factors using genome-wide association studies (GWAS) for cardiovascular disease especially in Caucasians. However, there is no GWAS of cardiovascular disease that have been reported in Hispanics. In the Costa Rican Heart Study we reported both the consistency and disparity of genetic effects on risk of coronary heart disease (CHD) between Hispanics and other ethnic groups. We demonstrated the improvement in the identified genetic markers on discrimination of CHD in Hispanics was modest. Future genetic research in Hispanics would consider the diversities in genetic structure, lifestyle and socioeconomics among various sub-populations, and comprehensively evaluate potential gene-environment interactions in relation to cardiovascular risk. PMID:22498015

The Genetic Drift Inventory: A Tool for Measuring What Advanced Undergraduates Have Mastered about Genetic Drift

ERIC Educational Resources Information Center

Price, Rebecca M.; Andrews, Tessa C.; McElhinny, Teresa L.; Mead, Louise S.; Abraham, Joel K.; Thanukos, Anna; Perez, Kathryn E.

2014-01-01

Understanding genetic drift is crucial for a comprehensive understanding of biology, yet it is difficult to learn because it combines the conceptual challenges of both evolution and randomness. To help assess strategies for teaching genetic drift, we have developed and evaluated the Genetic Drift Inventory (GeDI), a concept inventory that measures…

A genetic inventory of spacecraft and associated surfaces.

PubMed

La Duc, Myron T; Venkateswaran, Kasthuri; Conley, Catharine A

2014-01-01

Terrestrial organisms or other contaminants that are transported to Mars could interfere with efforts to study the potential for indigenous martian life. Similarly, contaminants that make the round-trip to Mars and back to Earth could compromise the ability to discriminate an authentic martian biosignature from a terrestrial organism. For this reason, it is important to develop a comprehensive inventory of microbes that are present on spacecraft to avoid interpreting their traces as authentic extraterrestrial biosignatures. Culture-based methods are currently used by NASA to assess spacecraft cleanliness but deliberately detect only a very small subset of total organisms present. The National Research Council has recommended that molecular (DNA)-based identification techniques should be developed as one aspect of managing the risk that terrestrial contamination could interfere with detection of life on (or returned from) Mars. The current understanding of the microbial diversity associated with spacecraft and clean room surfaces is expanding, but the capability to generate a comprehensive inventory of the microbial populations present on spacecraft outbound from Earth would address multiple considerations in planetary protection, relevant to both robotic and human missions. To this end, a 6-year genetic inventory study was undertaken by a NASA/JPL team. It was completed in 2012 and included delivery of a publicly available comprehensive final report. The genetic inventory study team evaluated the utility of three analytical technologies (conventional cloning techniques, PhyloChip DNA microarrays, and 454 tag-pyrosequencing) and combined them with a systematic methodology to collect, process, and archive nucleic acids as the first steps in assessing the phylogenetic breadth of microorganisms on spacecraft and associated surfaces.

A simulation test of the effectiveness of several methods for error-checking non-invasive genetic data

USGS Publications Warehouse

Roon, David A.; Waits, L.P.; Kendall, K.C.

2005-01-01

Non-invasive genetic sampling (NGS) is becoming a popular tool for population estimation. However, multiple NGS studies have demonstrated that polymerase chain reaction (PCR) genotyping errors can bias demographic estimates. These errors can be detected by comprehensive data filters such as the multiple-tubes approach, but this approach is expensive and time consuming as it requires three to eight PCR replicates per locus. Thus, researchers have attempted to correct PCR errors in NGS datasets using non-comprehensive error checking methods, but these approaches have not been evaluated for reliability. We simulated NGS studies with and without PCR error and 'filtered' datasets using non-comprehensive approaches derived from published studies and calculated mark-recapture estimates using CAPTURE. In the absence of data-filtering, simulated error resulted in serious inflations in CAPTURE estimates; some estimates exceeded N by ??? 200%. When data filters were used, CAPTURE estimate reliability varied with per-locus error (E??). At E?? = 0.01, CAPTURE estimates from filtered data displayed < 5% deviance from error-free estimates. When E?? was 0.05 or 0.09, some CAPTURE estimates from filtered data displayed biases in excess of 10%. Biases were positive at high sampling intensities; negative biases were observed at low sampling intensities. We caution researchers against using non-comprehensive data filters in NGS studies, unless they can achieve baseline per-locus error rates below 0.05 and, ideally, near 0.01. However, we suggest that data filters can be combined with careful technique and thoughtful NGS study design to yield accurate demographic information. ?? 2005 The Zoological Society of London.

Teaching practice and experiences of verifying the three laws of genetics based on the SSLP marker analysis.

PubMed

Huang, Xue-Ying; Fan, Kai; Ye, Yan-Fang; Wang, Bin; Wu, Wei-Ren; Lan, Tao

2017-09-20

We explored the practical effect of the genetic analysis of simple sequence length polymorphism (SSLP) molecular markers in rice in the genetics lab course. Two parents and their F 2 population were analyzed and detected with three SSLP molecular markers that located on two chromosomes of the rice genome. The markers' genotype data were used to verify the three laws of genetics, including segregation, independent assortment and linkage and crossing-over. Our practice has proved not only beneficial to deepen students' understandings about the three laws of genetics, but also conducive to cultivate students' interests in research and innovation and improve their skills and comprehensive analysis abilities. At the same time, the application scope of the experiment was discussed. This comprehensive experiment is also useful for the transformation of scientific research achievements into undergraduate experimental teaching.

The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients

PubMed Central

2010-01-01

Background Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia. Methods For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected. Results The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail. Conclusions The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes. PMID:21067598

Efficacy of a web-based intelligent tutoring system for communicating genetic risk of breast cancer: a fuzzy-trace theory approach.

PubMed

Wolfe, Christopher R; Reyna, Valerie F; Widmer, Colin L; Cedillos, Elizabeth M; Fisher, Christopher R; Brust-Renck, Priscila G; Weil, Audrey M

2015-01-01

. Many healthy women consider genetic testing for breast cancer risk, yet BRCA testing issues are complex. . To determine whether an intelligent tutor, BRCA Gist, grounded in fuzzy-trace theory (FTT), increases gist comprehension and knowledge about genetic testing for breast cancer risk, improving decision making. . In 2 experiments, 410 healthy undergraduate women were randomly assigned to 1 of 3 groups: an online module using a Web-based tutoring system (BRCA Gist) that uses artificial intelligence technology, a second group read highly similar content from the National Cancer Institute (NCI) Web site, and a third that completed an unrelated tutorial. . BRCA Gist applied FTT and was designed to help participants develop gist comprehension of topics relevant to decisions about BRCA genetic testing, including how breast cancer spreads, inherited genetic mutations, and base rates. . We measured content knowledge, gist comprehension of decision-relevant information, interest in testing, and genetic risk and testing judgments. . Control knowledge scores ranged from 54% to 56%, NCI improved significantly to 65% and 70%, and BRCA Gist improved significantly more to 75% and 77%, P < 0.0001. BRCA Gist scored higher on gist comprehension than NCI and control, P < 0.0001. Control genetic risk-assessment mean was 48% correct; BRCA Gist (61%) and NCI (56%) were significantly higher, P < 0.0001. BRCA Gist participants recommended less testing for women without risk factors (not good candidates; 24% and 19%) than controls (50%, both experiments) and NCI (32%), experiment 2, P < 0.0001. BRCA Gist testing interest was lower than in controls, P < 0.0001. . BRCA Gist has not been tested with older women from diverse groups. . Intelligent tutors, such as BRCA Gist, are scalable, cost-effective ways of helping people understand complex issues, improving decision making. © The Author(s) 2014.

Reading Development in Young Children: Genetic and Environmental Influences

PubMed Central

Logan, Jessica A. R.; Hart, Sara A.; Cutting, Laurie; Deater-Deckard, Kirby; Schatschneider, Chris; Petrill, Stephen

2013-01-01

The development of reading skills in typical students is commonly described as a rapid growth across early grades of active reading education, with a slowing down of growth as active instruction tapers. This study examined the extent to which genetics and environments influence these growth rates. Participants were 371 twin pairs, aged approximately 6 through 12, from the Western Reserve Reading Project. Development of word-level reading, reading comprehension, and rapid naming was examined using genetically sensitive latent quadratic growth curve modeling. Results confirmed the developmental trajectory described in the phenotypic literature. Furthermore, the same shared environmental influences were related to early reading skills and subsequent growth, but genetic influences on these factors were unique. PMID:23574275

Genetics of behavior in the silver fox.

PubMed

Kukekova, Anna V; Temnykh, Svetlana V; Johnson, Jennifer L; Trut, Lyudmila N; Acland, Gregory M

2012-02-01

The silver fox provides a rich resource for investigating the genetics of behavior, with strains developed by intensely selective breeding that display markedly different behavioral phenotypes. Until recently, however, the tools for conducting molecular genetic investigations in this species were very limited. In this review, the history of development of this resource and the tools to exploit it are described. Although the focus is on the genetics of domestication in the silver fox, there is a broader context. In particular, one expectation of the silver fox research is that it will be synergistic with studies in other species, including humans, to yield a more comprehensive understanding of the molecular mechanisms and evolution of a wider range of social cognitive behaviors.

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

PubMed

Reddy, Anupama; Zhang, Jenny; Davis, Nicholas S; Moffitt, Andrea B; Love, Cassandra L; Waldrop, Alexander; Leppa, Sirpa; Pasanen, Annika; Meriranta, Leo; Karjalainen-Lindsberg, Marja-Liisa; Nørgaard, Peter; Pedersen, Mette; Gang, Anne O; Høgdall, Estrid; Heavican, Tayla B; Lone, Waseem; Iqbal, Javeed; Qin, Qiu; Li, Guojie; Kim, So Young; Healy, Jane; Richards, Kristy L; Fedoriw, Yuri; Bernal-Mizrachi, Leon; Koff, Jean L; Staton, Ashley D; Flowers, Christopher R; Paltiel, Ora; Goldschmidt, Neta; Calaminici, Maria; Clear, Andrew; Gribben, John; Nguyen, Evelyn; Czader, Magdalena B; Ondrejka, Sarah L; Collie, Angela; Hsi, Eric D; Tse, Eric; Au-Yeung, Rex K H; Kwong, Yok-Lam; Srivastava, Gopesh; Choi, William W L; Evens, Andrew M; Pilichowska, Monika; Sengar, Manju; Reddy, Nishitha; Li, Shaoying; Chadburn, Amy; Gordon, Leo I; Jaffe, Elaine S; Levy, Shawn; Rempel, Rachel; Tzeng, Tiffany; Happ, Lanie E; Dave, Tushar; Rajagopalan, Deepthi; Datta, Jyotishka; Dunson, David B; Dave, Sandeep S

2017-10-05

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetics of pancreatic neuroendocrine tumors: implications for the clinic

PubMed Central

Pea, Antonio; Hruban, Ralph H.; Wood, Laura D.

2016-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID:26413978

A Comprehensive Analysis of High School Genetics Standards: Are States Keeping Pace with Modern Genetics?

PubMed Central

Dougherty, M.J.; Pleasants, C.; Solow, L.; Wong, A.; Zhang, H.

2011-01-01

Science education in the United States will increasingly be driven by testing and accountability requirements, such as those mandated by the No Child Left Behind Act, which rely heavily on learning outcomes, or “standards,” that are currently developed on a state-by-state basis. Those standards, in turn, drive curriculum and instruction. Given the importance of standards to teaching and learning, we investigated the quality of life sciences/biology standards with respect to genetics for all 50 states and the District of Columbia, using core concepts developed by the American Society of Human Genetics as normative benchmarks. Our results indicate that the states’ genetics standards, in general, are poor, with more than 85% of the states receiving overall scores of Inadequate. In particular, the standards in virtually every state have failed to keep pace with changes in the discipline as it has become genomic in scope, omitting concepts related to genetic complexity, the importance of environment to phenotypic variation, differential gene expression, and the differences between inherited and somatic genetic disease. Clearer, more comprehensive genetics standards are likely to benefit genetics instruction and learning, help prepare future genetics researchers, and contribute to the genetic literacy of the U.S. citizenry. PMID:21885828

Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand.

PubMed

Woon, See-Tarn; Ameratunga, Rohan

2016-01-01

New Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs). Since 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014. We undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobulinemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity. Thorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next generation sequencing will play an increasing role in disorders with locus heterogeneity.

Abnormal Processing of Emotional Prosody in Williams Syndrome: An Event-Related Potentials Study

ERIC Educational Resources Information Center

Pinheiro, Ana P.; Galdo-Alvarez, Santiago; Rauber, Andreia; Sampaio, Adriana; Niznikiewicz, Margaret; Goncalves, Oscar F.

2011-01-01

Williams syndrome (WS), a neurodevelopmental genetic disorder due to a microdeletion in chromosome 7, is described as displaying an intriguing socio-cognitive phenotype. Deficits in prosody production and comprehension have been consistently reported in behavioral studies. It remains, however, to be clarified the neurobiological processes…

Genetic variation and genetic structure of the endangered species Sinowilsonia henryi Hemsi. (Hamamelidaceae) revealed by amplified fragment length polymorphism (AFLP) markers.

PubMed

Zhang, H; Ji, W L; Li, M; Zhou, L Y

2015-10-14

Comprehensive research of genetic variation is crucial in designing conservation strategies for endangered and threatened species. Sinowilsonia henryi Hemsi. is a tertiary relic with a limited geographical distribution in the central and western areas of China. It is endangered because of climate change and habitat fragmentation over the last thousands of years. In this study, amplified fragment length polymorphism markers were utilized to estimate genetic diversity and genetic structure in and among S. henryi. In this study, Nei's genetic diversity and Shannon's information index were found to be 0.192 and 0.325 respectively, indicating a moderate-to-high genetic diversity in species. According to analysis of molecular variation results, 32% of the genetic variation was shown to be partitioned among populations, demonstrating a relatively high genetic divergence; this was supported by principal coordinate analysis and unweighted pair-group method with arithmetic average analysis. Moreover, the Mantel test showed that there was no significant correlation between genetic and geographical distances. The above results can be explained by the effects of habitat fragmentation, history traits, and gene drift. Based on the results, several implications were indicated and suggestions proposed for preservation strategies for this species.

A comprehensive survey of soft wheat grain quality in United States germplasm

USDA-ARS?s Scientific Manuscript database

Wheat (Triticum aestivum L.) quality is dependent upon both genetic and environmental factors, which work in combination to produce specific grain, milling, and baking characteristics. Along with these genetic and environmental factors, the adaptation of the genetics to the given growing environment...

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING.

PubMed

Hafler, Brian P

2017-03-01

Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Theory of mind reasoning in schizophrenia patients and non-psychotic relatives.

PubMed

Cassetta, Briana; Goghari, Vina

2014-08-15

Research consistently demonstrates that schizophrenia patients have theory of mind (ToM) impairments. Additionally, there is some evidence that family members of schizophrenia patients also demonstrate impairments in ToM, suggesting a genetic vulnerability for the disorder. This study assessed ToM abilities (i.e., sarcasm comprehension) in schizophrenia patients and their first-degree biological relatives during video-taped social interactions, to be representative of real-world interactions and to assess for disease-specific and/or genetic liability effects. Additionally, we assessed whether ToM abilities predicted social and global functioning in schizophrenia patients, and whether symptoms were associated with ToM deficits. Schizophrenia patients demonstrated impairments in sarcasm comprehension compared to controls and relatives, whereas relatives showed intact comprehension. Symptoms of schizophrenia significantly predicted worse ToM abilities. Furthermore, in schizophrenia patients, impaired ToM reasoning predicted worse social and global functioning. Given schizophrenia patients demonstrated impairments in ToM reasoning in a task that resembles real-life interactions, this might be a key area for remediation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

77 FR 7172 - Sequoyah National Wildlife Refuge, Sequoyah, Muskogee, and Haskell Counties, OK; Comprehensive...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-10

.... Scoping for the environmental assessment (EA) on use of specified genetically modified crops in... of genetically modified crops in association with the cooperative farming program was released on... assessment of using specified genetically modified crops into the CCP and determined that an environmental...

THE PATHOLOGY OF MENTAL RETARDATION.

ERIC Educational Resources Information Center

CROME, L.; STERN, J.

DATA FROM RECENT COMPREHENSIVE STUDIES OF THE PATHOLOGY OF MENTAL RETARDATION ARE ASSEMBLED, INCLUDING MATERIAL ON ETIOLOGY, MORPHOLOGY, BIOCHEMISTRY, AND LABORATORY DIAGNOSIS. AREAS COVERED ARE (1) GENETIC CAUSES OF MENTAL RETARDATION, (2) DISORDERS OF GESTATION, (3) BIRTH INJURY, (4) GENERAL CONSIDERATIONS OF POSTNATAL CAUSES OF MENTAL…

Erythropoietic Protoporphyria (EPP) or Protoporphyria

MedlinePlus

... protoporphyrin can differentiate X-linked protoporphyria from EPP. Molecular genetic testing can confirm a diagnosis of X-linked ... systematically and comprehensively plan an affected child’s treatment. Genetic ... expression and characterization of erythroid-specific 5-aminolevulinate ...

An E-Learning Module to Improve Nongenetic Health Professionals' Assessment of Colorectal Cancer Genetic Risk: Feasibility Study.

PubMed

Douma, Kirsten Freya Lea; Aalfs, Cora M; Dekker, Evelien; Tanis, Pieter J; Smets, Ellen M

2017-12-18

Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling. The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists. A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires. A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest. This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills. ©Kirsten Freya Lea Douma, Cora M Aalfs, Evelien Dekker, Pieter J Tanis, Ellen M Smets. Originally published in JMIR Medical Education (http://mededu.jmir.org), 18.12.2017.

An E-Learning Module to Improve Nongenetic Health Professionals’ Assessment of Colorectal Cancer Genetic Risk: Feasibility Study

PubMed Central

Aalfs, Cora M; Dekker, Evelien; Tanis, Pieter J; Smets, Ellen M

2017-01-01

Background Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling. Objective The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists. Methods A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires. Results A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest. Conclusions This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills. PMID:29254907

Family communication in a population at risk for hypertrophic cardiomyopathy.

PubMed

Batte, Brittany; Sheldon, Jane P; Arscott, Patricia; Huismann, Darcy J; Salberg, Lisa; Day, Sharlene M; Yashar, Beverly M

2015-04-01

Encouraging family communication is an integral component of genetic counseling; therefore, we sought to identify factors impacting communication to family members at risk for Hypertrophic Cardiomyopathy (HCM). Participants (N = 383) completed an online survey assessing: 1) demographics (gender, genetic test results, HCM family history, and disease severity); 2) illness representations; 3) family functioning and cohesiveness; 4) coping styles; 5) comprehension of HCM autosomal dominant inheritance; and 6) communication of HCM risk information to at-risk relatives. Participants were a national sample of individuals with HCM, recruited through the Hypertrophic Cardiomyopathy Association. Data from 183 participants were analyzed using a logistic regression analysis, with family communication as a dichotomous dependent variable. We found that female gender and higher comprehension of autosomal dominant inheritance were significant predictors of participants' communication of HCM risk information to all their siblings and children. Our results suggest that utilizing interventions that promote patient comprehension (e.g., a teaching-focused model of genetic counseling) are important and may positively impact family communication within families with HCM.

Next-generation sequencing-based molecular diagnosis of a Chinese patient cohort with autosomal recessive retinitis pigmentosa.

PubMed

Fu, Qing; Wang, Feng; Wang, Hui; Xu, Fei; Zaneveld, Jacques E; Ren, Huanan; Keser, Vafa; Lopez, Irma; Tuan, Han-Fang; Salvo, Jason S; Wang, Xia; Zhao, Li; Wang, Keqing; Li, Yumei; Koenekoop, Robert K; Chen, Rui; Sui, Ruifang

2013-06-14

Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. The prevalence of RP in China had been reported at 1 in 3800, resulting in an estimated total of 340,000 Chinese RP patients. However, genetic studies of Chinese RP patients have been very limited. To date, no comprehensive molecular diagnosis has been done for Chinese RP patients. With the emergence of next-generation sequencing (NGS), comprehensive molecular diagnosis of RP is now within reach. The purpose of this study was to perform the first NGS-based comprehensive molecular diagnosis for Chinese RP patients. Thirty-one well-characterized autosomal recessive RP (arRP) families were recruited. For each family, the DNA sample from one affected member was sequenced using our custom capture panel, which includes 163 retinal disease genes. Variants were called, filtered, and annotated by our in-house automatic pipeline. Twelve arRP families were successfully molecular diagnosed, achieving a diagnostic rate of approximately 40%. Interestingly, approximately 63% of the pathogenic mutations we identified are novel, which is higher than that observed in a similar study on European descent (45%). Moreover, the clinical diagnoses of two families were refined based on the pathogenic mutations identified in the patients. We conclude that comprehensive molecular diagnosis can be vital for an accurate clinical diagnosis of RP. Applying this tool on patients from different ethnic groups is essential for enhancing our knowledge of the global spectrum of RP disease-causing mutations.

International cooperation and networking in genetic health care provision: issues arising from the genetic services plan for the Emilia-Romagna region, Italy.

PubMed

Calzolari, E; Baroncini, A

2005-01-01

The aims of this report are to describe the genetic plan for Emilia-Romagna, a region in Italy, and to contribute to the international exchange of information on developing and applying policy frameworks to provide high-quality and comprehensive genetic health care in the publicly funded health systems. At the present time there is no national policy for genetic medicine in Italy, and only two regions, Emilia-Romagna and Liguria, have formally agreed to a strategic plan for health care in genetics. The current provision of genetic services in Emilia-Romagna is described focusing on the intra- and inter-organizational linkages to ensure a comprehensive system of coordinated activities. Strengths and implementation areas are highlighted. Points that must be solved within the regional or national context are the definition of the level of assistance required in genetic medicine, the formal professional recognition of the genetic counselor and the adjustment of the billing mechanisms to the complexities of clinical genetic services. Issues that need to be addressed at a wider level include full assessment of genetic tests before their introduction into clinical practice, networking to provide tests for the rarest genetic diseases, consensus on fundamental terminology and clinical and administrative data sets to promote a cohesive framework for the flow of information throughout the health care systems with respect to genetics. Copyright 2005 S. Karger AG, Basel.

Genome sequencing of Ewing sarcoma patients reveals genetic predisposition | Center for Cancer Research

Cancer.gov

The largest and most comprehensive genomic analysis of individuals with Ewing sarcoma performed to date reveals that some patients are genetically predisposed to developing the cancer.  Learn more...

PHENYLKETONURIA, A COMPREHENSIVE BIBLIOGRAPHY, 1964.

ERIC Educational Resources Information Center

Children's Bureau (DHEW), Washington, DC.

INTENDED AS AN AID TO PROFESSIONAL AND TECHNICAL PERSONS INTERESTED IN PHENYLKETONURIA (PKU), THE BIBLIOGRAPHY LISTS AND ANNOTATES 817 ITEMS. CONTENT DIVISIONS ARE (1) GENERAL--MONOGRAPHS AND ARTICLES, (2) BIOCHEMISTRY--METABOLISM, EXPERIMENTS, TESTS, AND CASES IN WHICH THE EMPHASIS IS ON BIOCHEMISTRY, (3) GENETICS--GENE STUDIES, HEREDITARY…

A novel mutation in SCN9A in a child with congenital insensitivity to pain.

PubMed

Shorer, Zamir; Wajsbrot, Einav; Liran, Tamir-Hostovsky; Levy, Jacov; Parvari, Ruti

2014-01-01

[corrected] Congenital insensitivity to pain (CIP) is a rare condition in which patients have no pain perception and anosmia but are otherwise essentially normal (OMIM 243000). The recent discovery of the genetic defects underlying 3 monogenic pain disorders has provided additional and important insights about some components of human pain. Genetic studies in families demonstrating recessively inherited channelopathy-associated insensitivity to pain have identified nonsense mutations that result in truncation of the voltage-gated sodium channel type IX subunit (SCN9A), a 113.5-kb gene comprising coding 26 exons. Here we describe a patient with CIP with a new mutation in SCN9A not described yet. All exons were sequenced. All 26 coding exons were sequenced and two changes were identified in homozygosity in exon 10: c.1126 A > C causing K376Q and c.1124delG causing p.G375Afs* frame shift. We report a novel, loss-of-function mutation in homozygosity that causes congenital insensitivity to pain and provide a comprehensive clinical description of the patient. This contributes to the clinical and neurophysiological characteristic of the sodium channel Nav1.7 channelopathy and expand our genetic knowledge which might provide more accurate and comprehensive clinical electrophysiological and genetic information. Copyright © 2014 Elsevier Inc. All rights reserved.

Genetic variation and biological activity of isolates of lymantria dispar multiple nucleopolyhedrovirus from north america, europe, and asia

USDA-ARS?s Scientific Manuscript database

Little is known about genetic variation of Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV; Baculoviridae: Alphabaculovirus) at the nucleotide sequence level. To obtain a more comprehensive view of genetic diversity among isolates of LdMNPV, partial sequences of the lef-8 gene were generated...

Comprehensive review of genetic factors contributing to head and neck squamous cell carcinoma development in low-risk, nontraditional patients.

PubMed

Gingerich, Morgan A; Smith, Joshua D; Michmerhuizen, Nicole L; Ludwig, Megan; Devenport, Samantha; Matovina, Chloe; Brenner, Chad; Chinn, Steven B

2018-05-01

The past 2 decades have seen an increased incidence of head and neck squamous cell carcinoma (HNSCC) in a nontraditional, low-risk patient population (ie, ≤45 years of age, no substance use history), owing to a combination of human papillomavirus (HPV) infection and individual genetic variation. Articles positing genetic variants as contributing factors in HNSCC incidence in low-risk, nontraditional patients were identified using a PubMed search, reviewed in detail, and concisely summarized herein. Recent data suggest that common polymorphisms in DNA repair enzymes, cell-cycle control proteins, apoptotic pathway members, and Fanconi anemia-associated genes likely modulate susceptibility to HNSCC development in low-risk, nontraditional patients. At present, there is a lack of robust, comprehensive data on genetic drivers of oncogenesis in low-risk patients and a clear need for further research on genetic alterations underlying the rising incidence of HNSCC in low-risk, nontraditional patients. © 2018 Wiley Periodicals, Inc.

Identification of a Comprehensive Spectrum of Genetic Factors for Hereditary Breast Cancer in a Chinese Population by Next-Generation Sequencing

PubMed Central

Yang, Xiaochen; Wu, Jiong; Lu, Jingsong; Liu, Guangyu; Di, Genhong; Chen, Canming; Hou, Yifeng; Sun, Menghong; Yang, Wentao; Xu, Xiaojing; Zhao, Ying; Hu, Xin; Li, Daqiang; Cao, Zhigang; Zhou, Xiaoyan; Huang, Xiaoyan; Liu, Zhebin; Chen, Huan; Gu, Yanzi; Chi, Yayun; Yan, Xia; Han, Qixia; Shen, Zhenzhou; Shao, Zhimin; Hu, Zhen

2015-01-01

The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi-gene analysis using NGS may be a supplement to traditional genetic counseling. PMID:25927356

INVOLVEMENT OF MULTIPLE MOLECULAR PATHWAYS IN THE GENETICS OF OCULAR REFRACTION AND MYOPIA.

PubMed

Wojciechowski, Robert; Cheng, Ching-Yu

2018-01-01

The prevalence of myopia has increased dramatically worldwide within the last three decades. Recent studies have shown that refractive development is influenced by environmental, behavioral, and inherited factors. This review aims to analyze recent progress in the genetics of refractive error and myopia. A comprehensive literature search of PubMed and OMIM was conducted to identify relevant articles in the genetics of refractive error. Genome-wide association and sequencing studies have increased our understanding of the genetics involved in refractive error. These studies have identified interesting candidate genes. All genetic loci discovered to date indicate that refractive development is a heterogeneous process mediated by a number of overlapping biological processes. The exact mechanisms by which these biological networks regulate eye growth are poorly understood. Although several individual genes and/or molecular pathways have been investigated in animal models, a systematic network-based approach in modeling human refractive development is necessary to understand the complex interplay between genes and environment in refractive error. New biomedical technologies and better-designed studies will continue to refine our understanding of the genetics and molecular pathways of refractive error, and may lead to preventative and therapeutic measures to combat the myopia epidemic.

The genetics of celiac disease: A comprehensive review of clinical implications.

PubMed

Dieli-Crimi, Romina; Cénit, M Carmen; Núñez, Concepción

2015-11-01

Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4(+) T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tipping Points in Seaweed Genetic Engineering: Scaling Up Opportunities in the Next Decade

PubMed Central

Lin, Hanzhi; Qin, Song

2014-01-01

Seaweed genetic engineering is a transgenic expression system with unique features compared with those of heterotrophic prokaryotes and higher plants. This study discusses several newly sequenced seaweed nuclear genomes and the necessity that research on vector design should consider endogenous promoters, codon optimization, and gene copy number. Seaweed viruses and artificial transposons can be applied as transformation methods after acquiring a comprehensive understanding of the mechanism of viral infections in seaweeds and transposon patterns in seaweed genomes. After cultivating transgenic algal cells and tissues in a photobioreactor, a biosafety assessment of genetically modified (GM) seaweeds must be conducted before open-sea application. We propose a set of programs for the evaluation of gene flow from GM seaweeds to local/geographical environments. The effective implementation of such programs requires fundamentally systematic and interdisciplinary studies on algal physiology and genetics, marine hydrology, reproductive biology, and ecology. PMID:24857961

Tipping points in seaweed genetic engineering: scaling up opportunities in the next decade.

PubMed

Lin, Hanzhi; Qin, Song

2014-05-22

Seaweed genetic engineering is a transgenic expression system with unique features compared with those of heterotrophic prokaryotes and higher plants. This study discusses several newly sequenced seaweed nuclear genomes and the necessity that research on vector design should consider endogenous promoters, codon optimization, and gene copy number. Seaweed viruses and artificial transposons can be applied as transformation methods after acquiring a comprehensive understanding of the mechanism of viral infections in seaweeds and transposon patterns in seaweed genomes. After cultivating transgenic algal cells and tissues in a photobioreactor, a biosafety assessment of genetically modified (GM) seaweeds must be conducted before open-sea application. We propose a set of programs for the evaluation of gene flow from GM seaweeds to local/geographical environments. The effective implementation of such programs requires fundamentally systematic and interdisciplinary studies on algal physiology and genetics, marine hydrology, reproductive biology, and ecology.

An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

PubMed

Eisenberger, Tobias; Decker, Christian; Hiersche, Milan; Hamann, Ruben C; Decker, Eva; Neuber, Steffen; Frank, Valeska; Bolz, Hanno J; Fehrenbach, Henry; Pape, Lars; Toenshoff, Burkhard; Mache, Christoph; Latta, Kay; Bergmann, Carsten

2015-01-01

Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs). Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING

PubMed Central

HAFLER, BRIAN P.

2017-01-01

Purpose Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. Methods A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Results Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Conclusion Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies. PMID:27753762

Genetic differentiation of Alaska Chinook salmon: the missing link for migratory studies.

PubMed

Templin, William D; Seeb, James E; Jasper, James R; Barclay, Andrew W; Seeb, Lisa W

2011-03-01

Most information about Chinook salmon genetic diversity and life history originates from studies from the West Coast USA, western Canada and southeast Alaska; less is known about Chinook salmon from western and southcentral Alaska drainages. Populations in this large area are genetically distinct from populations to the south and represent an evolutionary legacy of unique genetic, phenotypic and life history diversity. More genetic information is necessary to advance mixed stock analysis applications for studies involving these populations. We assembled a comprehensive, open-access baseline of 45 single nucleotide polymorphisms (SNPs) from 172 populations ranging from Russia to California. We compare SNP data from representative populations throughout the range with particular emphasis on western and southcentral Alaska. We grouped populations into major lineages based upon genetic and geographic characteristics, evaluated the resolution for identifying the composition of admixtures and performed mixed stock analysis on Chinook salmon caught incidentally in the walleye pollock fishery in the Bering Sea. SNP data reveal complex genetic structure within Alaska and can be used in applications to address not only regional issues, but also migration pathways, bycatch studies on the high seas, and potential changes in the range of the species in response to climate change. © 2011 Blackwell Publishing Ltd.

Genecology of Thurber’s needlegrass (Achnatherum thurberianum (Piper) Barkworth) in the Western U.S.

USDA-ARS?s Scientific Manuscript database

Thurber’s needlegrass (Achnatherum thurberianum (Piper) Barkworth) is a key restoration species in the Great Basin and surrounding areas, yet comprehensive studies of how climate relates to genetic variation and seed zones for restoration projects are lacking. Potentially adaptive phenotypic traits...

Integrated Analysis of Genetic and Proteomic Data Identifies Biomarkers Associated with Adverse Events Following Smallpox Vaccination

EPA Science Inventory

Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experi...

Nomenclature of mitochondrial DNA haplotypes for Oncorhynchus mykiss

USGS Publications Warehouse

Graziano, Sara L.; Brown, K.H.; Nielsen, Jennifer L.

2005-01-01

Congruence of genetic data is critical for comparative and collaborative studies on natural fish populations. A comprehensive list of reported mitochrondrial DNA haplotypes for Oncorhynchus mykiss generated using the S-Phe/P2 primer set is presented as a resource for future investigations of this species.

The application of secondary metabolites in the study of sorghum insect resistance

NASA Astrophysics Data System (ADS)

Chunming, Bai; Yifei, Liu; Xiaochun, Lu

2018-03-01

Insect attack is one of the main factors for limiting the production of rice and sorghum. To improve resistance to pests of rice and sorghum will be of great significance for meliorating their production and quality. However, the source and material of anti-pest was scarce. In this study, we will study on the expression patterns of hydrocyanic acid biosynthesis relative genes in sorghum firstly. And we will also genetically transform them into rice and sorghum by specific and constitutive promoters and verify their pest-resistant ability. Finally, high pest-resistant genetically modified new sorghum cultivars will be bred with favorable comprehensive agronomic traits.

al mena: a comprehensive resource of human genetic variants integrating genomes and exomes from Arab, Middle Eastern and North African populations.

PubMed

Koshy, Remya; Ranawat, Anop; Scaria, Vinod

2017-10-01

Middle East and North Africa (MENA) encompass very unique populations, with a rich history and encompasses characteristic ethnic, linguistic and genetic diversity. The genetic diversity of MENA region has been largely unknown. The recent availability of whole-exome and whole-genome sequences from the region has made it possible to collect population-specific allele frequencies. The integration of data sets from this region would provide insights into the landscape of genetic variants in this region. We integrated genetic variants from multiple data sets systematically, available from this region to create a compendium of over 26 million genetic variations. The variants were systematically annotated and their allele frequencies in the data sets were computed and available as a web interface which enables quick query. As a proof of principle for application of the compendium for genetic epidemiology, we analyzed the allele frequencies for variants in transglutaminase 1 (TGM1) gene, associated with autosomal recessive lamellar ichthyosis. Our analysis revealed that the carrier frequency of selected variants differed widely with significant interethnic differences. To the best of our knowledge, al mena is the first and most comprehensive repertoire of genetic variations from the Arab, Middle Eastern and North African region. We hope al mena would accelerate Precision Medicine in the region.

Stakeholder perspectives on decision-analytic modeling frameworks to assess genetic services policy.

PubMed

Guzauskas, Gregory F; Garrison, Louis P; Stock, Jacquie; Au, Sylvia; Doyle, Debra Lochner; Veenstra, David L

2013-01-01

Genetic services policymakers and insurers often make coverage decisions in the absence of complete evidence of clinical utility and under budget constraints. We evaluated genetic services stakeholder opinions on the potential usefulness of decision-analytic modeling to inform coverage decisions, and asked them to identify genetic tests for decision-analytic modeling studies. We presented an overview of decision-analytic modeling to members of the Western States Genetic Services Collaborative Reimbursement Work Group and state Medicaid representatives and conducted directed content analysis and an anonymous survey to gauge their attitudes toward decision-analytic modeling. Participants also identified and prioritized genetic services for prospective decision-analytic evaluation. Participants expressed dissatisfaction with current processes for evaluating insurance coverage of genetic services. Some participants expressed uncertainty about their comprehension of decision-analytic modeling techniques. All stakeholders reported openness to using decision-analytic modeling for genetic services assessments. Participants were most interested in application of decision-analytic concepts to multiple-disorder testing platforms, such as next-generation sequencing and chromosomal microarray. Decision-analytic modeling approaches may provide a useful decision tool to genetic services stakeholders and Medicaid decision-makers.

Comparing schizophrenia symptoms in the Iban of Sarawak with other populations to elucidate clinical heterogeneity.

PubMed

McLean, Duncan; Barrett, Robert; Loa, Peter; Thara, Rangaswamy; John, Sujit; McGrath, John; Gratten, Jake; Mowry, Bryan

2015-03-01

The symptom profile of schizophrenia can vary between ethnic groups. We explored selected symptom variables previously reported to be characteristic of schizophrenia in the Iban of Sarawak in transethnic populations from Australia, India, and Sarawak, Malaysia. We tested site differences to confirm previous research, and to explore implications of differences across populations for future investigations. We recruited schizophrenia samples in Australia (n = 609), India (n = 310) and Sarawak (n = 205) primarily for the purposes of genetic studies. We analyzed seven identified variables and their relationship to site using logistic regression, including: global delusions, bizarre delusions, thought broadcast/insertion/withdrawal delusions, global hallucinations, auditory hallucinations, disorganized behavior, and prodromal duration. We identified a distinct symptom profile in our Sarawak sample. Specifically, the Iban exhibit: low frequency of thought broadcast/insertion/withdrawal delusions, high frequency of auditory hallucinations and disorganized behavior, with a comparatively short prodrome when compared with Australian and Indian populations. Understanding between-site variation in symptom profile may complement future transethnic genetic studies, and provide important clues as to the nature of differing schizophrenia expression across ethnically distinct groups. A comprehensive approach to subtyping schizophrenia is warranted, utilizing comprehensively ascertained transethnic samples to inform both schizophrenia genetics and nosology. Copyright © 2013 Wiley Publishing Asia Pty Ltd.

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

PubMed

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic variation and forensic characterization of highland Tibetan ethnicity reveled by autosomal STR markers.

PubMed

He, Guanglin; Wang, Zheng; Su, Yongdong; Zou, Xing; Wang, Mengge; Liu, Jing; Hou, Yiping

2018-01-08

Understanding the origin and genetic background of Chinese high-altitude Tibetans play a pivotal role in medical genetics, archeology, anthropology, and forensics. In this study, to investigate the forensic characterization and genetic diversity of Chinese Tibetan, allele frequencies and corresponding forensic statistical parameters of 15 autosomal STRs included in the AmpFℓSTR® Sinofiler™ kit were obtained from 1220 Tibetan individuals residing in Lhasa country, Tibet Autonomous Region. We identified 191 alleles with corresponding allele frequencies varied from 0.0004 to 0.3984. The combined probability of discrimination and the combined probability of exclusion are 0.9999999999999999997 and 0.9999996, respectively. Our study provided the valuable dataset for forensic individual identification and parentage testing in the high-altitude Tibetan population. In addition, comprehensive population comparisons among 30 Chinese populations via PCA, AMOVA, MDS, and N-J tree demonstrated that the genetic components of Tibet Tibetan have received gene introgression from surrounding lowland populations (Such as Gansu Hui and Yunnan Bai) and Tibetan keeps the close genetic relationship with geographic neighboring populations.

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease.

PubMed

Xu, Yuejuan; Li, Tingting; Pu, Tian; Cao, Ruixue; Long, Fei; Chen, Sun; Sun, Kun; Xu, Rang

2017-12-01

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

Tackling the achilles' heel of genetic testing.

PubMed

Watkins, Hugh

2015-01-14

Assigning pathogenicity to rare genetic variants is at its hardest with the enormous titin gene, but comprehensive genomic analysis makes the task more tractable (Roberts et al., this issue). Copyright © 2015, American Association for the Advancement of Science.

Interactions Between Genetics, Lifestyle, and Environmental Factors for Healthcare.

PubMed

Lin, Yuxin; Chen, Jiajia; Shen, Bairong

2017-01-01

The occurrence and progression of diseases are strongly associated with a combination of genetic, lifestyle, and environmental factors. Understanding the interplay between genetic and nongenetic components provides deep insights into disease pathogenesis and promotes personalized strategies for people healthcare. Recently, the paradigm of systems medicine, which integrates biomedical data and knowledge at multidimensional levels, is considered to be an optimal way for disease management and clinical decision-making in the era of precision medicine. In this chapter, epigenetic-mediated genetics-lifestyle-environment interactions within specific diseases and different ethnic groups are systematically discussed, and data sources, computational models, and translational platforms for systems medicine research are sequentially presented. Moreover, feasible suggestions on precision healthcare and healthy longevity are kindly proposed based on the comprehensive review of current studies.

Assessment of the environmental and genetic factors influencing prevalence of metabolic syndrome in Saudi Arabia

PubMed Central

Gosadi, Ibrahim M.

2016-01-01

Metabolic syndrome (MS) is a combination of factors that increases the risk of cardiovascular atherosclerotic diseases including diabetes, obesity, dyslipidemia, and high blood pressure. Cardiovascular diseases are one of the leading causes of death in the adult Saudi population where the increase in cardiovascular-related mortality is augmented by the rise in the prevalence of MS. Metabolic syndrome is a multi-factorial disorder influenced by interactions between genetic and environmental components. This review aims to provide a comprehensive assessment of studied environmental and genetic factors explaining the prevalence of MS in the Kingdom of Saudi Arabia. Additionally, this review aims to illustrate factors related to the population genetics of Saudi Arabia, which might explain a proportion of the prevalence of MS. PMID:26739969

Mammalian synthetic biology for studying the cell

PubMed Central

Mathur, Melina; Xiang, Joy S.

2017-01-01

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. PMID:27932576

Genomic Analyses Yield Markers for Identifying Agronomically Important Genes in Potato

USDA-ARS?s Scientific Manuscript database

This study explores the genetic architecture underling the potato evolution through a comprehensive assessment of wild and cultivated potato species based on the re-sequencing of 201 accessions of Solanum section Petota with >12 × genome coverage. We identified 450 domesticated genes, which showed e...

List of gene variants developed for cancer cells from nine tissue types

Cancer.gov

NCI scientists have developed a comprehensive list of genetic variants for each of the types of cells that comprise what is known as the NCI-60 cell line collection. This new list adds depth to the most frequently studied human tumor cell lines in cancer

Genetic diversity and differentiation of exotic and American commercial cattle breeds raised in Brazil.

PubMed

Brasil, B S A F; Coelho, E G A; Drummond, M G; Oliveira, D A A

2013-11-18

The Brazilian cattle population is mainly composed of breeds of zebuine origin and their American derivatives. Comprehensive knowledge about the genetic diversity of these populations is fundamental for animal breeding programs and the conservation of genetic resources. This study aimed to assess the phylogenetic relationships, levels of genetic diversity, and patterns of taurine/zebuine admixture among 9 commercial cattle breeds raised in Brazil. Analysis of DNA polymorphisms was performed on 2965 animals using the 11 microsatellite markers recommended by the International Society of Animal Genetics. High genetic diversity was detected in all breeds, even though significant inbreeding was observed within some. Differences among the breeds accounted for 14.72% of the total genetic variability, and genetic differentiation was higher among taurine than among zebuine cattle. Of note, Nelore cattle presented with high levels of admixture, which is consistent with the history of frequent gene flow during the establishment of this breed in Brazil. Furthermore, significant genetic variability was partitioned within the commercial cattle breeds formed in America, which, therefore, comprise important resources of genetic diversity in the tropics. The genetic characterization of these important Brazilian breeds may now facilitate the development of management and breeding programs for these populations.

An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures.

PubMed

Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A; Joo, Jong Wha J; Kostem, Emrah; Zaitlen, Noah; Eskin, Eleazar; Han, Buhm

2018-05-11

Over the past few years, genome-wide association studies have identified many trait-associated loci that have different effects on females and males, which increased attention to the genetic architecture differences between the sexes. The between-sex differences in genetic architectures can cause a variety of phenomena such as differences in the effect sizes at trait-associated loci, differences in the magnitudes of polygenic background effects, and differences in the phenotypic variances. However, current association testing approaches for dealing with sex, such as including sex as a covariate, cannot fully account for these phenomena and can be suboptimal in statistical power. We present a novel association mapping framework, MetaSex, that can comprehensively account for the genetic architecture differences between the sexes. Through simulations and applications to real data, we show that our framework has superior performance than previous approaches in association mapping. Copyright © 2018, Genetics.

An interdisciplinary approach to personalized medicine: case studies from a cardiogenetics clinic.

PubMed

Erskine, Kathleen E; Griffith, Eleanor; Degroat, Nicole; Stolerman, Marina; Silverstein, Louise B; Hidayatallah, Nadia; Wasserman, David; Paljevic, Esma; Cohen, Lilian; Walsh, Christine A; McDonald, Thomas; Marion, Robert W; Dolan, Siobhan M

2013-01-01

In the genomic age, the challenges presented by various inherited conditions present a compelling argument for an interdisciplinary model of care. Cardiac arrhythmias with a genetic basis, such as long QT syndrome, require clinicians with expertise in many specialties to address the complex genetic, psychological, ethical and medical issues involved in treatment. The Montefiore-Einstein Center for CardioGenetics has been established to provide personalized, interdisciplinary care for families with a history of sudden cardiac death or an acute cardiac event. Four vignettes of patient care are presented to illustrate the unique capacity of an interdisciplinary model to address genetic, psychological, ethical and medical issues. Because interdisciplinary clinics facilitate collaboration among multiple specialties, they allow for individualized, comprehensive care to be delivered to families who experience complex inherited medical conditions. As the genetic basis of many complex conditions is discovered, the advantages of an interdisciplinary approach for delivering personalized medicine will become more evident.

The Clinical Delivery of Pharmacogenetic Testing Services: A Proposed Partnership between Genetic Counselors and Pharmacists

PubMed Central

Mills, Rachel; Haga, Susanne B.

2013-01-01

One of the basic questions in the early uses of pharmacogenetic (PGx) testing revolves around the clinical delivery of testing. Because multiple health professionals may play a role in the delivery of PGx testing, various clinical delivery models have begun to be studied. We propose that a partnership between genetic counselors and pharmacists can assist clinicians in the delivery of comprehensive PGx services. Based on their expert knowledge of pharmacokinetics and pharmacodynamics, pharmacists can facilitate the appropriate application of PGx test results to adjust medication use as warranted and act as a liaison to the healthcare team recommending changes in medication based on test results and patient input. Genetic counselors are well-trained in genetics as well as risk communication and counseling methodology, but have limited knowledge of pharmaceuticals. The complementary knowledge and skill set supports the partnership between genetic counselors and pharmacists to provide effective PGx testing services. PMID:23746189

A powerful and robust test in genetic association studies.

PubMed

Cheng, Kuang-Fu; Lee, Jen-Yu

2014-01-01

There are several well-known single SNP tests presented in the literature for detecting gene-disease association signals. Having in place an efficient and robust testing process across all genetic models would allow a more comprehensive approach to analysis. Although some studies have shown that it is possible to construct such a test when the variants are common and the genetic model satisfies certain conditions, the model conditions are too restrictive and in general difficult to verify. In this paper, we propose a powerful and robust test without assuming any model restrictions. Our test is based on the selected 2 × 2 tables derived from the usual 2 × 3 table. By signals from these tables, we show through simulations across a wide range of allele frequencies and genetic models that this approach may produce a test which is almost uniformly most powerful in the analysis of low- and high-frequency variants. Two cancer studies are used to demonstrate applications of the proposed test. © 2014 S. Karger AG, Basel.

Legal protection of public health through control over genetically modified food.

PubMed

Gutorova, Nataliya; Batyhina, Olena; Trotska, Maryna

2018-01-01

Introduction: Science is constantly being developed which leads to both positive and negative changes in public health and the environment. One of the results of scientific progress is introduction of food based on genetically modified organisms whose effects on human health, to date, remain scantily studied and are ambiguous. The aim: to determine how human health can be influenced by food production based on genetically modified organisms. Materials and methods: international acts, data of international organizations and conclusions of scientists have been examined and used in the study. The article also summarizes information from scientific journals and monographs from a medical and legal point of view with scientific methods. This article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. Conclusions: Genetically modified organisms are specific human-made organisms being a result of using modern biotechnology techniques. They have both positive and negative effects on human health and the environment. The main disadvantage is not sufficient study of them in various spheres of public life.

Integrated analyses for genetic markers of polycystic ovary syndrome with 9 case-control studies of gene expression profiles.

PubMed

Lu, Chenqi; Liu, Xiaoqin; Wang, Lin; Jiang, Ning; Yu, Jun; Zhao, Xiaobo; Hu, Hairong; Zheng, Saihua; Li, Xuelian; Wang, Guiying

2017-01-10

Due to genetic heterogeneity and variable diagnostic criteria, genetic studies of polycystic ovary syndrome are particularly challenging. Furthermore, lack of sufficiently large cohorts limits the identification of susceptibility genes contributing to polycystic ovary syndrome. Here, we carried out a systematic search of studies deposited in the Gene Expression Omnibus database through August 31, 2016. The present analyses included studies with: 1) patients with polycystic ovary syndrome and normal controls, 2) gene expression profiling of messenger RNA, and 3) sufficient data for our analysis. Ultimately, a total of 9 studies with 13 datasets met the inclusion criteria and were performed for the subsequent integrated analyses. Through comprehensive analyses, there were 13 genetic factors overlapped in all datasets and identified as significant specific genes for polycystic ovary syndrome. After quality control assessment, there were six datasets remained. Further gene ontology enrichment and pathway analyses suggested that differentially expressed genes mainly enriched in oocyte pathways. These findings provide potential molecular markers for diagnosis and prognosis of polycystic ovary syndrome, and need in-depth studies on the exact function and mechanism in polycystic ovary syndrome.

Computational intelligence in bioinformatics: SNP/haplotype data in genetic association study for common diseases.

PubMed

Kelemen, Arpad; Vasilakos, Athanasios V; Liang, Yulan

2009-09-01

Comprehensive evaluation of common genetic variations through association of single-nucleotide polymorphism (SNP) structure with common complex disease in the genome-wide scale is currently a hot area in human genome research due to the recent development of the Human Genome Project and HapMap Project. Computational science, which includes computational intelligence (CI), has recently become the third method of scientific enquiry besides theory and experimentation. There have been fast growing interests in developing and applying CI in disease mapping using SNP and haplotype data. Some of the recent studies have demonstrated the promise and importance of CI for common complex diseases in genomic association study using SNP/haplotype data, especially for tackling challenges, such as gene-gene and gene-environment interactions, and the notorious "curse of dimensionality" problem. This review provides coverage of recent developments of CI approaches for complex diseases in genetic association study with SNP/haplotype data.

Host genetics of HIV acquisition and viral control.

PubMed

Shea, Patrick R; Shianna, Kevin V; Carrington, Mary; Goldstein, David B

2013-01-01

Since the discovery of HIV as the cause of AIDS, numerous insights have been gained from studies of its natural history and epidemiology. It has become clear that there are substantial interindividual differences in the risk of HIV acquisition and course of disease. Meanwhile, the field of human genetics has undergone a series of rapid transitions that have fundamentally altered the approach to studying HIV host genetics. We aim to describe the field as it has transitioned from the era of candidate-gene studies and the era of genome-wide association studies (GWAS) to its current state in the infancy of comprehensive sequencing. In some ways the field has come full circle, having evolved from being driven almost exclusively by our knowledge of immunology, to a bias-free GWAS approach, to a point where our ability to catalogue human variation far outstrips our ability to biologically interpret it.

Pigments in fruits and vegetables: genomics and dietetics

USDA-ARS?s Scientific Manuscript database

This comprehensive treatise provides a systemic and insightful overview of current advances in the biosynthetic genomics/genetics and preventive dietetics of carotenoids, flavonoids and betalains, from a general perspective, and in specific fruits and vegetables as well. Genomics/genetics focuses on...

Structure-function analysis of genetically defined neuronal populations.

PubMed

Groh, Alexander; Krieger, Patrik

2013-10-01

Morphological and functional classification of individual neurons is a crucial aspect of the characterization of neuronal networks. Systematic structural and functional analysis of individual neurons is now possible using transgenic mice with genetically defined neurons that can be visualized in vivo or in brain slice preparations. Genetically defined neurons are useful for studying a particular class of neurons and also for more comprehensive studies of the neuronal content of a network. Specific subsets of neurons can be identified by fluorescence imaging of enhanced green fluorescent protein (eGFP) or another fluorophore expressed under the control of a cell-type-specific promoter. The advantages of such genetically defined neurons are not only their homogeneity and suitability for systematic descriptions of networks, but also their tremendous potential for cell-type-specific manipulation of neuronal networks in vivo. This article describes a selection of procedures for visualizing and studying the anatomy and physiology of genetically defined neurons in transgenic mice. We provide information about basic equipment, reagents, procedures, and analytical approaches for obtaining three-dimensional (3D) cell morphologies and determining the axonal input and output of genetically defined neurons. We exemplify with genetically labeled cortical neurons, but the procedures are applicable to other brain regions with little or no alterations.

Genetic Inventory Task Final Report. Volume 2

NASA Technical Reports Server (NTRS)

Venkateswaran, Kasthuri; LaDuc, Myron T.; Vaishampayan, Parag

2012-01-01

Contaminant terrestrial microbiota could profoundly impact the scientific integrity of extraterrestrial life-detection experiments. It is therefore important to know what organisms persist on spacecraft surfaces so that their presence can be eliminated or discriminated from authentic extraterrestrial biosignatures. Although there is a growing understanding of the biodiversity associated with spacecraft and cleanroom surfaces, it remains challenging to assess the risk of these microbes confounding life-detection or sample-return experiments. A key challenge is to provide a comprehensive inventory of microbes present on spacecraft surfaces. To assess the phylogenetic breadth of microorganisms on spacecraft and associated surfaces, the Genetic Inventory team used three technologies: conventional cloning techniques, PhyloChip DNA microarrays, and 454 tag-encoded pyrosequencing, together with a methodology to systematically collect, process, and archive nucleic acids. These three analysis methods yielded considerably different results: Traditional approaches provided the least comprehensive assessment of microbial diversity, while PhyloChip and pyrosequencing illuminated more diverse microbial populations. The overall results stress the importance of selecting sample collection and processing approaches based on the desired target and required level of detection. The DNA archive generated in this study can be made available to future researchers as genetic-inventory-oriented technologies further mature.

Cancer genetics education in a low- to middle-income country: evaluation of an interactive workshop for clinicians in Kenya.

PubMed

Hill, Jessica A; Lee, Su Yeon; Njambi, Lucy; Corson, Timothy W; Dimaras, Helen

2015-01-01

Clinical genetic testing is becoming an integral part of medical care for inherited disorders. While genetic testing and counseling are readily available in high-income countries, in low- and middle-income countries like Kenya genetic testing is limited and genetic counseling is virtually non-existent. Genetic testing is likely to become widespread in Kenya within the next decade, yet there has not been a concomitant increase in genetic counseling resources. To address this gap, we designed an interactive workshop for clinicians in Kenya focused on the genetics of the childhood eye cancer retinoblastoma. The objectives were to increase retinoblastoma genetics knowledge, build genetic counseling skills and increase confidence in those skills. The workshop was conducted at the 2013 Kenyan National Retinoblastoma Strategy meeting. It included a retinoblastoma genetics presentation, small group discussion of case studies and genetic counseling role-play. Knowledge was assessed by standardized test, and genetic counseling skills and confidence by questionnaire. Knowledge increased significantly post-workshop, driven by increased knowledge of retinoblastoma causative genetics. One-year post-workshop, participant knowledge had returned to baseline, indicating that knowledge retention requires more frequent reinforcement. Participants reported feeling more confident discussing genetics with patients, and had integrated more genetic counseling into patient interactions. A comprehensive retinoblastoma genetics workshop can increase the knowledge and skills necessary for effective retinoblastoma genetic counseling.

Influence of race/ethnicity on genetic counseling and testing for hereditary breast and ovarian cancer.

PubMed

Forman, Andrea D; Hall, Michael J

2009-01-01

Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 (BRCA1/2) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed.

A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families.

PubMed

Amundsen, Silja Svanstrøm; Adamovic, Svetlana; Hellqvist, Asa; Nilsson, Staffan; Gudjónsdóttir, Audur H; Ascher, Henry; Ek, Johan; Larsson, Kristina; Wahlström, Jan; Lie, Benedicte A; Sollid, Ludvig M; Naluai, Asa Torinsson

2007-09-01

Celiac disease (CD) is a gluten-induced enteropathy, which results from the interplay between environmental and genetic factors. There is a strong human leukocyte antigen (HLA) association with the disease, and HLA-DQ alleles represent a major genetic risk factor. In addition to HLA-DQ, non-HLA genes appear to be crucial for CD development. Chromosomal region 5q31-33 has demonstrated linkage with CD in several genome-wide studies, including in our Swedish/Norwegian cohort. In a European meta-analysis 5q31-33 was the only region that reached a genome-wide level of significance except for the HLA region. To identify the genetic variant(s) responsible for this linkage signal, we performed a comprehensive single nucleotide polymorphism (SNP) association screen in 97 Swedish/Norwegian multiplex families who demonstrate linkage to the region. We selected tag SNPs from a 16 Mb region representing the 95% confidence interval of the linkage peak. A total of 1,404 SNPs were used for the association analysis. We identified several regions with SNPs demonstrating moderate single- or multipoint associations. However, the isolated association signals appeared insufficient to account for the linkage signal seen in our cohort. Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings.

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity.

PubMed

Revelas, Mary; Thalamuthu, Anbupalam; Oldmeadow, Christopher; Evans, Tiffany-Jane; Armstrong, Nicola J; Kwok, John B; Brodaty, Henry; Schofield, Peter R; Scott, Rodney J; Sachdev, Perminder S; Attia, John R; Mather, Karen A

2018-06-08

Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls. Copyright © 2018. Published by Elsevier B.V.

Case study 6.1: DNA survey for fisher in northern Idaho

Treesearch

Samuel Cushman; Kevin McKelvey; Michael Schwartz

2008-01-01

Unique haplotypes indicating the presence of a residual native population of fisher were found in central Idaho (Vinkey et al. 2006). Fishers had been detected previously using camera sets in the Selkirk Mountains just south of the Canadian border, but their population status and genetic composition were unknown. The purpose of the study was to provide a comprehensive...

Origins of Individual Differences in Theory of Mind: From Nature to Nurture?

ERIC Educational Resources Information Center

Hughes, Claire; Jaffee, Sara R.; Happ, Francesca; Taylor, Alan; Caspi, Avshalom; Moffitt, Terrie E.

2005-01-01

In this study of the origins of individual differences in theory of mind (ToM), the Environmental Risk (E-Risk) Longitudinal Twin Study sample of 1,116 sixty-month-old twin pairs completed a comprehensive battery of ToM tasks. Individual differences in ToM were striking and strongly associated with verbal ability. Behavioral genetic models of the…

A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases.

PubMed

Bullich, Gemma; Domingo-Gallego, Andrea; Vargas, Iván; Ruiz, Patricia; Lorente-Grandoso, Laura; Furlano, Mónica; Fraga, Gloria; Madrid, Álvaro; Ariceta, Gema; Borregán, Mar; Piñero-Fernández, Juan Alberto; Rodríguez-Peña, Lidia; Ballesta-Martínez, Maria Juliana; Llano-Rivas, Isabel; Meñica, Mireia Aguirre; Ballarín, José; Torrents, David; Torra, Roser; Ars, Elisabet

2018-05-22

Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Comprehensive analysis of the mutation spectrum in 301 German ALS families.

PubMed

Müller, Kathrin; Brenner, David; Weydt, Patrick; Meyer, Thomas; Grehl, Torsten; Petri, Susanne; Grosskreutz, Julian; Schuster, Joachim; Volk, Alexander E; Borck, Guntram; Kubisch, Christian; Klopstock, Thomas; Zeller, Daniel; Jablonka, Sibylle; Sendtner, Michael; Klebe, Stephan; Knehr, Antje; Günther, Kornelia; Weis, Joachim; Claeys, Kristl G; Schrank, Berthold; Sperfeld, Anne-Dorte; Hübers, Annemarie; Otto, Markus; Dorst, Johannes; Meitinger, Thomas; Strom, Tim M; Andersen, Peter M; Ludolph, Albert C; Weishaupt, Jochen H

2018-04-12

Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families. 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1 , whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes. We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe. © 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.

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy.

PubMed

Iarossi, Giancarlo; Bertelli, Matteo; Maltese, Paolo Enrico; Gusson, Elena; Marchini, Giorgio; Bruson, Alice; Benedetti, Sabrina; Volpetti, Sabrina; Catena, Gino; Buzzonetti, Luca; Ziccardi, Lucia

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4 , LRP5 , TSPAN12 , and NDP . Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands ( NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy

PubMed Central

Marchini, Giorgio; Volpetti, Sabrina; Catena, Gino

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7–19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family. PMID:28758032

A global reference for human genetic variation

PubMed Central

2016-01-01

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. PMID:26432245

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

PubMed

Giri, Veda N; Knudsen, Karen E; Kelly, William K; Abida, Wassim; Andriole, Gerald L; Bangma, Chris H; Bekelman, Justin E; Benson, Mitchell C; Blanco, Amie; Burnett, Arthur; Catalona, William J; Cooney, Kathleen A; Cooperberg, Matthew; Crawford, David E; Den, Robert B; Dicker, Adam P; Eggener, Scott; Fleshner, Neil; Freedman, Matthew L; Hamdy, Freddie C; Hoffman-Censits, Jean; Hurwitz, Mark D; Hyatt, Colette; Isaacs, William B; Kane, Christopher J; Kantoff, Philip; Karnes, R Jeffrey; Karsh, Lawrence I; Klein, Eric A; Lin, Daniel W; Loughlin, Kevin R; Lu-Yao, Grace; Malkowicz, S Bruce; Mann, Mark J; Mark, James R; McCue, Peter A; Miner, Martin M; Morgan, Todd; Moul, Judd W; Myers, Ronald E; Nielsen, Sarah M; Obeid, Elias; Pavlovich, Christian P; Peiper, Stephen C; Penson, David F; Petrylak, Daniel; Pettaway, Curtis A; Pilarski, Robert; Pinto, Peter A; Poage, Wendy; Raj, Ganesh V; Rebbeck, Timothy R; Robson, Mark E; Rosenberg, Matt T; Sandler, Howard; Sartor, Oliver; Schaeffer, Edward; Schwartz, Gordon F; Shahin, Mark S; Shore, Neal D; Shuch, Brian; Soule, Howard R; Tomlins, Scott A; Trabulsi, Edouard J; Uzzo, Robert; Vander Griend, Donald J; Walsh, Patrick C; Weil, Carol J; Wender, Richard; Gomella, Leonard G

2018-02-01

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Mammalian synthetic biology for studying the cell.

PubMed

Mathur, Melina; Xiang, Joy S; Smolke, Christina D

2017-01-02

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. © 2017 Mathur et al.

EcoTurf - a case study: genetic variation and agronomic potential of bermudagrass (Cynodon spp.) germplasm collected from Australian biodiversity

USDA-ARS?s Scientific Manuscript database

Australian Cynodon germplasm has not been comprehensively exploited for bermudagrass improvement. In this paper we will describe ‘EcoTurf’ a four year (2007-2011) project to develop water and nutrient use efficient bermudagrasses from Australian biodiversity. We describe the sampling strategies of A...

Comprehension of Metaphor and Metonymy in Children with Williams Syndrome

ERIC Educational Resources Information Center

Annaz, Dagmara; Van Herwegen, Jo; Thomas, Michael; Fishman, Roza; Karmiloff-Smith, Annette; Rundblad, Gabriella

2009-01-01

Background: Figurative language, such as metaphor and metonymy, is very common in daily language use. Its underlying cognitive processes are sometimes viewed as lying at the interface of language and thought. Williams syndrome, which is a rare genetic developmental disorder, provides an opportunity to study this interface because individuals with…

Gene-Environment Interplay in Internalizing Disorders: Consistent Findings across Six Environmental Risk Factors

ERIC Educational Resources Information Center

Hicks, Brian M.; Dirago, Ana C.; Iacono, William G.; McGue, Matt

2009-01-01

Background: Behavior genetic methods can help to elucidate gene-environment (G-E) interplay in the development of internalizing (INT) disorders (i.e., major depression and anxiety disorders). To date, however, no study has conducted a comprehensive analysis examining multiple environmental risk factors with the purpose of delineating general…

Climate-related genetic variation in drought-resistance of Douglas-fir ( Pseudotsuga menziesii )

Treesearch

Sheel Bansal; Constance A. Harrington; Peter J. Gould; J. Bradley St.Clair

2014-01-01

There is a general assumption that intraspecific populations originating from relatively arid climates will be better adapted to cope with the expected increase in drought from climate change. For ecologically and economically important species, more comprehensive, genecological studies that utilize large distributions of populations and direct measures of traits...

Design and implementation of the cacao genome database

USDA-ARS?s Scientific Manuscript database

The Cacao Genome Database (CGD, www.cacaogenomedb.org) is being developed to provide a comprehensive data mining resource of genomic, genetic and breeding data for Theobroma cacao. Designed using Chado and a collection of Drupal modules, known as Tripal, CGD currently contains the genetically anchor...

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version

Cancer.gov

Genetics of Kidney Cancer (Renal Cell) includes the hereditary cancer syndromes von Hippel-Lindau disease, hereditary leiomyomatosis and renal cell cancer, Birt-Hogg-Dubé syndrome, and hereditary papillary renal carcinoma. Get comprehensive information on these syndromes in this clinician summary.

Population genetic testing for cancer susceptibility: founder mutations to genomes.

PubMed

Foulkes, William D; Knoppers, Bartha Maria; Turnbull, Clare

2016-01-01

The current standard model for identifying carriers of high-risk mutations in cancer-susceptibility genes (CSGs) generally involves a process that is not amenable to population-based testing: access to genetic tests is typically regulated by health-care providers on the basis of a labour-intensive assessment of an individual's personal and family history of cancer, with face-to-face genetic counselling performed before mutation testing. Several studies have shown that application of these selection criteria results in a substantial proportion of mutation carriers being missed. Population-based genetic testing has been proposed as an alternative approach to determining cancer susceptibility, and aims for a more-comprehensive detection of mutation carriers. Herein, we review the existing data on population-based genetic testing, and consider some of the barriers, pitfalls, and challenges related to the possible expansion of this approach. We consider mechanisms by which population-based genetic testing for cancer susceptibility could be delivered, and suggest how such genetic testing might be integrated into existing and emerging health-care structures. The existing models of genetic testing (including issues relating to informed consent) will very likely require considerable alteration if the potential benefits of population-based genetic testing are to be fully realized.

Molecular genetics of human obesity: A comprehensive review.

PubMed

Singh, Rajan Kumar; Kumar, Permendra; Mahalingam, Kulandaivelu

2017-02-01

Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci. Copyright © 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Evolutionary genetics of the Drosophila alcohol dehydrogenase gene-enzyme system.

PubMed

Heinstra, P W

1993-01-01

Evolutionary genetics embodies a broad research area that ranges from the DNA level to studies of genetic aspects in populations. In all cases the purpose is to determine the impact of genetic variation on evolutionary change. The broad range of evolutionary genetics requires the involvement of a diverse group of researchers: molecular biologists, (population) geneticists, biochemists, physiologists, ecologists, ethologists and theorists, each of which has its own insights and interests. For example, biochemists are often not concerned with the physiological function of a protein (with respect to pH, substrates, temperature, etc.), while ecologists, in turn, are often not interested in the biochemical-physiological aspects underlying the traits they study. This review deals with several evolutionary aspects of the Drosophila alcohol dehydrogenase gene-enzyme system, and includes my own personal viewpoints. I have tried to condense and integrate the current knowledge in this field as it has developed since the comprehensive review by van Delden (1982). Details on specific issues may be gained from Sofer and Martin (1987), Sullivan, Atkinson and Starmer (1990); Chambers (1988, 1991); Geer, Miller and Heinstra (1991); and Winberg and McKinley-McKee (1992).

BeetleBase in 2010: Revisions to Provide Comprehensive Genomic Information for Tribolium castaneum

USDA-ARS?s Scientific Manuscript database

BeetleBase (http://www.beetlebase.org) has been updated to provide more comprehensive genomic information for the red flour beetle Tribolium castaneum. The database contains genomic sequence scaffolds mapped to 10 linkage groups (genome assembly release Tcas_3.0), genetic linkage maps, the official ...

Dynamics and ethics of comprehensive preimplantation genetic testing: a review of the challenges.

PubMed

Hens, Kristien; Dondorp, Wybo; Handyside, Alan H; Harper, Joyce; Newson, Ainsley J; Pennings, Guido; Rehmann-Sutter, Christoph; de Wert, Guido

2013-01-01

Genetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues. The paper is a joint endeavour by the presenters at an explorative 'campus meeting' organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands). The increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. Combinations of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others. As comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.

Comprehensive curation and analysis of global interaction networks in Saccharomyces cerevisiae

PubMed Central

Reguly, Teresa; Breitkreutz, Ashton; Boucher, Lorrie; Breitkreutz, Bobby-Joe; Hon, Gary C; Myers, Chad L; Parsons, Ainslie; Friesen, Helena; Oughtred, Rose; Tong, Amy; Stark, Chris; Ho, Yuen; Botstein, David; Andrews, Brenda; Boone, Charles; Troyanskya, Olga G; Ideker, Trey; Dolinski, Kara; Batada, Nizar N; Tyers, Mike

2006-01-01

Background The study of complex biological networks and prediction of gene function has been enabled by high-throughput (HTP) methods for detection of genetic and protein interactions. Sparse coverage in HTP datasets may, however, distort network properties and confound predictions. Although a vast number of well substantiated interactions are recorded in the scientific literature, these data have not yet been distilled into networks that enable system-level inference. Results We describe here a comprehensive database of genetic and protein interactions, and associated experimental evidence, for the budding yeast Saccharomyces cerevisiae, as manually curated from over 31,793 abstracts and online publications. This literature-curated (LC) dataset contains 33,311 interactions, on the order of all extant HTP datasets combined. Surprisingly, HTP protein-interaction datasets currently achieve only around 14% coverage of the interactions in the literature. The LC network nevertheless shares attributes with HTP networks, including scale-free connectivity and correlations between interactions, abundance, localization, and expression. We find that essential genes or proteins are enriched for interactions with other essential genes or proteins, suggesting that the global network may be functionally unified. This interconnectivity is supported by a substantial overlap of protein and genetic interactions in the LC dataset. We show that the LC dataset considerably improves the predictive power of network-analysis approaches. The full LC dataset is available at the BioGRID () and SGD () databases. Conclusion Comprehensive datasets of biological interactions derived from the primary literature provide critical benchmarks for HTP methods, augment functional prediction, and reveal system-level attributes of biological networks. PMID:16762047

From genetics to genomics: ethics, policy, and parental decision-making.

PubMed

Wilfond, Benjamin; Ross, Lainie Friedman

2009-07-01

Ethical evaluation of genetic testing in children is traditionally based on balancing clinical benefits and risks. However, this focus can be inconsistent with the general practice of respecting parental decision-making about their children's health care. We argue that respect for parental decision-making should play a larger role in shaping pediatric genetic testing practices, and play a similar role regarding decisions to use emerging genomic technologies. Genomic testing involves the examination of thousands of DNA markers spanning genes throughout the genome and their interrelationships, yielding virtually limitless interpretations. We presume that parents and providers should proceed cautiously in applying genomic testing in children, as we explore how genomic testing will stress the fault lines of the traditional ethical analysis. Empirical data about the psychosocial risks and benefits of genetic testing of children do not reveal serious harms, yet virtually no such data exist yet about genomic testing. Unless empirical social and behavioral data indicate that genomic testing is highly likely to cause serious harms to the children, parental decisions to obtain comprehensive genomic testing in their children should be respected. Once comprehensive genomic testing of children becomes routine, resultant information may be more easily integrated by families than anticipated. Research on the social and behavioral impact of comprehensive genomic testing on children and their families is needed to further inform parents, clinicians, and policy makers.

Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease.

PubMed

Ashbrook, David G; Williams, Robert W; Lu, Lu; Stein, Jason L; Hibar, Derrek P; Nichols, Thomas E; Medland, Sarah E; Thompson, Paul M; Hager, Reinmar

2014-10-03

Variation in hippocampal volume has been linked to significant differences in memory, behavior, and cognition among individuals. To identify genetic variants underlying such differences and associated disease phenotypes, multinational consortia such as ENIGMA have used large magnetic resonance imaging (MRI) data sets in human GWAS studies. In addition, mapping studies in mouse model systems have identified genetic variants for brain structure variation with great power. A key challenge is to understand how genetically based differences in brain structure lead to the propensity to develop specific neurological disorders. We combine the largest human GWAS of brain structure with the largest mammalian model system, the BXD recombinant inbred mouse population, to identify novel genetic targets influencing brain structure variation that are linked to increased risk for neurological disorders. We first use a novel cross-species, comparative analysis using mouse and human genetic data to identify a candidate gene, MGST3, associated with adult hippocampus size in both systems. We then establish the coregulation and function of this gene in a comprehensive systems-analysis. We find that MGST3 is associated with hippocampus size and is linked to a group of neurodegenerative disorders, such as Alzheimer's.

Model Invariance across Genders of the Broad Autism Phenotype Questionnaire

ERIC Educational Resources Information Center

Broderick, Neill; Wade, Jordan L.; Meyer, J. Patrick; Hull, Michael; Reeve, Ronald E.

2015-01-01

ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates…

FLP recombinase-mediated site-specific recombination in silkworm, Bombyx mori

USDA-ARS?s Scientific Manuscript database

A comprehensive understanding of gene function and the production of site-specific genetically modified mutants are two major goals of genetic engineering in the post-genomic era. Although site-specific recombination systems have been powerful tools for genome manipulation of many organisms, they h...

Young Adults’ Belief in Genetic Determinism, and Knowledge and Attitudes towards Modern Genetics and Genomics: The PUGGS Questionnaire

PubMed Central

Carver, Rebecca Bruu; Castéra, Jérémy; Gericke, Niklas; Evangelista, Neima Alice Menezes

2017-01-01

In this paper we present the development and validation a comprehensive questionnaire to assess college students’ knowledge about modern genetics and genomics, their belief in genetic determinism, and their attitudes towards applications of modern genetics and genomic-based technologies. Written in everyday language with minimal jargon, the Public Understanding and Attitudes towards Genetics and Genomics (PUGGS) questionnaire is intended for use in research on science education and public understanding of science, as a means to investigate relationships between knowledge, determinism and attitudes about modern genetics, which are to date little understood. We developed a set of core ideas and initial items from reviewing the scientific literature on genetics and previous studies on public and student knowledge and attitudes about genetics. Seventeen international experts from different fields (e.g., genetics, education, philosophy of science) reviewed the initial items and their feedback was used to revise the questionnaire. We validated the questionnaire in two pilot tests with samples of university freshmen students. The final questionnaire contains 45 items, including both multiple choice and Likert scale response formats. Cronbach alpha showed good reliability for each section of the questionnaire. In conclusion, the PUGGS questionnaire is a reliable tool for investigating public understanding and attitudes towards modern genetics and genomic-based technologies. PMID:28114357

Young Adults' Belief in Genetic Determinism, and Knowledge and Attitudes towards Modern Genetics and Genomics: The PUGGS Questionnaire.

PubMed

Carver, Rebecca Bruu; Castéra, Jérémy; Gericke, Niklas; Evangelista, Neima Alice Menezes; El-Hani, Charbel N

2017-01-01

In this paper we present the development and validation a comprehensive questionnaire to assess college students' knowledge about modern genetics and genomics, their belief in genetic determinism, and their attitudes towards applications of modern genetics and genomic-based technologies. Written in everyday language with minimal jargon, the Public Understanding and Attitudes towards Genetics and Genomics (PUGGS) questionnaire is intended for use in research on science education and public understanding of science, as a means to investigate relationships between knowledge, determinism and attitudes about modern genetics, which are to date little understood. We developed a set of core ideas and initial items from reviewing the scientific literature on genetics and previous studies on public and student knowledge and attitudes about genetics. Seventeen international experts from different fields (e.g., genetics, education, philosophy of science) reviewed the initial items and their feedback was used to revise the questionnaire. We validated the questionnaire in two pilot tests with samples of university freshmen students. The final questionnaire contains 45 items, including both multiple choice and Likert scale response formats. Cronbach alpha showed good reliability for each section of the questionnaire. In conclusion, the PUGGS questionnaire is a reliable tool for investigating public understanding and attitudes towards modern genetics and genomic-based technologies.

Comprehensive Molecular Profiling of African-American Prostate Cancer to Inform on Prognosis and Disease Biology

DTIC Science & Technology

2017-10-01

development and patterning, and to become more knowledgeable in molecular genetics and the pathology of human prostatic diseases. Specific Aims: 1...AWARD NUMBER: W81XWH-15-1-0661 TITLE: Comprehensive Molecular Profiling of African-American Prostate Cancer to Inform on Prognosis and...COVERED 30 Sept 2016 – 29 Sept 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Comprehensive Molecular Profiling of African-American Prostate Cancer to

McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient.

PubMed

Vasilev, Vladimir; Daly, Adrian F; Thiry, Albert; Petrossians, Patrick; Fina, Frederic; Rostomyan, Liliya; Silvy, Monique; Enjalbert, Alain; Barlier, Anne; Beckers, Albert

2014-10-01

McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging. The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues. This was a comprehensive autopsy and genetic analysis. The study was conducted at a tertiary referral university hospital. An adult male patient with MAS and severe disease burden including gigantism was the subject of the study. Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues. Pathological findings and the presence of GNAS1 mutations were measured. The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas. This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1-related pathology across a wide range of affected organs.

WISARD: workbench for integrated superfast association studies for related datasets.

PubMed

Lee, Sungyoung; Choi, Sungkyoung; Qiao, Dandi; Cho, Michael; Silverman, Edwin K; Park, Taesung; Won, Sungho

2018-04-20

A Mendelian transmission produces phenotypic and genetic relatedness between family members, giving family-based analytical methods an important role in genetic epidemiological studies-from heritability estimations to genetic association analyses. With the advance in genotyping technologies, whole-genome sequence data can be utilized for genetic epidemiological studies, and family-based samples may become more useful for detecting de novo mutations. However, genetic analyses employing family-based samples usually suffer from the complexity of the computational/statistical algorithms, and certain types of family designs, such as incorporating data from extended families, have rarely been used. We present a Workbench for Integrated Superfast Association studies for Related Data (WISARD) programmed in C/C++. WISARD enables the fast and a comprehensive analysis of SNP-chip and next-generation sequencing data on extended families, with applications from designing genetic studies to summarizing analysis results. In addition, WISARD can automatically be run in a fully multithreaded manner, and the integration of R software for visualization makes it more accessible to non-experts. Comparison with existing toolsets showed that WISARD is computationally suitable for integrated analysis of related subjects, and demonstrated that WISARD outperforms existing toolsets. WISARD has also been successfully utilized to analyze the large-scale massive sequencing dataset of chronic obstructive pulmonary disease data (COPD), and we identified multiple genes associated with COPD, which demonstrates its practical value.

Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis

PubMed Central

Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

2009-01-01

Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed. PMID:19015126

Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis.

PubMed

Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

2009-01-01

Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed.

GAN: a platform of genomics and genetics analysis and application in Nicotiana

PubMed Central

Yang, Shuai; Zhang, Xingwei; Li, Huayang; Chen, Yudong

2018-01-01

Abstract Nicotiana is an important Solanaceae genus, and plays a significant role in modern biological research. Massive Nicotiana biological data have emerged from in-depth genomics and genetics studies. From big data to big discovery, large-scale analysis and application with new platforms is critical. Based on data accumulation, a comprehensive platform of Genomics and Genetics Analysis and Application in Nicotiana (GAN) has been developed, and is publicly available at http://biodb.sdau.edu.cn/gan/. GAN consists of four main sections: (i) Sources, a total of 5267 germplasm lines, along with detailed descriptions of associated characteristics, are all available on the Germplasm page, which can be queried using eight different inquiry modes. Seven fully sequenced species with accompanying sequences and detailed genomic annotation are available on the Genomics page. (ii) Genetics, detailed descriptions of 10 genetic linkage maps, constructed by different parents, 2239 KEGG metabolic pathway maps and 209 945 gene families across all catalogued genes, along with two co-linearity maps combining N. tabacum with available tomato and potato linkage maps are available here. Furthermore, 3 963 119 genome-SSRs, 10 621 016 SNPs, 12 388 PIPs and 102 895 reverse transcription-polymerase chain reaction primers, are all available to be used and searched on the Markers page. (iii) Tools, the genome browser JBrowse and five useful online bioinformatics softwares, Blast, Primer3, SSR-detect, Nucl-Protein and E-PCR, are provided on the JBrowse and Tools pages. (iv) Auxiliary, all the datasets are shown on a Statistics page, and are available for download on a Download page. In addition, the user’s manual is provided on a Manual page in English and Chinese languages. GAN provides a user-friendly Web interface for searching, browsing and downloading the genomics and genetics datasets in Nicotiana. As far as we can ascertain, GAN is the most comprehensive source of bio-data available, and the most applicable resource for breeding, gene mapping, gene cloning, the study of the origin and evolution of polyploidy, and related studies in Nicotiana. Database URL: http://biodb.sdau.edu.cn/gan/ PMID:29688356

Integrating multiple evidences in taxonomy: species diversity and phylogeny of mustached bats (Mormoopidae: Pteronotus).

PubMed

Pavan, Ana Carolina; Marroig, Gabriel

2016-10-01

A phylogenetic systematic perspective is instrumental in recovering new species and their evolutionary relationships. The advent of new technologies for molecular and morphological data acquisition and analysis, allied to the integration of knowledge from different areas, such as ecology and population genetics, allows for the emergence of more rigorous, accurate and complete scientific hypothesis on species diversity. Mustached bats (genus Pteronotus) are a good model for the application of this integrative approach. They are a widely distributed and a morphologically homogeneous group, but comprising species with remarkable differences in their echolocation strategy and feeding behavior. The latest systematic review suggested six species with 17 subspecies in Pteronotus. Subsequent studies using discrete morphological characters supported the same arrangement. However, recent papers reported high levels of genetic divergence among conspecific taxa followed by bioacoustic and geographic agreement, suggesting an underestimated diversity in the genus. To date, no study merging genetic evidences and morphometric variation along the entire geographic range of this group has been attempted. Based on a comprehensive sampling including representatives of all current taxonomic units, we attempt to delimit species in Pteronotus through the application of multiple methodologies and hierarchically distinct datasets. The molecular approach includes six molecular markers from three genetic transmission systems; morphological investigations used 41 euclidean distances estimated through three-dimensional landmarks collected from 1628 skulls. The phylogenetic analysis reveals a greater diversity than previously reported, with a high correspondence among the genetic lineages and the currently recognized subspecies in the genus. Discriminant analysis of variables describing size and shape of cranial bones support the rising of the genetic groups to the specific status. Based on multiples evidences, we present an updated taxonomic arrangement composed by 16 extant species and a new and more robust phylogenetic hypothesis for the species included in the genus Pteronotus. Studies developed under such integrative taxonomic approach are timely for a deeper and wider comprehension of Neotropical diversity, representing the first step for answering broader questions on evolutionary and ecological aspects of Neotropical life history. Copyright © 2016 Elsevier Inc. All rights reserved.

Physico-chemical study of some areas of fundamental significance to biophysics. Final report, 1974--1977

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGlynn, S.P.

1977-08-18

The comprehensive report includes a complete list of publications resulting from the work and a review of studies made in the vacuum ultraviolet, photoelectron spectroscopy, excited states and electron structure of inorganic salts, a model for polar molecules, application of abstract mathematics to the genetic code, the orbital approximation in which orbital properties are related to state properties. (JSR)

Pharmacogenetics of drugs withdrawn from the market.

PubMed

Zhang, Wei; Roederer, Mary W; Chen, Wang-Qing; Fan, Lan; Zhou, Hong-Hao

2012-01-01

The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market.

Using temporal sampling to improve attribution of source populations for invasive species.

PubMed

Goldstien, Sharyn J; Inglis, Graeme J; Schiel, David R; Gemmell, Neil J

2013-01-01

Numerous studies have applied genetic tools to the identification of source populations and transport pathways for invasive species. However, there are many gaps in the knowledge obtained from such studies because comprehensive and meaningful spatial sampling to meet these goals is difficult to achieve. Sampling populations as they arrive at the border should fill the gaps in source population identification, but such an advance has not yet been achieved with genetic data. Here we use previously acquired genetic data to assign new incursions as they invade populations within New Zealand ports and marinas. We also investigated allelelic frequency change in these recently established populations over a two-year period, and assessed the effect of temporal genetic sampling on our ability to assign new incursions to their population of source. We observed shifts in the allele frequencies among populations, as well as the complete loss of some alleles and the addition of alleles novel to New Zealand, within these recently established populations. There was no significant level of genetic differentiation observed in our samples between years, and the use of these temporal data did alter the assignment probability of new incursions. Our study further suggests that new incursions can add genetic variation to the population in a single introduction event as the founders themselves are often more genetically diverse than theory initially predicted.

Toxicogenomics and Cancer Susceptibility: Advances with Next-Generation Sequencing

PubMed Central

Ning, Baitang; Su, Zhenqiang; Mei, Nan; Hong, Huixiao; Deng, Helen; Shi, Leming; Fuscoe, James C.; Tolleson, William H.

2017-01-01

The aim of this review is to comprehensively summarize the recent achievements in the field of toxicogenomics and cancer research regarding genetic-environmental interactions in carcinogenesis and detection of genetic aberrations in cancer genomes by next-generation sequencing technology. Cancer is primarily a genetic disease in which genetic factors and environmental stimuli interact to cause genetic and epigenetic aberrations in human cells. Mutations in the germline act as either high-penetrance alleles that strongly increase the risk of cancer development, or as low-penetrance alleles that mildly change an individual’s susceptibility to cancer. Somatic mutations, resulting from either DNA damage induced by exposure to environmental mutagens or from spontaneous errors in DNA replication or repair are involved in the development or progression of the cancer. Induced or spontaneous changes in the epigenome may also drive carcinogenesis. Advances in next-generation sequencing technology provide us opportunities to accurately, economically, and rapidly identify genetic variants, somatic mutations, gene expression profiles, and epigenetic alterations with single-base resolution. Whole genome sequencing, whole exome sequencing, and RNA sequencing of paired cancer and adjacent normal tissue present a comprehensive picture of the cancer genome. These new findings should benefit public health by providing insights in understanding cancer biology, and in improving cancer diagnosis and therapy. PMID:24875441

Comprehensive Mutation Scanning of LMNA in 268 Patients With Lone Atrial Fibrillation

PubMed Central

Brauch, Katharine M.; Chen, Lin Y.; Olson, Timothy M.

2009-01-01

Atrial fibrillation (AF) is a heritable, genetically heterogeneous disorder. To identify gene defects that cause or confer susceptibility to AF, a cohort of 268 unrelated patients with idiopathic forms of familial and sporadic AF was recruited. LMNA, encoding the nuclear membrane proteins, lamin A/C, was selected as a candidate gene for lone AF based on its established association with a syndrome of dilated cardiomyopathy, conduction system disease, and AF. Comprehensive mutation scanning identified only 1 potentially pathogenic mutation. In conclusion, LMNA mutations rarely cause lone AF and routine genetic testing of LMNA in these patients does not appear warranted. PMID:19427440

Theobroma cacao: A genetically integrated physical map and genome-scale comparative synteny analysis

USDA-ARS?s Scientific Manuscript database

A comprehensive integrated genomic framework is considered a centerpiece of genomic research. In collaboration with the USDA-ARS (SHRS) and Mars Inc., the Clemson University Genomics Institute (CUGI) has developed a genetically anchored physical map of the T. cacao genome. Three BAC libraries contai...

Genetic Testing for Cardiomyopathies in Clinical Practice.

PubMed

Ingles, Jodie; Bagnall, Richard D; Semsarian, Christopher

2018-04-01

Cardiac genetic testing for inherited cardiomyopathies has become a routine aspect of care. Advances in genetic testing technologies have made testing more comprehensive and affordable. With this increase come greater understanding of the genetic basis of these diseases, but also shines a light on the challenges. Ability to ascertain whether a rare variant is causative of disease is problematic. A genetic diagnosis in a family can offer an invaluable tool for cascade genetic testing of at-risk relatives and avenues for reproductive testing options. A careful approach to cardiac genetic testing that recognizes where there is potential for harm ensures the best possible outcomes for families. Copyright © 2017 Elsevier Inc. All rights reserved.

Understanding Genetic Breast Cancer Risk: Processing Loci of the BRCA Gist Intelligent Tutoring System

PubMed Central

Wolfe, Christopher R.; Reyna, Valerie F.; Widmer, Colin L.; Cedillos-Whynott, Elizabeth M.; Brust-Renck, Priscila G; Weil, Audrey M.; Hu, Xiangen

2016-01-01

The BRCA Gist Intelligent Tutoring System helps women understand and make decisions about genetic testing for breast cancer risk. BRCA Gist is guided by Fuzzy-Trace Theory, (FTT) and built using AutoTutor Lite. It responds differently to participants depending on what they say. Seven tutorial dialogues requiring explanation and argumentation are guided by three FTT concepts: forming gist explanations in one’s own words, emphasizing decision-relevant information, and deliberating the consequences of decision alternatives. Participants were randomly assigned to BRCA Gist, a control, or impoverished BRCA Gist conditions removing gist explanation dialogues, argumentation dialogues, or FTT images. All BRCA Gist conditions performed significantly better than controls on knowledge, comprehension, and risk assessment. Significant differences in knowledge, comprehension, and fine-grained dialogue analyses demonstrate the efficacy of gist explanation dialogues. FTT images significantly increased knowledge. Providing more elements in arguments against testing correlated with increased knowledge and comprehension. PMID:28008216

Understanding Genetic Breast Cancer Risk: Processing Loci of the BRCA Gist Intelligent Tutoring System.

PubMed

Wolfe, Christopher R; Reyna, Valerie F; Widmer, Colin L; Cedillos-Whynott, Elizabeth M; Brust-Renck, Priscila G; Weil, Audrey M; Hu, Xiangen

2016-07-01

The BRCA Gist Intelligent Tutoring System helps women understand and make decisions about genetic testing for breast cancer risk. BRCA Gist is guided by Fuzzy-Trace Theory, (FTT) and built using AutoTutor Lite. It responds differently to participants depending on what they say. Seven tutorial dialogues requiring explanation and argumentation are guided by three FTT concepts: forming gist explanations in one's own words, emphasizing decision-relevant information, and deliberating the consequences of decision alternatives. Participants were randomly assigned to BRCA Gist , a control, or impoverished BRCA Gist conditions removing gist explanation dialogues, argumentation dialogues, or FTT images. All BRCA Gist conditions performed significantly better than controls on knowledge, comprehension, and risk assessment. Significant differences in knowledge, comprehension, and fine-grained dialogue analyses demonstrate the efficacy of gist explanation dialogues. FTT images significantly increased knowledge. Providing more elements in arguments against testing correlated with increased knowledge and comprehension.

Low genetic diversity and strong population structure shaped by anthropogenic habitat fragmentation in a critically endangered primate, Trachypithecus leucocephalus.

PubMed

Wang, W; Qiao, Y; Li, S; Pan, W; Yao, M

2017-06-01

Habitat fragmentation may strongly impact population genetic structure and reduce the genetic diversity and viability of small and isolated populations. The white-headed langur (Trachypithecus leucocephalus) is a critically endangered primate species living in a highly fragmented and human-modified habitat in southern China. We examined the population genetic structure and genetic diversity of the species and investigated the environmental and anthropogenic factors that may have shaped its population structure. We used 214 unique multi-locus genotypes from 41 social groups across the main distribution area of T. leucocephalus, and found strong genetic structure and significant genetic differentiation among local populations. Our landscape genetic analyses using a causal modelling framework suggest that a large habitat gap and geographical distance represent the primary landscape elements shaping genetic structure, yet high levels of genetic differentiation also exist between patches separated by a small habitat gap or road. This is the first comprehensive study that has evaluated the population genetic structure and diversity of T. leucocephalus using nuclear markers. Our results indicate strong negative impacts of anthropogenic land modifications and habitat fragmentation on primate genetic connectivity between forest patches. Our analyses suggest that two management units of the species could be defined, and indicate that habitat continuity should be enforced and restored to reduce genetic isolation and enhance population viability.

Updates on the COPD gene list

PubMed Central

Bossé, Yohan

2012-01-01

A genetic contribution to develop chronic obstructive pulmonary disease (COPD) is well established. However, the specific genes responsible for enhanced risk or host differences in susceptibility to smoke exposure remain poorly understood. The goal of this review is to provide a comprehensive literature overview on the genetics of COPD, highlight the most promising findings during the last few years, and ultimately provide an updated COPD gene list. Candidate gene studies on COPD and related phenotypes indexed in PubMed before January 5, 2012 are tabulated. An exhaustive list of publications for any given gene was looked for. This well-documented COPD candidate-gene list is expected to serve many purposes for future replication studies and meta-analyses as well as for reanalyzing collected genomic data in the field. In addition, this review summarizes recent genetic loci identified by genome-wide association studies on COPD, lung function, and related complications. Assembling resources, integrative genomic approaches, and large sample sizes of well-phenotyped subjects is part of the path forward to elucidate the genetic basis of this debilitating disease. PMID:23055711

Genetics and language: a neurobiological perspective on the missing link (-ing hypotheses).

PubMed

Poeppel, David

2011-12-01

The paper argues that both evolutionary and genetic approaches to studying the biological foundations of speech and language could benefit from fractionating the problem at a finer grain, aiming not to map genetics to "language"-or even subdomains of language such as "phonology" or "syntax"-but rather to link genetic results to component formal operations that underlie processing the comprehension and production of linguistic representations. Neuroanatomic and neurophysiological research suggests that language processing is broken down in space (distributed functional anatomy along concurrent pathways) and time (concurrent processing on multiple time scales). These parallel neuronal pathways and their local circuits form the infrastructure of speech and language and are the actual targets of evolution/genetics. Therefore, investigating the mapping from gene to brain circuit to linguistic phenotype at the level of generic computational operations (subroutines actually executable in these circuits) stands to provide a new perspective on the biological foundations in the healthy and challenged brain.

ETHNOS: A versatile electronic tool for the development and curation of national genetic databases

PubMed Central

2010-01-01

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available software which runs more than half of the NEMDBs currently available. Given the emerging need for NEMDB in genetic testing services and the fact that ETHNOS is the only off-the-shelf software available for NEMDB development and curation, its adoption in subsequent NEMDB development would contribute towards data content uniformity, unlike the diverse contents and quality of the available gene (locus)-specific databases. Finally, we allude to the potential applications of NEMDBs, not only as worldwide central allele frequency repositories, but also, and most importantly, as data warehouses of individual-level genomic data, hence allowing for a comprehensive ethnicity-specific documentation of genomic variation. PMID:20650823

ETHNOS : A versatile electronic tool for the development and curation of national genetic databases.

PubMed

van Baal, Sjozef; Zlotogora, Joël; Lagoumintzis, George; Gkantouna, Vassiliki; Tzimas, Ioannis; Poulas, Konstantinos; Tsakalidis, Athanassios; Romeo, Giovanni; Patrinos, George P

2010-06-01

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available software which runs more than half of the NEMDBs currently available. Given the emerging need for NEMDB in genetic testing services and the fact that ETHNOS is the only off-the-shelf software available for NEMDB development and curation, its adoption in subsequent NEMDB development would contribute towards data content uniformity, unlike the diverse contents and quality of the available gene (locus)-specific databases. Finally, we allude to the potential applications of NEMDBs, not only as worldwide central allele frequency repositories, but also, and most importantly, as data warehouses of individual-level genomic data, hence allowing for a comprehensive ethnicity-specific documentation of genomic variation.

Research Issues in Genetic Testing of Adolescents for Obesity

PubMed Central

Segal, Mary E.; Sankar, Pamela; Reed, Danielle R.

2006-01-01

Obesity is often established in adolescence, and advances are being made in identifying its genetic underpinnings. We examine issues related to the eventual likelihood of genetic tests for obesity targeted to adolescents: family involvement; comprehension of the test’s meaning; how knowledge of genetic status may affect psychological adaptation; minors’ ability to control events; parental/child autonomy; ability to make informed medical decisions; self-esteem; unclear distinctions between early/late onset for this condition; and social stigmatization. The public health arena will be important in educating families about possible future genetic tests for obesity. PMID:15478685

Word Reading and Reading Comprehension: Stability, Overlap and Independence

ERIC Educational Resources Information Center

Betjemann, Rebecca S.; Willcutt, Erik G.; Olson, Richard K.; Keenan, Janice M.; Defries, John C.; Wadsworth, Sally J.

2008-01-01

Longitudinal twin data were analyzed to investigate the etiology of the stability of genetic and environmental influences on word reading and reading comprehension, as well as the stability of those influences on their relationship. Participating twin pairs were initially tested at a mean age of 10.3 years, and retested approximately five years…

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative

PubMed Central

Auchus, Richard J.; Witchel, Selma Feldman; Leight, Kelly R.; Aisenberg, Javier; Azziz, Ricardo; Bachega, Tânia A.; Baker, Linda A.; Baratz, Arlene B.; Baskin, Laurence S.; Berenbaum, Sheri A.; Breault, David T.; Cerame, Barbara I.; Conway, Gerard S.; Eugster, Erica A.; Fracassa, Stephanie; Gearhart, John P.; Geffner, Mitchell E.; Harris, Katharine B.; Hurwitz, Richard S.; Katz, Aviva L.; Kalro, Brinda N.; Lee, Peter A.; Alger Lin, Gretchen; Loechner, Karen J.; Marshall, Ian; Merke, Deborah P.; Migeon, Claude J.; Miller, Walter L.; Nenadovich, Tamara L.; Oberfield, Sharon E.; Pass, Kenneth A.; Poppas, Dix P.; Lloyd-Puryear, Michele A.; Quigley, Charmian A.; Riepe, Felix G.; Rink, Richard C.; Rivkees, Scott A.; Sandberg, David E.; Schaeffer, Traci L.; Schlussel, Richard N.; Schneck, Francis X.; Seely, Ellen W.; Snyder, Diane; Speiser, Phyllis W.; Therrell, Bradford L.; VanRyzin, Carol; Vogiatzi, Maria G.; Wajnrajch, Michael P.; White, Perrin C.; Zuckerman, Alan E.

2010-01-01

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a “roadmap” for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH. PMID:21274448

Intertidal population genetic dynamics at a microgeographic seascape scale.

PubMed

Hu, Zi-Min

2013-06-01

The intertidal community is among the most physically harsh niches on earth, with highly heterogeneous environmental and biological factors that impose strong habitat selection on population abundance, genetic connectivity and ecological adaptation of organisms in nature. However, most genetic studies to date have concentrated on the influence of basin-wide or regional marine environments (e.g. habitat discontinuities, oceanic currents and fronts, and geographic barriers) on spatiotemporal distribution and composition of intertidal invertebrates having planktonic stages or long-distance dispersal capability. Little is known about sessile marine organisms (e.g. seaweeds) in the context of topographic tidal gradients and reproductive traits at the microgeographic scale. In this issue of Molecular Ecology, Krueger-Hadfield et al. () implemented an elaborate sampling strategy with red seaweed (Chondrus crispus) from a 90-m transect stand near Roscoff and comprehensively detected genome-scale genetic differentiation and biases in ploidy level. This study not only revealed that tidal height resulted in genetic differentiation between high- and low-shore stands and restricted the genetic exchange within the high-shore habitat, but also demonstrated that intergametophytic nonrandom fertilization in C. crispus can cause significant deviation from Hardy-Weinberg equilibrium. Such new genetic insights highlight the importance of microgeographic genetic dynamics and life history characteristics for better understanding the evolutionary processes of speciation and diversification of intertidal marine organisms. © 2013 John Wiley & Sons Ltd.

Ascending Aortic Aneurysm Is an Inherited Disease: A Contemporary Literature Review Based on Hill's Criteria of Specificity, Strength of Association, and Biological Coherence.

PubMed

Ahmad, Mirza Mujadil; Kiani, Immad Arif; Ammar, Khawaja Afzal; Ahmad, Mirza Nubair; Khandheria, Bijoy K; Paterick, Timothy E; Jain, Renuka; Tajik, A Jamil

There is growing evidence of a differential etiological basis for thoracic aortic aneurysms (TAA), with ascending (As) TAAs being genetically mediated and descending (Des) TAAs more strongly related to acquired pathologies. A comprehensive literature review of this hypothesis has not been carried out. We carried out a systematic literature review based on the latest guidelines on TAA endorsed by the American Heart Association. The etiologies were classified as genetic and inherited, the studies were tabulated accordingly, and Hill's epidemiological criteria of causality were applied. We found 38 studies addressing the etiology of TAAs. Out of these, 17 were about genetic causes, 9 about acquired causes, and 4 had information regarding both etiologies. Multiple genetic studies showed a strong association of As TAA with different genetic mutations. Contrary to commonly held beliefs, acquired causes, that is, dyslipidemia, diabetes, and atherosclerosis, were negatively associated with As TAA and positively associated with Des TAA. Hypertension was only associated with Des TAA and dissections (TAAD), not with As TAA. Multiple studies fulfilled the criteria of strength of association (n = 4), consistency (n = 9), specificity (n = 5), temporality (24), biological gradient (n = 3), plausibility (n = 38), biological coherence (n = 25), experiment (n = 4), and analogy (n = 6). Our literature review supports the hypothesis that As TAA is genetically mediated and Des TAA is predominantly an acquired pathology, and supports the argument for genetic testing in all cases of As TAA.

High-throughput genotyping of hop (Humulus lupulus L.) utilising diversity arrays technology (DArT).

PubMed

Howard, E L; Whittock, S P; Jakše, J; Carling, J; Matthews, P D; Probasco, G; Henning, J A; Darby, P; Cerenak, A; Javornik, B; Kilian, A; Koutoulis, A

2011-05-01

Implementation of molecular methods in hop (Humulus lupulus L.) breeding is dependent on the availability of sizeable numbers of polymorphic markers and a comprehensive understanding of genetic variation. However, use of molecular marker technology is limited due to expense, time inefficiency, laborious methodology and dependence on DNA sequence information. Diversity arrays technology (DArT) is a high-throughput cost-effective method for the discovery of large numbers of quality polymorphic markers without reliance on DNA sequence information. This study is the first to utilise DArT for hop genotyping, identifying 730 polymorphic markers from 92 hop accessions. The marker quality was high and similar to the quality of DArT markers previously generated for other species; although percentage polymorphism and polymorphism information content (PIC) were lower than in previous studies deploying other marker systems in hop. Genetic relationships in hop illustrated by DArT in this study coincide with knowledge generated using alternate methods. Several statistical analyses separated the hop accessions into genetically differentiated North American and European groupings, with hybrids between the two groups clearly distinguishable. Levels of genetic diversity were similar in the North American and European groups, but higher in the hybrid group. The markers produced from this time and cost-efficient genotyping tool will be a valuable resource for numerous applications in hop breeding and genetics studies, such as mapping, marker-assisted selection, genetic identity testing, guidance in the maintenance of genetic diversity and the directed breeding of superior cultivars.

The genetic architecture of economic and political preferences.

PubMed

Benjamin, Daniel J; Cesarini, David; van der Loos, Matthijs J H M; Dawes, Christopher T; Koellinger, Philipp D; Magnusson, Patrik K E; Chabris, Christopher F; Conley, Dalton; Laibson, David; Johannesson, Magnus; Visscher, Peter M

2012-05-22

Preferences are fundamental building blocks in all models of economic and political behavior. We study a new sample of comprehensively genotyped subjects with data on economic and political preferences and educational attainment. We use dense single nucleotide polymorphism (SNP) data to estimate the proportion of variation in these traits explained by common SNPs and to conduct genome-wide association study (GWAS) and prediction analyses. The pattern of results is consistent with findings for other complex traits. First, the estimated fraction of phenotypic variation that could, in principle, be explained by dense SNP arrays is around one-half of the narrow heritability estimated using twin and family samples. The molecular-genetic-based heritability estimates, therefore, partially corroborate evidence of significant heritability from behavior genetic studies. Second, our analyses suggest that these traits have a polygenic architecture, with the heritable variation explained by many genes with small effects. Our results suggest that most published genetic association studies with economic and political traits are dramatically underpowered, which implies a high false discovery rate. These results convey a cautionary message for whether, how, and how soon molecular genetic data can contribute to, and potentially transform, research in social science. We propose some constructive responses to the inferential challenges posed by the small explanatory power of individual SNPs.

A real world study on the genetic, cognitive and psychopathological differences of obese patients clustered according to eating behaviours.

PubMed

Caroleo, Mariarita; Primerano, Amedeo; Rania, Marianna; Aloi, Matteo; Pugliese, Valentina; Magliocco, Fabio; Fazia, Gilda; Filippo, Andrea; Sinopoli, Flora; Ricchio, Marco; Arturi, Franco; Jimenez-Murcia, Susana; Fernandez-Aranda, Fernando; De Fazio, Pasquale; Segura-Garcia, Cristina

2018-02-01

Considering that specific genetic profiles, psychopathological conditions and neurobiological systems underlie human behaviours, the phenotypic differentiation of obese patients according to eating behaviours should be investigated. The aim of this study was to classify obese patients according to their eating behaviours and to compare these clusters in regard to psychopathology, personality traits, neurocognitive patterns and genetic profiles. A total of 201 obese outpatients seeking weight reduction treatment underwent a dietetic visit, psychological and psychiatric assessment and genotyping for SCL6A2 polymorphisms. Eating behaviours were clustered through two-step cluster analysis, and these clusters were subsequently compared. Two groups emerged: cluster 1 contained patients with predominantly prandial hyperphagia, social eating, an increased frequency of the long allele of the 5-HTTLPR and low scores in all tests; and cluster 2 included patients with more emotionally related eating behaviours (emotional eating, grazing, binge eating, night eating, post-dinner eating, craving for carbohydrates), dysfunctional personality traits, neurocognitive impairment, affective disorders and increased frequencies of the short (S) allele and the S/S genotype. Aside from binge eating, dysfunctional eating behaviours were useful symptoms to identify two different phenotypes of obese patients from a comprehensive set of parameters (genetic, clinical, personality and neuropsychology) in this sample. Grazing and emotional eating were the most important predictors for classifying obese patients, followed by binge eating. This clustering overcomes the idea that 'binging' is the predominant altered eating behaviour, and could help physicians other than psychiatrists to identify whether an obese patient has an eating disorder. Finally, recognising different types of obesity may not only allow a more comprehensive understanding of this illness, but also make it possible to tailor patient-specific treatment pathways. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The Danish High Risk and Resilience Study--VIA 7--a cohort study of 520 7-year-old children born of parents diagnosed with either schizophrenia, bipolar disorder or neither of these two mental disorders.

PubMed

Thorup, Anne A E; Jepsen, Jens Richardt; Ellersgaard, Ditte Vestbjerg; Burton, Birgitte Klee; Christiani, Camilla Jerlang; Hemager, Nicoline; Skjærbæk, Mette; Ranning, Anne; Spang, Katrine Søborg; Gantriis, Ditte Lou; Greve, Aja Neergaard; Zahle, Kate Kold; Mors, Ole; Plessen, Kerstin Jessica; Nordentoft, Merete

2015-10-02

Severe mental illnesses like schizophrenia and bipolar disorder are known to be diseases that to some extent, but not entirely can be understood genetically. The dominating hypothesis is that these disorders should be understood in a neurodevelopmental perspective where genes and environment as well as gene-environment-interactions contribute to the risk of developing the disease. We aim to analyse the influences of genetic risk and environmental factors in a population of 520 7-year-old children with either 0, 1 or 2 parents diagnosed with schizophrenia spectrum psychosis or bipolar disorder on mental health and level of functioning. We hypothesize that a larger proportion of children growing up with an ill parent will display abnormal or delayed development, behavioural problems or psychiatric symptoms compared to the healthy controls. We are establishing a cohort of 5207 year old children and both their parents for a comprehensive investigation with main outcome measures being neurocognition, behaviour, psychopathology and neuromotor development of the child. Parents and children are examined with a comprehensive battery of instruments and are asked for genetic material (saliva or blood) for genetic analyses. The participants are recruited via Danish registers to ensure representativity. Data from registers concerning social status, birth complications, somatic illnesses and hospitalization are included in the database. Psychological and relational factors like emotional climate in the family, degree of stimulation and support in the home and attachment style are also investigated. Data collection started January 1, 2013, and is successfully ongoing. By Aug 2015 424 families are included. About 20% of the invited families decline to participate, equal for all groups.

Recent advances in the molecular genetics of epilepsy.

PubMed

Hildebrand, Michael S; Dahl, Hans-Henrik M; Damiano, John Anthony; Smith, Richard J H; Scheffer, Ingrid E; Berkovic, Samuel F

2013-05-01

Recent advances in molecular genetics have translated into the increasing utilisation of genetic testing in the routine clinical practice of neurologists. There has been a steady, incremental increase in understanding the genetic variation associated with epilepsies. Genetic testing in the epilepsies is not yet widely practiced, but the advent of new screening technologies promises to exponentially expand both knowledge and clinical utility. To maximise the value of this new genetic insight we need to rapidly extrapolate genetic findings to inform patients of their diagnosis, prognosis, recurrence risk and the clinical management options available for their specific genetic condition. Comprehensive, highly specific and sensitive genetic test results improve the management of patients by neurologists and clinical geneticists. Here we discuss the latest developments in clinical genetic testing for epilepsy and describe new molecular genetics platforms that will transform both genetic screening and novel gene discovery.

Relating Human Genetic Variation to Variation in Drug Responses

PubMed Central

Madian, Ashraf G.; Wheeler, Heather E.; Jones, Richard Baker; Dolan, M. Eileen

2012-01-01

Although sequencing a single human genome was a monumental effort a decade ago, more than one thousand genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology with the ultimate goal of developing more effective personalized clinical treatment strategies. PMID:22840197

[Index screening and comprehensive evaluation of phenotypic traits of low nitrogen tolerance using BILs population derived from Dongxiang wild rice (Oryza rufipogon Griff)].

PubMed

Hu, Biao-lin; Li, Xia; Wan, Yong; Qiu, Zai-hui; Nie, Yuan-yuan; Xie, Jian-kun

2015-08-01

To identify the low nitrogen tolerance of Dongxiang wild rice (DXWR) and its progenies, ten phenotypic traits including plant height (PH), heading day (HD), panicle length (PL), number of effective tillers per plant (NETP), number of filled grains per panicle (NFGP), number of grains per panicle (NGP), grain density (GD), spikelet fertility (SF), 1000-grain mass (TGM) and grain yield per plant (GYP) were studied under normal and low nitrogen treatments, using backcross inbred lines (BILs) of Xieqingzao B//DXWR/Xieqingzao B in BC1 F12. Comprehensive evaluation on the low nitrogen tolerance of the BILs population was conducted using principal component analysis and the subordinate function. The evaluation results indicated that the low nitrogen tolerance of the line 116, 143 and 157 was the strongest, which could be served as the intermediate materials for genetic studies on the low nitrogen tolerance of DXWR and breeding for the low nitrogen tolerance in rice. The optimal regression equation of the low nitrogen tolerance in rice was established using stepwise regression analysis. The relative values of five traits including PH, NGP, SF, TGM and GYP were screened out and could be used as comprehensive evaluation indices for the low nitrogen tolerance in the whole growth stage. Therefore, more attention should be paid to the relative values of these five traits, especially for NGP and GYP, in the genetic improvement of the low nitrogen tolerance in rice.

Seeing the whole picture: A comprehensive imaging approach to functional mapping of circuits in behaving zebrafish.

PubMed

Feierstein, C E; Portugues, R; Orger, M B

2015-06-18

In recent years, the zebrafish has emerged as an appealing model system to tackle questions relating to the neural circuit basis of behavior. This can be attributed not just to the growing use of genetically tractable model organisms, but also in large part to the rapid advances in optical techniques for neuroscience, which are ideally suited for application to the small, transparent brain of the larval fish. Many characteristic features of vertebrate brains, from gross anatomy down to particular circuit motifs and cell-types, as well as conserved behaviors, can be found in zebrafish even just a few days post fertilization, and, at this early stage, the physical size of the brain makes it possible to analyze neural activity in a comprehensive fashion. In a recent study, we used a systematic and unbiased imaging method to record the pattern of activity dynamics throughout the whole brain of larval zebrafish during a simple visual behavior, the optokinetic response (OKR). This approach revealed the broadly distributed network of neurons that were active during the behavior and provided insights into the fine-scale functional architecture in the brain, inter-individual variability, and the spatial distribution of behaviorally relevant signals. Combined with mapping anatomical and functional connectivity, targeted electrophysiological recordings, and genetic labeling of specific populations, this comprehensive approach in zebrafish provides an unparalleled opportunity to study complete circuits in a behaving vertebrate animal. Copyright © 2014. Published by Elsevier Ltd.

Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Nigg, Joel T.

2010-01-01

Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multi-stage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the…

A Global Genomic Screening Strategy Reveals Genetic and Chemical Activators ofPeroxisome Proliferator-Activated Receptor alpha (PPARalpha)

EPA Science Inventory

A comprehensive survey of chemical, diet and genetic perturbations that activate PPARalpha in the mouse liver has not been carried out but would be useful to identify the factors that may contribute to PPARalpha-dependent liver tumors. A gene signature dependent on PPARalpha ac...

QTL meta-analysis provides a comprehensive view of loci controlling partial resistance to Aphanomyces euteiches in four sources of resistance in pea

USDA-ARS?s Scientific Manuscript database

More knowledge about diversity of Quantitative Trait Loci (QTL) controlling polygenic disease resistance in natural genetic variation of crop species is required for durably improving plant genetic resistances to pathogens. Polygenic partial resistance to Aphanomyces root rot, due to Aphanomcyces eu...

Cognition in people with Prader-Willi syndrome: Insights into genetic influences on cognitive and social development.

PubMed

Whittington, Joyce; Holland, Anthony

2017-01-01

We present a mini-review of cognition in Prader-Willi syndrome. Studies cited include findings on general ability (IQ), IQ correlates with family members, strengths and weaknesses in cognitive profiles in genetic subtypes, attainment in literacy and numeracy, language, comprehension, modality preferences, executive functions, and social cognition. The latter includes investigations of theory of mind, emotion recognition, face processing and knowledge of social norms. Results from research on mouse models and brain imaging studies relevant to cognition are briefly discussed. The importance of these studies to understanding and managing education and behaviour in PWS and the limitations of the studies in terms of small numbers, non-representativeness, and lack of replication is also touched upon. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of genetic diversity of Panicum turgidum Forssk from Saudi Arabia.

PubMed

Assaeed, Abdulaziz M; Al-Faifi, Sulieman A; Migdadi, Hussein M; El-Bana, Magdy I; Al Qarawi, Abdulaziz A; Khan, Mohammad Altaf

2018-01-01

The genetic diversity of 177 accessions of Panicum turgidum Forssk, representing ten populations collected from four geographical regions in Saudi Arabia, was analyzed using amplified fragment length polymorphism (AFLP) markers. A set of four primer-pairs with two/three selective nucleotides scored 836 AFLP amplified fragments (putative loci/genome landmarks), all of which were polymorphic. Populations collected from the southern region of the country showed the highest genetic diversity parameters, whereas those collected from the central regions showed the lowest values. Analysis of molecular variance (AMOVA) revealed that 78% of the genetic variability was attributable to differences within populations. Pairwise values for population differentiation and genetic structure were statistically significant for all variances. The UPGMA dendrogram, validated by principal coordinate analysis-grouped accessions, corresponded to the geographical origin of the accessions. Mantel's test showed that there was a significant correlation between the genetic and geographical distances ( r  = 0.35, P  < 0.04). In summary, the AFLP assay demonstrated the existence of substantial genetic variation in P. turgidum . The relationship between the genetic diversity and geographical source of P. turgidum populations of Saudi Arabia, as revealed through this comprehensive study, will enable effective resource management and restoration of new areas without compromising adaptation and genetic diversity.

Sports genetics moving forward: lessons learned from medical research.

PubMed

Mattsson, C Mikael; Wheeler, Matthew T; Waggott, Daryl; Caleshu, Colleen; Ashley, Euan A

2016-03-01

Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy. Copyright © 2016 the American Physiological Society.

Preferences for prenatal testing among pregnant women, partners and health professionals.

PubMed

Lund, Ida Charlotte Bay; Becher, Naja; Petersen, Olav Bjørn; Hill, Melissa; Chitty, Lyn; Vogel, Ida

2018-05-01

Cell-free DNA testing (cfDNA testing) in maternal plasma has recently been implemented in Danish healthcare. Prior to that we wanted to evaluate the preferences among pregnant women, partners and health professionals regarding cfDNA testing compared with invasive prenatal diagnostics. Responders were recruited at public hospitals in the Central and North Denmark Regions. Stated preferences for prenatal testing were obtained through an online questionnaire incorporating a discrete choice experiment. Test choices differed according to attributes such as risk of miscarriage (none or small) and genetic information provided by the test; simple (Down syndrome only) or comprehensive (chromosomal abnormalities beyond Down syndrome). No risk of miscarriage was the key attribute affecting the preferences of women (n = 315) and partners (n = 102). However, women with experiences of invasive testing placed more emphasis on comprehensive genetic information and less on risk of miscarriage compared with other women. Likewise, foetal medicine experts, obstetricians and sonographers (n = 57) had a greater preference for comprehensive genetic information than midwives who were not directly involved in counselling for prenatal testing (n = 48). As safety seems to affect the majority of pregnant couples' choice behaviour, thorough pre-test counselling by trained health professionals is of paramount importance. Aarhus University and The Foundation of 17-12-1981. This study was registered with the Danish Data Protection Agency (1-16-02-586-13/ 2007-58-0010). Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

PubMed

Lee, Cha Gon; Lee, Jeehun; Lee, Munhyang

2018-01-01

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Osteosarcoma

Cancer.gov

The TARGET Osteosarcoma (OS) project elucidates comprehensive molecular characterization to determine the genetic changes that drive the initiation and progression of high-risk or hard-to-treat childhood cancers.The OS project has produced comprehensive genomic profiles of nearly 100 clinically annotated patient cases within the discovery dataset. Each fully-characterized TARGET OS case includes data from nucleic acid samples extracted from tumor and normal tissue.

EHR based Genetic Testing Knowledge Base (iGTKB) Development

PubMed Central

2015-01-01

Background The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). Methods We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). Results Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. Conclusions In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics. PMID:26606281

EHR based Genetic Testing Knowledge Base (iGTKB) Development.

PubMed

Zhu, Qian; Liu, Hongfang; Chute, Christopher G; Ferber, Matthew

2015-01-01

The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics.

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

PubMed

Balci, T B; Hartley, T; Xi, Y; Dyment, D A; Beaulieu, C L; Bernier, F P; Dupuis, L; Horvath, G A; Mendoza-Londono, R; Prasad, C; Richer, J; Yang, X-R; Armour, C M; Bareke, E; Fernandez, B A; McMillan, H J; Lamont, R E; Majewski, J; Parboosingh, J S; Prasad, A N; Rupar, C A; Schwartzentruber, J; Smith, A C; Tétreault, M; Innes, A M; Boycott, K M

2017-09-01

Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Regional genetic differentiation in the blue mussel from the Baltic Sea area

NASA Astrophysics Data System (ADS)

Larsson, J.; Lind, E. E.; Corell, H.; Grahn, M.; Smolarz, K.; Lönn, M.

2017-08-01

Connectivity plays an important role in shaping the genetic structure and in evolution of local adaptation. In the marine environment barriers to gene flow are in most cases caused by gradients in environmental factors, ocean circulation and/or larval behavior. Despite the long pelagic larval stages, with high potential for dispersal many marine organisms have been shown to have a fine scale genetic structuring. In this study, by using a combination of high-resolution genetic markers, species hybridization data and biophysical modeling we can present a comprehensive picture of the evolutionary landscape for a keystone species in the Baltic Sea, the blue mussel. We identified distinct genetic differentiation between the West Coast, Baltic Proper and Bothnian Sea regions, with lower gene diversity in the Bothnian Sea. Oceanographic connectivity together with salinity and to some extent species identity provides explanations for the genetic differentiation between the West Coast and the Baltic Sea (Baltic Proper and Bothnian Sea). The genetic differentiation between the Baltic Proper and Bothnian Sea cannot be directly explained by oceanographic connectivity, species identity or salinity, while the lower connectivity to the Bothnian Sea may explain the lower gene diversity.

Genetics and epigenetics of obesity.

PubMed

Herrera, Blanca M; Keildson, Sarah; Lindgren, Cecilia M

2011-05-01

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Stocking activities for the Arctic charr in Lake Geneva: Genetic effects in space and time.

PubMed

Savary, Romain; Dufresnes, Christophe; Champigneulle, Alexis; Caudron, Arnaud; Dubey, Sylvain; Perrin, Nicolas; Fumagalli, Luca

2017-07-01

Artificial stocking practices are widely used by resource managers worldwide, in order to sustain fish populations exploited by both recreational and commercial activities, but their benefits are controversial. Former practices involved exotic strains, although current programs rather consider artificial breeding of local fishes (supportive breeding). Understanding the complex genetic effects of these management strategies is an important challenge with economic and conservation implications, especially in the context of population declines. In this study, we focus on the declining Arctic charr ( Salvelinus alpinus ) population from Lake Geneva (Switzerland and France), which has initially been restocked with allochtonous fishes in the early eighties, followed by supportive breeding. In this context, we conducted a genetic survey to document the evolution of the genetic diversity and structure throughout the last 50 years, before and after the initiation of hatchery supplementation, using contemporary and historical samples. We show that the introduction of exotic fishes was associated with a genetic bottleneck in the 1980-1990s, a break of Hardy-Weinberg Equilibrium (HWE), a reduction in genetic diversity, an increase in genetic structure among spawning sites, and a change in their genetic composition. Together with better environmental conditions, three decades of subsequent supportive breeding using local fishes allowed to re-establish HWE and the initial levels of genetic variation. However, current spawning sites have not fully recovered their original genetic composition and were extensively homogenized across the lake. Our study demonstrates the drastic genetic consequences of different restocking tactics in a comprehensive spatiotemporal framework and suggests that genetic alteration by nonlocal stocking may be partly reversible through supportive breeding. We recommend that conservation-based programs consider local diversity and implement adequate protocols to limit the genetic homogenization of this Arctic charr population.

An integrated analysis of genes and functional pathways for aggression in human and rodent models.

PubMed

Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Hess, Jonathan L; Malki, Karim; Glatt, Stephen J; Cormand, Bru; Faraone, Stephen V

2018-06-01

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

Comprehensive Screening for Naturally Occurring Hepatitis C Virus Resistance to Direct-Acting Antivirals in the NS3, NS5A, and NS5B Genes in Worldwide Isolates of Viral Genotypes 1 to 6.

PubMed

Patiño-Galindo, Juan Ángel; Salvatierra, Karina; González-Candelas, Fernando; López-Labrador, F Xavier

2016-04-01

There is no comprehensive study available on the natural hepatitis C virus (HCV) polymorphism in sites associated with resistance including all viral genotypes which may present variable susceptibilities to particular direct-acting antivirals (DAAs). This study aimed to analyze the frequencies, genetic barriers, and evolutionary histories of naturally occurring resistance-associated variants (RAVs) in the six main HCV genotypes. A comprehensive analysis of up to 103 RAVs was performed in 2,901, 2,216, and 1,344 HCV isolates for the NS3, NS5A, and NS5B genes, respectively. We report significant intergenotypic differences in the frequencies of natural RAVs for these three HCV genes. In addition, we found a low genetic barrier for the generation of new RAVs, irrespective of the viral genotype. Furthermore, in 1,126 HCV genomes, including sequences spanning the three genes, haplotype analysis revealed a remarkably high frequency of viruses carrying more than one natural RAV to DAAs (53% of HCV-1a, 28.5% of HCV-1b, 67.1% of HCV-6, and 100% of genotype 2, 3, 4, and 5 haplotypes). With the exception of HCV-1a, the most prevalent haplotypes showed RAVs in at least two different viral genes. Finally, evolutionary analyses revealed that, while most natural RAVs appeared recently, others have been efficiently transmitted over time and cluster in well-supported clades. In summary, and despite the observed high efficacy of DAA-based regimens, we show that naturally occurring RAVs are common in all HCV genotypes and that there is an overall low genetic barrier for the selection of resistance mutations. There is a need for natural DAA resistance profiling specific for each HCV genotype. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Informing the Design of Direct-to-Consumer Interactive Personal Genomics Reports

PubMed Central

Shaer, Orit; Okerlund, Johanna; Balestra, Martina; Stowell, Elizabeth; Ascher, Laura; Bi, Joanna; Schlenker, Claire; Ball, Madeleine

2015-01-01

Background In recent years, people who sought direct-to-consumer genetic testing services have been increasingly confronted with an unprecedented amount of personal genomic information, which influences their decisions, emotional state, and well-being. However, these users of direct-to-consumer genetic services, who vary in their education and interests, frequently have little relevant experience or tools for understanding, reasoning about, and interacting with their personal genomic data. Online interactive techniques can play a central role in making personal genomic data useful for these users. Objective We sought to (1) identify the needs of diverse users as they make sense of their personal genomic data, (2) consequently develop effective interactive visualizations of genomic trait data to address these users’ needs, and (3) evaluate the effectiveness of the developed visualizations in facilitating comprehension. Methods The first two user studies, conducted with 63 volunteers in the Personal Genome Project and with 36 personal genomic users who participated in a design workshop, respectively, employed surveys and interviews to identify the needs and expectations of diverse users. Building on the two initial studies, the third study was conducted with 730 Amazon Mechanical Turk users and employed a controlled experimental design to examine the effectiveness of different design interventions on user comprehension. Results The first two studies identified searching, comparing, sharing, and organizing data as fundamental to users’ understanding of personal genomic data. The third study demonstrated that interactive and visual design interventions could improve the understandability of personal genomic reports for consumers. In particular, results showed that a new interactive bubble chart visualization designed for the study resulted in the highest comprehension scores, as well as the highest perceived comprehension scores. These scores were significantly higher than scores received using the industry standard tabular reports currently used for communicating personal genomic information. Conclusions Drawing on multiple research methods and populations, the findings of the studies reported in this paper offer deep understanding of users’ needs and practices, and demonstrate that interactive online design interventions can improve the understandability of personal genomic reports for consumers. We discuss implications for designers and researchers. PMID:26070951

Informing the Design of Direct-to-Consumer Interactive Personal Genomics Reports.

PubMed

Shaer, Orit; Nov, Oded; Okerlund, Johanna; Balestra, Martina; Stowell, Elizabeth; Ascher, Laura; Bi, Joanna; Schlenker, Claire; Ball, Madeleine

2015-06-12

In recent years, people who sought direct-to-consumer genetic testing services have been increasingly confronted with an unprecedented amount of personal genomic information, which influences their decisions, emotional state, and well-being. However, these users of direct-to-consumer genetic services, who vary in their education and interests, frequently have little relevant experience or tools for understanding, reasoning about, and interacting with their personal genomic data. Online interactive techniques can play a central role in making personal genomic data useful for these users. We sought to (1) identify the needs of diverse users as they make sense of their personal genomic data, (2) consequently develop effective interactive visualizations of genomic trait data to address these users' needs, and (3) evaluate the effectiveness of the developed visualizations in facilitating comprehension. The first two user studies, conducted with 63 volunteers in the Personal Genome Project and with 36 personal genomic users who participated in a design workshop, respectively, employed surveys and interviews to identify the needs and expectations of diverse users. Building on the two initial studies, the third study was conducted with 730 Amazon Mechanical Turk users and employed a controlled experimental design to examine the effectiveness of different design interventions on user comprehension. The first two studies identified searching, comparing, sharing, and organizing data as fundamental to users' understanding of personal genomic data. The third study demonstrated that interactive and visual design interventions could improve the understandability of personal genomic reports for consumers. In particular, results showed that a new interactive bubble chart visualization designed for the study resulted in the highest comprehension scores, as well as the highest perceived comprehension scores. These scores were significantly higher than scores received using the industry standard tabular reports currently used for communicating personal genomic information. Drawing on multiple research methods and populations, the findings of the studies reported in this paper offer deep understanding of users' needs and practices, and demonstrate that interactive online design interventions can improve the understandability of personal genomic reports for consumers. We discuss implications for designers and researchers.

Comprehensive study of mtDNA among Southwest Asian dogs contradicts independent domestication of wolf, but implies dog–wolf hybridization

PubMed Central

Ardalan, Arman; Kluetsch, Cornelya F C; Zhang, Ai-bing; Erdogan, Metin; Uhlén, Mathias; Houshmand, Massoud; Tepeli, Cafer; Ashtiani, Seyed Reza Miraei; Savolainen, Peter

2011-01-01

Studies of mitochondrial DNA (mtDNA) diversity indicate explicitly that dogs were domesticated, probably exclusively, in southern East Asia. However, Southwest Asia (SwAsia) has had poor representation and geographical coverage in these studies. Other studies based on archaeological and genome-wide SNP data have suggested an origin of dogs in SwAsia. Hence, it has been suspected that mtDNA evidence for this scenario may have remained undetected. In the first comprehensive investigation of genetic diversity among SwAsian dogs, we analyzed 582 bp of mtDNA for 345 indigenous dogs from across SwAsia, and compared with 1556 dogs across the Old World. We show that 97.4% of SwAsian dogs carry haplotypes belonging to a universal mtDNA gene pool, but that only a subset of this pool, five of the 10 principal haplogroups, is represented in SwAsia. A high frequency of haplogroup B, potentially signifying a local origin, was not paralleled with the high genetic diversity expected for a center of origin. Meanwhile, 2.6% of the SwAsian dogs carried the rare non-universal haplogroup d2. Thus, mtDNA data give no indication that dogs originated in SwAsia through independent domestication of wolf, but dog–wolf hybridization may have formed the local haplogroup d2 within this region. Southern East Asia remains the only region with virtually full extent of genetic variation, strongly indicating it to be the primary and probably sole center of wolf domestication. An origin of dogs in southern East Asia may have been overlooked by other studies due to a substantial lack of samples from this region. PMID:22393507

Comprehensive Analysis of Non-Synonymous Natural Variants of G Protein-Coupled Receptors.

PubMed

Kim, Hee Ryung; Duc, Nguyen Minh; Chung, Ka Young

2018-03-01

G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane receptors and have vital signaling functions in various organs. Because of their critical roles in physiology and pathology, GPCRs are the most commonly used therapeutic target. It has been suggested that GPCRs undergo massive genetic variations such as genetic polymorphisms and DNA insertions or deletions. Among these genetic variations, non-synonymous natural variations change the amino acid sequence and could thus alter GPCR functions such as expression, localization, signaling, and ligand binding, which may be involved in disease development and altered responses to GPCR-targeting drugs. Despite the clinical importance of GPCRs, studies on the genotype-phenotype relationship of GPCR natural variants have been limited to a few GPCRs such as β-adrenergic receptors and opioid receptors. Comprehensive understanding of non-synonymous natural variations within GPCRs would help to predict the unknown genotype-phenotype relationship and yet-to-be-discovered natural variants. Here, we analyzed the non-synonymous natural variants of all non-olfactory GPCRs available from a public database, UniProt. The results suggest that non-synonymous natural variations occur extensively within the GPCR superfamily especially in the N-terminus and transmembrane domains. Within the transmembrane domains, natural variations observed more frequently in the conserved residues, which leads to disruption of the receptor function. Our analysis also suggests that only few non-synonymous natural variations have been studied in efforts to link the variations with functional consequences.

Impact of changes in weight, fat depth, and loin muscle depth on carcass yield and value and implications for selection and pricing of rams from terminal-sire sheep breeds

USDA-ARS?s Scientific Manuscript database

Breeding objectives and selection indexes are necessary to support comprehensive genetic improvement programs. This study used off-test body weights (OTBW) or chilled carcass weights (CCW), ultrasonic measurements of fat depth (USFD, mm), and predicted ultrasound loin muscle depths (USLMD, mm) from ...

A median third eye: pineal gland retraces evolution of vertebrate photoreceptive organs.

PubMed

Mano, Hiroaki; Fukada, Yoshitaka

2007-01-01

In many vertebrates, the pineal gland serves as a photoreceptive neuroendocrine organ. Morphological and functional similarities between the pineal and retinal photoreceptor cells indicate their close evolutionary relationship, and hence the comparative studies on the pineal gland and the retina are the keys to deciphering the evolutionary traces of the vertebrate photoreceptive organs. Several studies have suggested common genetic and molecular mechanisms responsible for their similarities, but largely unknown are those underlying pineal-specific development and physiological functions. Recent studies have identified several cis-acting DNA elements that participate in transcriptional control of the pineal-specific genes. Genetic approaches in the zebrafish have also contributed to elucidating the genetic network regulating the pineal development and neurogenesis. These efforts toward elucidating the molecular instrumentation intrinsic to the pineal gland, back to back with those to the retina, should lead to a comprehensive understanding of the evolutionary history of the vertebrate photoreceptive structures. This article summarizes the current status of research on these topics.

Evolving rule-based systems in two medical domains using genetic programming.

PubMed

Tsakonas, Athanasios; Dounias, Georgios; Jantzen, Jan; Axer, Hubertus; Bjerregaard, Beth; von Keyserlingk, Diedrich Graf

2004-11-01

To demonstrate and compare the application of different genetic programming (GP) based intelligent methodologies for the construction of rule-based systems in two medical domains: the diagnosis of aphasia's subtypes and the classification of pap-smear examinations. Past data representing (a) successful diagnosis of aphasia's subtypes from collaborating medical experts through a free interview per patient, and (b) correctly classified smears (images of cells) by cyto-technologists, previously stained using the Papanicolaou method. Initially a hybrid approach is proposed, which combines standard genetic programming and heuristic hierarchical crisp rule-base construction. Then, genetic programming for the production of crisp rule based systems is attempted. Finally, another hybrid intelligent model is composed by a grammar driven genetic programming system for the generation of fuzzy rule-based systems. Results denote the effectiveness of the proposed systems, while they are also compared for their efficiency, accuracy and comprehensibility, to those of an inductive machine learning approach as well as to those of a standard genetic programming symbolic expression approach. The proposed GP-based intelligent methodologies are able to produce accurate and comprehensible results for medical experts performing competitive to other intelligent approaches. The aim of the authors was the production of accurate but also sensible decision rules that could potentially help medical doctors to extract conclusions, even at the expense of a higher classification score achievement.

Effects of Cancer Genetic Panel Testing on at-Risk Individuals.

PubMed

Frost, Anja S; Toaff, Miriam; Biagi, Tara; Stark, Elizabeth; McHenry, Allison; Kaltman, Rebecca

2018-06-01

To evaluate the role of screening patients at increased risk for hereditary cancer syndromes with an extended panel of cancer predisposition genes to identify actionable genetic mutations. A retrospective chart review was conducted of all patients presenting to a multidisciplinary cancer program for genetic counseling and testing from January 2015 to December 2016. Individuals presenting to the program were identified as at-risk by a personal or family history of cancer, by their health care provider, or by self-referral. All participants met current National Comprehensive Cancer Network criteria for genetic risk evaluation for hereditary cancer. The results of testing and its implications for management, based on National Comprehensive Cancer Network guidelines, were recorded. Of 670 at-risk patients who underwent genetic testing, 66 (9.9%) had BRCA-limited testing; of these, 26 of 670 (3.9%) had a deleterious or likely pathogenic mutation. Expanded panel testing was done for 560 of the 670 patients (83.4%), and abnormal results were found in 65 of 670 (9.7%); non-BRCA mutations (predominantly CHEK2) were found in 49 of the 65 (75%). Abnormal genetic testing was associated with increased surveillance in 96% of those with deleterious mutations, whereas negative testing for a known familial mutation in 45 patients was associated with a downgrade of their risk and reduction of subsequent surveillance and management. Guideline-based management is frequently altered by genetic testing, including panel testing, in patients at risk for cancer. We recommend that obstetrics and gynecology providers routinely refer at-risk patients for genetic counseling and testing when clinically appropriate.

Genetic Testing for Hereditary Breast Cancer: The Decision to Decline.

PubMed

White, V Brook; Walsh, Kendall K; Foss, Kimberly Showers; Amacker-North, Lisa; Lenarcic, Stacy; McNeely, Lindsay; White, Richard L

2018-01-01

Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision-making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population.

A comparative phylogenetic study of genetics and folk music.

PubMed

Pamjav, Horolma; Juhász, Zoltán; Zalán, Andrea; Németh, Endre; Damdin, Bayarlkhagva

2012-04-01

Computer-aided comparison of folk music from different nations is one of the newest research areas. We were intrigued to have identified some important similarities between phylogenetic studies and modern folk music. First of all, both of them use similar concepts and representation tools such as multidimensional scaling for modelling relationship between populations. This gave us the idea to investigate whether these connections are merely accidental or if they mirror population migrations from the past. We raised the question; does the complex structure of musical connections display a clear picture and can this system be interpreted by the genetic analysis? This study is the first to systematically investigate the incidental genetic background of the folk music context between different populations. Paternal (42 populations) and maternal lineages (56 populations) were compared based on Fst genetic distances of the Y chromosomal and mtDNA haplogroup frequencies. To test this hypothesis, the corresponding musical cultures were also compared using an automatic overlap analysis of parallel melody styles for 31 Eurasian nations. We found that close musical relations of populations indicate close genetic distances (<0.05) with a probability of 82%. It was observed that there is a significant correlation between population genetics and folk music; maternal lineages have a more important role in folk music traditions than paternal lineages. Furthermore, the combination of these disciplines establishing a new interdisciplinary research field of "music-genetics" can be an efficient tool to get a more comprehensive picture on the complex behaviour of populations in prehistoric time.

Genetic monitoring of horses in the Czech Republic: A large-scale study with a focus on the Czech autochthonous breeds.

PubMed

Putnová, L; Štohl, R; Vrtková, I

2018-02-01

We propose the first comprehensive in-depth study monitoring horses in the Czech Republic. We scanned 9,289 animals from 44 populations for 17 equine STRs. Other equids analysed involved Equus przewalskii and Equus asinus. The total of 228 different alleles were detected, with the mean number of 13.4 per locus. The highest allelic richness (AR) was found in the Welsh Part Bred (6.01), followed by the Camargue (5.93) and Czech Sport Pony (5.91), whereas the Friesian exhibited the lowest AR (3.06). Interpopulation differences explained approximately nine per cent of the total genetic diversity. Reynold's genetic distance ranged from 0.003 between the Czech Warmblood and the Slovak Warmblood to 0.404 between the Friesian and donkeys. Close genetic proximity between the Silesian Noriker and Noriker was revealed. The Moravian Warmblood was better differentiated and more distant from the Czech Warmblood than the Kinsky Horse and retained the original genes of the old Austro-Hungarian tribes. A high gene flow level and a lack of genetic structure were found in the seven studied populations. Despite the historical bottlenecks and previous inbreeding, the Czech-Moravian Belgian Horse, Hucul, Old Kladruber Horse and Silesian Noriker did not suffer a serious loss of genetic diversity due to genetic drift/low effective population size. A NeighborNet dendrogram revealed breeds not classified in their groups according to the nomenclature (the Friesian, Hafling and Merens). © 2018 Blackwell Verlag GmbH.

Spatiotemporal Dynamics of Genetic Variation in the Iberian Lynx along Its Path to Extinction Reconstructed with Ancient DNA

PubMed Central

Casas-Marce, Mireia; Marmesat, Elena; Soriano, Laura; Martínez-Cruz, Begoña; Lucena-Perez, Maria; Nocete, Francisco; Rodríguez-Hidalgo, Antonio; Canals, Antoni; Nadal, Jordi; Detry, Cleia; Bernáldez-Sánchez, Eloísa; Fernández-Rodríguez, Carlos; Pérez-Ripoll, Manuel; Stiller, Mathias; Hofreiter, Michael; Rodríguez, Alejandro; Revilla, Eloy; Delibes, Miguel; Godoy, José A.

2017-01-01

Abstract There is the tendency to assume that endangered species have been both genetically and demographically healthier in the past, so that any genetic erosion observed today was caused by their recent decline. The Iberian lynx (Lynx pardinus) suffered a dramatic and continuous decline during the 20th century, and now shows extremely low genome- and species-wide genetic diversity among other signs of genomic erosion. We analyze ancient (N = 10), historical (N = 245), and contemporary (N = 172) samples with microsatellite and mitogenome data to reconstruct the species' demography and investigate patterns of genetic variation across space and time. Iberian lynx populations transitioned from low but significantly higher genetic diversity than today and shallow geographical differentiation millennia ago, through a structured metapopulation with varying levels of diversity during the last centuries, to two extremely genetically depauperate and differentiated remnant populations by 2002. The historical subpopulations show varying extents of genetic drift in relation to their recent size and time in isolation, but these do not predict whether the populations persisted or went finally extinct. In conclusion, current genetic patterns were mainly shaped by genetic drift, supporting the current admixture of the two genetic pools and calling for a comprehensive genetic management of the ongoing conservation program. This study illustrates how a retrospective analysis of demographic and genetic patterns of endangered species can shed light onto their evolutionary history and this, in turn, can inform conservation actions. PMID:28962023

A systematic review on pharmacogenetics in cardiovascular disease: is it ready for clinical application?

PubMed

Verschuren, Jeffrey J W; Trompet, Stella; Wessels, Judith A M; Guchelaar, Henk-Jan; de Maat, Moniek P M; Simoons, Maarten L; Jukema, J Wouter

2012-01-01

Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important application of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions. Many studies focusing on drug-gene interactions have been published in recent years, some of which led to adaptation of FDA recommendations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides a comprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of cardiovascular diseases.

[The public perception of information about the potential risks of genetically modified crops in the food chain].

PubMed

Furnival, Ariadne Chloë; Pinheiro, Sônia Maria

2008-01-01

At a time when genetically modified (GM) crops are entering the Brazilian food chain, we present the findings of a study that makes use of a qualitative technique involving focal groups to look into the public's interpretation of the information available about this biotechnological innovation. This methodology produced results that revealed the interconnections drawn by the research subjects between this form of biotechnology, changes to the environment, and food production in general. The mistrust expressed about GM crops was particularly attributed by the participants to the non-availability of comprehensible information in the mass media or on product labels.

Genetic diversity and population structure of Plasmodium falciparum over space and time in an African archipelago.

PubMed

Salgueiro, Patrícia; Vicente, José Luís; Figueiredo, Rita Carrilho; Pinto, João

2016-09-01

The archipelago of São Tomé and Principe (STP), West Africa, has suffered the heavy burden of malaria since the 16th century. Until the last decade, when after a successful control program STP has become a low transmission country and one of the few nations with decreases of more than 90% in malaria admission and death rates. We carried out a longitudinal study to determine the genetic structure of STP parasite populations over time and space. Twelve microsatellite loci were genotyped in Plasmodium falciparum samples from two islands collected in 1997, 2000 and 2004. Analysis was performed on proportions of mixed genotype infections, allelic diversity, population differentiation, effective population size and bottleneck effects. We have found high levels of genetic diversity and minimal inter-population genetic differentiation typical of African continental regions with intense and stable malaria transmission. We detected significant differences between the years, with special emphasis for 1997 that showed the highest proportion of samples infected with P. falciparum and the highest mean number of haplotypes per isolate. This study establishes a comprehensive genetic data baseline of a pre-intervention scenario for future studies; taking into account the most recent and successful control intervention on the territory. Copyright © 2016 Elsevier B.V. All rights reserved.

Comprehensive genetic testing for female and male infertility using next-generation sequencing.

PubMed

Patel, Bonny; Parets, Sasha; Akana, Matthew; Kellogg, Gregory; Jansen, Michael; Chang, Chihyu; Cai, Ying; Fox, Rebecca; Niknazar, Mohammad; Shraga, Roman; Hunter, Colby; Pollock, Andrew; Wisotzkey, Robert; Jaremko, Malgorzata; Bisignano, Alex; Puig, Oscar

2018-05-19

To develop a comprehensive genetic test for female and male infertility in support of medical decisions during assisted reproductive technology (ART) protocols. We developed a next-generation sequencing (NGS) gene panel consisting of 87 genes including promoters, 5' and 3' untranslated regions, exons, and selected introns. In addition, sex chromosome aneuploidies and Y chromosome microdeletions were analyzed concomitantly using the same panel. The NGS panel was analytically validated by retrospective analysis of 118 genomic DNA samples with known variants in loci representative of female and male infertility. Our results showed analytical accuracy of > 99%, with > 98% sensitivity for single-nucleotide variants (SNVs) and > 91% sensitivity for insertions/deletions (indels). Clinical sensitivity was assessed with samples containing variants representative of male and female infertility, and it was 100% for SNVs/indels, CFTR IVS8-5T variants, sex chromosome aneuploidies, and copy number variants (CNVs) and > 93% for Y chromosome microdeletions. Cost analysis shows potential savings when comparing this single NGS assay with the standard approach, which includes multiple assays. A single, comprehensive, NGS panel can simplify the ordering process for healthcare providers, reduce turnaround time, and lower the overall cost of testing for genetic assessment of infertility in females and males, while maintaining accuracy.

[Teaching design and practice of human blood type traits in genetics comprehensive laboratory course].

PubMed

Zhao, Jian; Hu, Dong-mei; Yu, Da-de; Dong, Ming-liang; Li, Yun; Fan, Ying-ming; Wang, Yan-wei; Zhang, Jin-feng

2016-05-01

Comprehensive laboratory courses, which enable students to aptly apply theoretic knowledge and master experiment skills, play an important role in the present educational reform of laboratory courses. We utilized human ABO blood type as the experimental subject, and designed the experiment--"Molecular Genotyping of Human ABO Blood Type and Analysis of Population Genetic Equilibrium". In the experiment, DNA in mucosal cells is extracted from students' saliva, and each student's genotype is identified using a series of molecular genetics technologies, including PCR amplification of target fragments, enzymatic digestion, and electrophoretic separation. Then, taking the whole class as an analogous Mendel population, a survey of genotype frequency of ABO blood type is conducted, followed with analyses of various population genetic parameters using Popgene. Through the open laboratory course, students can not only master molecular genetic experimental skills, but also improve their understanding of theoretic knowledge through independent design and optimization of molecular techniques. After five years of research and practice, a stable experimental system of molecular genetics has been established to identify six genotypes of ABO blood types, namely I(A)I(A), I(A)i, I(B)I(B), I(B)i, I(A)I(B) and ii. Laboratory courses of molecular and population genetics have been integrated by calculating the frequencies of the six genotypes and three multiple alleles and testing population genetic equilibrium. The goal of the open laboratory course with independent design and implementation by the students has been achieved. This laboratory course has proved effective and received good reviews from the students. It could be applied as a genetics laboratory course for the biology majors directly, and its ideas and methods could be promoted and applied to other biological laboratory courses.

Translation and validation of a Spanish-language genetic health literacy screening tool.

PubMed

Rodríguez, Sally Ann; Roter, Debra L; Castillo-Salgado, Carlos; Hooker, Gillian W; Erby, Lori H

2015-02-01

Literacy deficits and underutilization of medical services have been linked to health disparities among minorities, and this appears especially relevant for the Latino population. Given the increasing importance of genetics, assessment of genetic health literacy may direct future efforts to better serve this vulnerable population. The current study was designed to contribute to this area by translating and validating a Spanish-language genetic health literacy measure. This was a cross-sectional study involving an interviewer-administered questionnaire. Eligible individuals were Latinos between the ages of 18 and 75 residing in Maryland, who self-reported Spanish as their primary language, recruited through convenience sampling. The genetic health literacy measure components were adapted from existing English-language measures [Erby, Roter, Larson, & Cho's (2008) Rapid Estimate of Adult Literacy in Genetics (REAL-G) and Hooker et al.'s (2014) Genetic Literacy and Comprehension]. An existing Spanish-language general health literacy measure was used to establish preliminary concurrent validity [Lee, Bender, Ruiz, & Cho's (2006) SAHLSA]. 116 individuals completed the assessment. The Spanish-language REAL-G (REAL-G-Sp) was found to correlate well with the SAHLSA (Pearson's r = .77, p < .01). A cut-off score of 59 (out of 62) distinguished low versus high genetic health literacy with a sensitivity of 86% and specificity of 71%, identifying 28% of participants as having inadequate genetic health literacy. The REAL-G-Sp was found to have preliminary concurrent validity with an existing health literacy measure in the Latino population residing in Maryland. Significant proportions of this population are predicted to have limitations in genetic health literacy, even when information is provided in Spanish.

Roles of lipocalin 2 and adiponectin in iron overload cardiomyopathy.

PubMed

Siri-Angkul, Natthaphat; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2018-07-01

Thalassemia is among the most common genetic diseases worldwide. Ineffective erythropoiesis, chronic hemolysis, and regular blood transfusion in thalassemia patients lead to increased iron burden. Iron overload cardiomyopathy is the most severe co-morbidity and most common cause of mortality in thalassemia patients. Although its associated mechanisms are still not completely understood, cellular iron mishandling, chronic inflammation, and oxidative stress appear to be the key processes involved. In order to acquire a more comprehensive insight of the impact of cardiac iron overload, these alterations need to be intensively investigated. This comprehensive mini-review focuses on two emergent molecules which have been shown to potentially play significant roles in iron overload cardiomyopathy. These two molecules are an iron-transporting protein, lipocalin 2, and an anti-inflammatory adipokine, adiponectin. Reports from in vitro and in vivo studies are comprehensively summarized. Clinical studies examining the roles of these molecules in thalassemia patients are also presented and discussed. © 2017 Wiley Periodicals, Inc.

Model invariance across genders of the Broad Autism Phenotype Questionnaire.

PubMed

Broderick, Neill; Wade, Jordan L; Meyer, J Patrick; Hull, Michael; Reeve, Ronald E

2015-10-01

ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates psychometric properties superior to other self-report measures. To examine evidence regarding validity of the BAPQ, the current study used confirmatory factor analysis to test the assumption of model invariance across genders. Results of the current study upheld model invariance at each level of parameter constraint; however, model fit indices suggested limited goodness-of-fit between the proposed model and the sample. Exploratory analyses investigated alternate factor structure models but ultimately supported the proposed three-factor structure model.

DNA Methylation in Schizophrenia.

PubMed

Pries, Lotta-Katrin; Gülöksüz, Sinan; Kenis, Gunter

2017-01-01

Schizophrenia is a highly heritable psychiatric condition that displays a complex phenotype. A multitude of genetic susceptibility loci have now been identified, but these fail to explain the high heritability estimates of schizophrenia. In addition, epidemiologically relevant environmental risk factors for schizophrenia may lead to permanent changes in brain function. In conjunction with genetic liability, these environmental risk factors-likely through epigenetic mechanisms-may give rise to schizophrenia, a clinical syndrome characterized by florid psychotic symptoms and moderate to severe cognitive impairment. These pathophysiological features point to the involvement of epigenetic processes. Recently, a wave of studies examining aberrant DNA modifications in schizophrenia was published. This chapter aims to comprehensively review the current findings, from both candidate gene studies and genome-wide approaches, on DNA methylation changes in schizophrenia.

Reprogramming neurodegeneration in the big data era.

PubMed

Zhou, Lujia; Verstreken, Patrik

2018-02-01

Recent genome-wide association studies (GWAS) have identified numerous genetic risk variants for late-onset Alzheimer's disease (AD) and Parkinson's disease (PD). However, deciphering the functional consequences of GWAS data is challenging due to a lack of reliable model systems to study the genetic variants that are often of low penetrance and non-coding identities. Pluripotent stem cell (PSC) technologies offer unprecedented opportunities for molecular phenotyping of GWAS variants in human neurons and microglia. Moreover, rapid technological advances in whole-genome RNA-sequencing and epigenome mapping fuel comprehensive and unbiased investigations of molecular alterations in PSC-derived disease models. Here, we review and discuss how integrated studies that utilize PSC technologies and genome-wide approaches may bring new mechanistic insight into the pathogenesis of AD and PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transposable element genomic fissuring in Pyrenophora teres is associated with genome expansion and dynamics of host-pathogen genetic interactions

USDA-ARS?s Scientific Manuscript database

Pyrenophora teres, P. teres f. teres (PTT) and P. teres f. maculata (PTM) cause significant diseases in barley, but little is known about the large-scale genomic differences that may distinguish the two forms. Comprehensive genome assemblies were constructed from long DNA reads, optical and genetic ...

Genetic diversity and conservation of Mexican forest trees

Treesearch

C. Wehenkel; S. Mariscal-Lucero; J.P. Jaramillo-Correa; C.A. López-Sánchez; J.J. Vargas Hernández; C. Sáenz-Romero

2017-01-01

Over the last 200 years, humans have impacted the genetic diversity of forest trees. Because of widespread deforestation and over-exploitation, about 9,000 tree species are listed worldwide as threatened with extinction, including more than half of the ~600 known conifer taxa. A comprehensive review of the floristic-taxonomic literature compiled a list of 4,331...

Recommendations for genetic variation data capture in developing countries to ensure a comprehensive worldwide data collection.

PubMed

Patrinos, George P; Al Aama, Jumana; Al Aqeel, Aida; Al-Mulla, Fahd; Borg, Joseph; Devereux, Andrew; Felice, Alex E; Macrae, Finlay; Marafie, Makia J; Petersen, Michael B; Qi, Ming; Ramesar, Rajkumar S; Zlotogora, Joel; Cotton, Richard G H

2011-01-01

Developing countries have significantly contributed to the elucidation of the genetic basis of both common and rare disorders, providing an invaluable resource of cases due to large family sizes, consanguinity, and potential founder effects. Moreover, the recognized depth of genomic variation in indigenous African populations, reflecting the ancient origins of humanity on the African continent, and the effect of selection pressures on the genome, will be valuable in understanding the range of both pathological and nonpathological variations. The involvement of these populations in accurately documenting the extant genetic heterogeneity is more than essential. Developing nations are regarded as key contributors to the Human Variome Project (HVP; http://www.humanvariomeproject.org), a major effort to systematically collect mutations that contribute to or cause human disease and create a cyber infrastructure to tie databases together. However, biomedical research has not been the primary focus in these countries even though such activities are likely to produce economic and health benefits for all. Here, we propose several recommendations and guidelines to facilitate participation of developing countries in genetic variation data documentation, ensuring an accurate and comprehensive worldwide data collection. We also summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.

Conventional and genetic talent identification in sports: will recent developments trace talent?

PubMed

Breitbach, Sarah; Tug, Suzan; Simon, Perikles

2014-11-01

The purpose of talent identification (TI) is the earliest possible selection of auspicious athletes with the goal of systematically maximizing their potential. The literature proposes excellent reviews on various facets of talent research on different scientific issues such as sports sciences or genetics. However, the approaches of conventional and genetic testing have only been discussed separately by and for the respective groups of interest. In this article, we combine the discoveries of these disciplines into a single review to provide a comprehensive overview and elucidate the prevailing limitations. Fundamental problems in TI reside in the difficulties of defining the construct ‘talent’ or groups of different performance levels that represent the target variable of testing. Conventional and genetic testing reveal a number of methodological and technical limitations, and parallels are summarised in terms of the test designs, the point in time of testing, psychological skills or traits and unknown interactions between different variables. In conclusion, many deficiencies in the current talent research have gained attention. Alternative solutions include the talent development approach, while genetic testing is re-emphasised as a tool for risk stratification in sport participation. Future research needs to clearly define the group of interest and comprehensively implement all methodological improvement suggestions.

A multivariate analysis of genetic constraints to life history evolution in a wild population of red deer.

PubMed

Walling, Craig A; Morrissey, Michael B; Foerster, Katharina; Clutton-Brock, Tim H; Pemberton, Josephine M; Kruuk, Loeske E B

2014-12-01

Evolutionary theory predicts that genetic constraints should be widespread, but empirical support for their existence is surprisingly rare. Commonly applied univariate and bivariate approaches to detecting genetic constraints can underestimate their prevalence, with important aspects potentially tractable only within a multivariate framework. However, multivariate genetic analyses of data from natural populations are challenging because of modest sample sizes, incomplete pedigrees, and missing data. Here we present results from a study of a comprehensive set of life history traits (juvenile survival, age at first breeding, annual fecundity, and longevity) for both males and females in a wild, pedigreed, population of red deer (Cervus elaphus). We use factor analytic modeling of the genetic variance-covariance matrix ( G: ) to reduce the dimensionality of the problem and take a multivariate approach to estimating genetic constraints. We consider a range of metrics designed to assess the effect of G: on the deflection of a predicted response to selection away from the direction of fastest adaptation and on the evolvability of the traits. We found limited support for genetic constraint through genetic covariances between traits, both within sex and between sexes. We discuss these results with respect to other recent findings and to the problems of estimating these parameters for natural populations. Copyright © 2014 Walling et al.

A Multivariate Analysis of Genetic Constraints to Life History Evolution in a Wild Population of Red Deer

PubMed Central

Walling, Craig A.; Morrissey, Michael B.; Foerster, Katharina; Clutton-Brock, Tim H.; Pemberton, Josephine M.; Kruuk, Loeske E. B.

2014-01-01

Evolutionary theory predicts that genetic constraints should be widespread, but empirical support for their existence is surprisingly rare. Commonly applied univariate and bivariate approaches to detecting genetic constraints can underestimate their prevalence, with important aspects potentially tractable only within a multivariate framework. However, multivariate genetic analyses of data from natural populations are challenging because of modest sample sizes, incomplete pedigrees, and missing data. Here we present results from a study of a comprehensive set of life history traits (juvenile survival, age at first breeding, annual fecundity, and longevity) for both males and females in a wild, pedigreed, population of red deer (Cervus elaphus). We use factor analytic modeling of the genetic variance–covariance matrix (G) to reduce the dimensionality of the problem and take a multivariate approach to estimating genetic constraints. We consider a range of metrics designed to assess the effect of G on the deflection of a predicted response to selection away from the direction of fastest adaptation and on the evolvability of the traits. We found limited support for genetic constraint through genetic covariances between traits, both within sex and between sexes. We discuss these results with respect to other recent findings and to the problems of estimating these parameters for natural populations. PMID:25278555

Advances in Genetical Genomics of Plants

PubMed Central

Joosen, R.V.L.; Ligterink, W.; Hilhorst, H.W.M.; Keurentjes, J.J.B.

2009-01-01

Natural variation provides a valuable resource to study the genetic regulation of quantitative traits. In quantitative trait locus (QTL) analyses this variation, captured in segregating mapping populations, is used to identify the genomic regions affecting these traits. The identification of the causal genes underlying QTLs is a major challenge for which the detection of gene expression differences is of major importance. By combining genetics with large scale expression profiling (i.e. genetical genomics), resulting in expression QTLs (eQTLs), great progress can be made in connecting phenotypic variation to genotypic diversity. In this review we discuss examples from human, mouse, Drosophila, yeast and plant research to illustrate the advances in genetical genomics, with a focus on understanding the regulatory mechanisms underlying natural variation. With their tolerance to inbreeding, short generation time and ease to generate large families, plants are ideal subjects to test new concepts in genetics. The comprehensive resources which are available for Arabidopsis make it a favorite model plant but genetical genomics also found its way to important crop species like rice, barley and wheat. We discuss eQTL profiling with respect to cis and trans regulation and show how combined studies with other ‘omics’ technologies, such as metabolomics and proteomics may further augment current information on transcriptional, translational and metabolomic signaling pathways and enable reconstruction of detailed regulatory networks. The fast developments in the ‘omics’ area will offer great potential for genetical genomics to elucidate the genotype-phenotype relationships for both fundamental and applied research. PMID:20514216

Modeling mania in preclinical settings: a comprehensive review

PubMed Central

Sharma, Ajaykumar N.; Fries, Gabriel R.; Galvez, Juan F.; Valvassori, Samira S.; Soares, Jair C.; Carvalho, André F.; Quevedo, Joao

2015-01-01

The current pathophysiological understanding of mechanisms leading to onset and progression of bipolar manic episodes remains limited. At the same time, available animal models for mania have limited face, construct, and predictive validities. Additionally, these models fail to encompass recent pathophysiological frameworks of bipolar disorder (BD), e.g. neuroprogression. Therefore, there is a need to search for novel preclinical models for mania that could comprehensively address these limitations. Herein we review the history, validity, and caveats of currently available animal models for mania. We also review new genetic models for mania, namely knockout mice for genes involved in neurotransmission, synapse formation, and intracellular signaling pathways. Furthermore, we review recent trends in preclinical models for mania that may aid in the comprehension of mechanisms underlying the neuroprogressive and recurring nature of BD. In conclusion, the validity of animal models for mania remains limited. Nevertheless, novel (e.g. genetic) animal models as well as adaptation of existing paradigms hold promise. PMID:26545487

Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value.

PubMed

Farhat, Maha R; Sultana, Razvan; Iartchouk, Oleg; Bozeman, Sam; Galagan, James; Sisk, Peter; Stolte, Christian; Nebenzahl-Guimaraes, Hanna; Jacobson, Karen; Sloutsky, Alexander; Kaur, Devinder; Posey, James; Kreiswirth, Barry N; Kurepina, Natalia; Rigouts, Leen; Streicher, Elizabeth M; Victor, Tommie C; Warren, Robin M; van Soolingen, Dick; Murray, Megan

2016-09-01

The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance-conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs. To determine the optimal molecular approach needed, we sought to create a comprehensive catalog of resistance mutations and assess their sensitivity and specificity in diagnosing drug resistance. We developed and validated molecular inversion probes for DNA capture and deep sequencing of 28 drug-resistance loci in M. tuberculosis. We used the probes for targeted sequencing of a geographically diverse set of 1,397 clinical M. tuberculosis isolates with known drug resistance phenotypes. We identified a minimal set of mutations to predict resistance to first- and second-line antituberculosis drugs and validated our predictions in an independent dataset. We constructed and piloted a web-based database that provides public access to the sequence data and prediction tool. The predicted resistance to rifampicin and isoniazid exceeded 90% sensitivity and specificity but was lower for other drugs. The number of mutations needed to diagnose resistance is large, and for the 13 drugs studied it was 238 across 18 genetic loci. These data suggest that a comprehensive M. tuberculosis drug resistance diagnostic will need to allow for a high dimension of mutation detection. They also support the hypothesis that currently unknown genetic determinants, potentially discoverable by whole-genome sequencing, encode resistance to second-line tuberculosis drugs.

Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value

PubMed Central

Sultana, Razvan; Iartchouk, Oleg; Bozeman, Sam; Galagan, James; Sisk, Peter; Stolte, Christian; Nebenzahl-Guimaraes, Hanna; Jacobson, Karen; Sloutsky, Alexander; Kaur, Devinder; Posey, James; Kreiswirth, Barry N.; Kurepina, Natalia; Rigouts, Leen; Streicher, Elizabeth M.; Victor, Tommie C.; Warren, Robin M.; van Soolingen, Dick; Murray, Megan

2016-01-01

Rationale: The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance–conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs. Objectives: To determine the optimal molecular approach needed, we sought to create a comprehensive catalog of resistance mutations and assess their sensitivity and specificity in diagnosing drug resistance. Methods: We developed and validated molecular inversion probes for DNA capture and deep sequencing of 28 drug-resistance loci in M. tuberculosis. We used the probes for targeted sequencing of a geographically diverse set of 1,397 clinical M. tuberculosis isolates with known drug resistance phenotypes. We identified a minimal set of mutations to predict resistance to first- and second-line antituberculosis drugs and validated our predictions in an independent dataset. We constructed and piloted a web-based database that provides public access to the sequence data and prediction tool. Measurements and Main Results: The predicted resistance to rifampicin and isoniazid exceeded 90% sensitivity and specificity but was lower for other drugs. The number of mutations needed to diagnose resistance is large, and for the 13 drugs studied it was 238 across 18 genetic loci. Conclusions: These data suggest that a comprehensive M. tuberculosis drug resistance diagnostic will need to allow for a high dimension of mutation detection. They also support the hypothesis that currently unknown genetic determinants, potentially discoverable by whole-genome sequencing, encode resistance to second-line tuberculosis drugs. PMID:26910495

Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.

PubMed

McNally, Elizabeth M; Mestroni, Luisa

2017-09-15

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management. © 2017 American Heart Association, Inc.

The role of AMH and its receptor SNP in the pathogenesis of PCOS.

PubMed

Wang, Fang; Niu, Wen-Bin; Kong, Hui-Juan; Guo, Yi-Hong; Sun, Ying-Pu

2017-01-05

The etiology of polycystic ovaries syndrome (PCOS) is unknown. Studies probing the role of genetic variants of anti-Mullerian hormone (AMH) and its type II receptor (AMHR2) in the pathogenesis of PCOS have yielded inconsistent results. Thus, we performed a systematic review and meta-analysis to determine the role of genetic variants of AMH/AMHR2 in the pathogenesis of PCOS. A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). Pooled Odds Ratios (OR) (95% confidence intervals) were determined to assess the association between genetic variants of AMH/AMHR2 and PCOS. Five studies, involving a total of 2042 PCOS cases and 1071 controls, were included in the meta-analysis. Single nucleotide polymorphisms of AMH and AMHR2 did not appear to confer a heightened risk for PCOS (OR: 0.954, 95% CI: 0.848-1.073; P = 0.435; and OR: 1.074, 95% CI: 0.875-1.318; P = 0.494, respectively). In this study, genetic variants of AMH or AMHR2 were not found to be associated with a higher risk for PCOS. Copyright © 2016. Published by Elsevier Ireland Ltd.

Genomic approaches for the elucidation of genes and gene networks underlying cardiovascular traits.

PubMed

Adriaens, M E; Bezzina, C R

2018-06-22

Genome-wide association studies have shed light on the association between natural genetic variation and cardiovascular traits. However, linking a cardiovascular trait associated locus to a candidate gene or set of candidate genes for prioritization for follow-up mechanistic studies is all but straightforward. Genomic technologies based on next-generation sequencing technology nowadays offer multiple opportunities to dissect gene regulatory networks underlying genetic cardiovascular trait associations, thereby aiding in the identification of candidate genes at unprecedented scale. RNA sequencing in particular becomes a powerful tool when combined with genotyping to identify loci that modulate transcript abundance, known as expression quantitative trait loci (eQTL), or loci modulating transcript splicing known as splicing quantitative trait loci (sQTL). Additionally, the allele-specific resolution of RNA-sequencing technology enables estimation of allelic imbalance, a state where the two alleles of a gene are expressed at a ratio differing from the expected 1:1 ratio. When multiple high-throughput approaches are combined with deep phenotyping in a single study, a comprehensive elucidation of the relationship between genotype and phenotype comes into view, an approach known as systems genetics. In this review, we cover key applications of systems genetics in the broad cardiovascular field.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

PubMed

Mariath, Luiza Monteavaro; Silva, Alexandre Mauat da; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; Araujo, Gustavo Andrade de; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

2017-01-01

Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene

PubMed Central

Mariath, Luiza Monteavaro; da Silva, Alexandre Mauat; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; de Araujo, Gustavo Andrade; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

2017-01-01

Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability. PMID:28534928

Internet-Based Direct-to-Consumer Genetic Testing: A Systematic Review.

PubMed

Covolo, Loredana; Rubinelli, Sara; Ceretti, Elisabetta; Gelatti, Umberto

2015-12-14

Direct-to-consumer genetic tests (DTC-GT) are easily purchased through the Internet, independent of a physician referral or approval for testing, allowing the retrieval of genetic information outside the clinical context. There is a broad debate about the testing validity, their impact on individuals, and what people know and perceive about them. The aim of this review was to collect evidence on DTC-GT from a comprehensive perspective that unravels the complexity of the phenomenon. A systematic search was carried out through PubMed, Web of Knowledge, and Embase, in addition to Google Scholar according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist with the key term "Direct-to-consumer genetic test." In the final sample, 118 articles were identified. Articles were summarized in five categories according to their focus on (1) knowledge of, attitude toward use of, and perception of DTC-GT (n=37), (2) the impact of genetic risk information on users (n=37), (3) the opinion of health professionals (n=20), (4) the content of websites selling DTC-GT (n=16), and (5) the scientific evidence and clinical utility of the tests (n=14). Most of the articles analyzed the attitude, knowledge, and perception of DTC-GT, highlighting an interest in using DTC-GT, along with the need for a health care professional to help interpret the results. The articles investigating the content analysis of the websites selling these tests are in agreement that the information provided by the companies about genetic testing is not completely comprehensive for the consumer. Given that risk information can modify consumers' health behavior, there are surprisingly few studies carried out on actual consumers and they do not confirm the overall concerns on the possible impact of DTC-GT. Data from studies that investigate the quality of the tests offered confirm that they are not informative, have little predictive power, and do not measure genetic risk appropriately. The impact of DTC-GT on consumers' health perceptions and behaviors is an emerging concern. However, negative effects on consumers or health benefits have yet to be observed. Nevertheless, since the online market of DTC-GT is expected to grow, it is important to remain aware of a possible impact.

Internet-Based Direct-to-Consumer Genetic Testing: A Systematic Review

PubMed Central

Rubinelli, Sara; Ceretti, Elisabetta; Gelatti, Umberto

2015-01-01

Background Direct-to-consumer genetic tests (DTC-GT) are easily purchased through the Internet, independent of a physician referral or approval for testing, allowing the retrieval of genetic information outside the clinical context. There is a broad debate about the testing validity, their impact on individuals, and what people know and perceive about them. Objective The aim of this review was to collect evidence on DTC-GT from a comprehensive perspective that unravels the complexity of the phenomenon. Methods A systematic search was carried out through PubMed, Web of Knowledge, and Embase, in addition to Google Scholar according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist with the key term “Direct-to-consumer genetic test.” Results In the final sample, 118 articles were identified. Articles were summarized in five categories according to their focus on (1) knowledge of, attitude toward use of, and perception of DTC-GT (n=37), (2) the impact of genetic risk information on users (n=37), (3) the opinion of health professionals (n=20), (4) the content of websites selling DTC-GT (n=16), and (5) the scientific evidence and clinical utility of the tests (n=14). Most of the articles analyzed the attitude, knowledge, and perception of DTC-GT, highlighting an interest in using DTC-GT, along with the need for a health care professional to help interpret the results. The articles investigating the content analysis of the websites selling these tests are in agreement that the information provided by the companies about genetic testing is not completely comprehensive for the consumer. Given that risk information can modify consumers’ health behavior, there are surprisingly few studies carried out on actual consumers and they do not confirm the overall concerns on the possible impact of DTC-GT. Data from studies that investigate the quality of the tests offered confirm that they are not informative, have little predictive power, and do not measure genetic risk appropriately. Conclusions The impact of DTC-GT on consumers’ health perceptions and behaviors is an emerging concern. However, negative effects on consumers or health benefits have yet to be observed. Nevertheless, since the online market of DTC-GT is expected to grow, it is important to remain aware of a possible impact. PMID:26677835

Molecular characterization and population structure study of cambuci: strategy for conservation and genetic improvement.

PubMed

Santos, D N; Nunes, C F; Setotaw, T A; Pio, R; Pasqual, M; Cançado, G M A

2016-12-19

Cambuci (Campomanesia phaea) belongs to the Myrtaceae family and is native to the Atlantic Forest of Brazil. It has ecological and social appeal but is exposed to problems associated with environmental degradation and expansion of agricultural activities in the region. Comprehensive studies on this species are rare, making its conservation and genetic improvement difficult. Thus, it is important to develop research activities to understand the current situation of the species as well as to make recommendations for its conservation and use. This study was performed to characterize the cambuci accessions found in the germplasm bank of Coordenadoria de Assistência Técnica Integral using inter-simple sequence repeat markers, with the goal of understanding the plant's population structure. The results showed the existence of some level of genetic diversity among the cambuci accessions that could be exploited for the genetic improvement of the species. Principal coordinate analysis and discriminant analysis clustered the 80 accessions into three groups, whereas Bayesian model-based clustering analysis clustered them into two groups. The formation of two cluster groups and the high membership coefficients within the groups pointed out the importance of further collection to cover more areas and more genetic variability within the species. The study also showed the lack of conservation activities; therefore, more attention from the appropriate organizations is needed to plan and implement natural and ex situ conservation activities.

Biophysical connectivity explains population genetic structure in a highly dispersive marine species

NASA Astrophysics Data System (ADS)

Truelove, Nathan K.; Kough, Andrew S.; Behringer, Donald C.; Paris, Claire B.; Box, Stephen J.; Preziosi, Richard F.; Butler, Mark J.

2017-03-01

Connectivity, the exchange of individuals among locations, is a fundamental ecological process that explains how otherwise disparate populations interact. For most marine organisms, dispersal occurs primarily during a pelagic larval phase that connects populations. We paired population structure from comprehensive genetic sampling and biophysical larval transport modeling to describe how spiny lobster ( Panulirus argus) population differentiation is related to biological oceanography. A total of 581 lobsters were genotyped with 11 microsatellites from ten locations around the greater Caribbean. The overall F ST of 0.0016 ( P = 0.005) suggested low yet significant levels of structuring among sites. An isolation by geographic distance model did not explain spatial patterns of genetic differentiation in P. argus ( P = 0.19; Mantel r = 0.18), whereas a biophysical connectivity model provided a significant explanation of population differentiation ( P = 0.04; Mantel r = 0.47). Thus, even for a widely dispersing species, dispersal occurs over a continuum where basin-wide larval retention creates genetic structure. Our study provides a framework for future explorations of wide-scale larval dispersal and marine connectivity by integrating empirical genetic research and probabilistic modeling.

[Genome-wide association in type 2 diabetes and its clinical application].

PubMed

Esparza-Castro, Dagoberto; Andrade-Ancira, Francisco Javier; Merelo-Arias, Carlos Adrián; Cruz, Miguel; Valladares-Salgado, Adán

2015-01-01

Diabetes mellitus is a complex and chronical disease, which represents one of the biggest health issues the world, with alarming numbers and constantly increasing it demands the creation of new diagnostic, therapeutic and preventive techniques. The complete Genome Wide Association (GWA) in type 2 diabetes (T2D) is a useful research tool for the characterization of genetic markers and physiopathogenic pathways, with potential clinical utility either as a T2D risk prediction or its complications. In Mexico is necessary to make a comprehensive dissection of the genetic background of T2D by the complex genetic mosaic of our population and increase the knowledge of the molecular and pathophysiological mechanisms that lead to this condition. There are several genetic studies for the Mexican population, linked to the 1000 genomes project, which have led to define some specific genetic markers for our population which are not described in European populations, until the moment, 78 loci have been associated with T2D. Recently in the global meta-analysis, with the participation of Mexico, we demonstrated at least 7 new variants associated with T2D.

The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility.

PubMed

Charoute, Hicham; Nahili, Halima; Abidi, Omar; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Barakat, Abdelhamid

2014-03-01

National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma.

Comprehensive List of Cancer-Related Genetic Variations of the NCI-60 Panel | Center for Cancer Research

Cancer.gov

The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. The panel of cell lines represents nine different types of cancer: breast, ovary, prostate, colon, lung, kidney, brain, leukemia, and melanoma. Originally developed to screen anticancer compounds by the NCI Developmental Therapeutics Program (DTP), the NCI-60 panel has generated

Comprehensive Evaluation of the Association of APOE Genetic Variation with Plasma Lipoprotein Traits in U.S. Whites and African Blacks

PubMed Central

Radwan, Zaheda H.; Wang, Xingbin; Waqar, Fahad; Pirim, Dilek; Niemsiri, Vipavee; Hokanson, John E.; Hamman, Richard F.; Bunker, Clareann H.; Barmada, M. Michael; Demirci, F. Yesim; Kamboh, M. Ilyas

2014-01-01

Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol. PMID:25502880

Genetic Testing and Eye Disease

MedlinePlus

Subspecialties Cataract/Anterior Segment Comprehensive Ophthalmology Cornea/External Disease Glaucoma Neuro-Ophthalmology/Orbit Pediatric Ophthalmology/Strabismus Ocular Pathology/Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis ...

The Influence of Gene-Environment Interactions on Alcohol Consumption and Alcohol Use Disorders: A Comprehensive Review

PubMed Central

Young-Wolff, Kelly C.; Enoch, Mary-Anne; Prescott, Carol A.

2011-01-01

Since 2005, a rapidly expanding literature has evaluated whether environmental factors such as socio-cultural context and environmental adversity interact with genetic influences on drinking behaviors. This article critically reviews empirical research on alcohol-related genotype-environment interactions (GxE) and provides a contextual framework for understanding how genetic factors combine with (or are shaped by) environmental influences to influence the development of drinking behaviors and alcohol use disorders. Collectively, evidence from twin, adoption, and molecular genetic studies indicates that the degree of importance of genetic influences on risk for drinking outcomes can vary in different populations and under different environmental circumstances. However, methodological limitations and lack of consistent replications in this literature make it difficult to draw firm conclusions regarding the nature and effect size of alcohol-related GxE. On the basis of this review, we describe several methodological challenges as they relate to current research on GxE in drinking behaviors and provide recommendations to aid future research. PMID:21530476

From Novice to Seasoned Practitioner: a Qualitative Investigation of Genetic Counselor Professional Development.

PubMed

Zahm, Kimberly Wehner; Veach, Patricia McCarthy; Martyr, Meredith A; LeRoy, Bonnie S

2016-08-01

Research on genetic counselor professional development would characterize typical developmental processes, inform training and supervision, and promote life-long development opportunities. To date, however no studies have comprehensively examined this phenomenon. The aims of this study were to investigate the nature of professional development for genetic counselors (processes, influences, and outcomes) and whether professional development varies across experience levels. Thirty-four genetic counselors participated in semi-structured telephone interviews exploring their perspectives on their professional development. Participants were sampled from three levels of post-degree genetic counseling experience: novice (0-5 years), experienced (6-14 years), and seasoned (>15 years). Using modified Consensual Qualitative Research and grounded theory methods, themes, domains, and categories were extracted from the data. The themes reflect genetic counselors' evolving perceptions of their professional development and its relationship to: (a) being a clinician, (b) their professional identity, and (c) the field itself. Across experience levels, prevalent influences on professional development were interpersonal (e.g., experiences with patients, genetic counseling colleagues) and involved professional and personal life events. Common developmental experiences included greater confidence and less anxiety over time, being less information-driven and more emotion-focused with patients, delivering "bad news" to patients remains challenging, and individuals' professional development experiences parallel genetic counseling's development as a field. With a few noteworthy exceptions, professional development was similar across experience levels. A preliminary model of genetic counselor professional development is proposed suggesting development occurs in a non-linear fashion throughout the professional lifespan. Each component of the model mutually influences the others, and there are positive and negative avenues of development.

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

PubMed

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Etiological theories of addiction: A comprehensive update on neurobiological, genetic and behavioural vulnerability.

PubMed

Ouzir, Mounir; Errami, Mohammed

2016-09-01

Currently, about 246 million people around the world have used an illicit drug. The reasons for this use are multiple: e.g. to augment the sensation of pleasure or to reduce the withdrawal and other aversive effects of a given substance. This raises the problem of addiction, which remains a disease of modern society. This review offers a comprehensive update of the different theories about the etiology of addictive behaviors with emphasis on the neurobiological, environmental, psychopathological, behavioural and genetic aspects of addictions, discussed from an evolutionary perspective. The main conclusion of this review is that vulnerability to drug addiction suggests an interaction between many brain systems (including the reward, decision-making, serotonergic, oxytocin, interoceptive insula, CRF, norepinephrine, dynorphin/KOR, orexin and vasopressin systems), genetic predisposition, sociocultural context, impulsivity and drugs types. Further advances in biological and psychological science are needed to address the problems of addiction at its roots. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes.

PubMed

Nielsen, H Bjørn; Almeida, Mathieu; Juncker, Agnieszka Sierakowska; Rasmussen, Simon; Li, Junhua; Sunagawa, Shinichi; Plichta, Damian R; Gautier, Laurent; Pedersen, Anders G; Le Chatelier, Emmanuelle; Pelletier, Eric; Bonde, Ida; Nielsen, Trine; Manichanh, Chaysavanh; Arumugam, Manimozhiyan; Batto, Jean-Michel; Quintanilha Dos Santos, Marcelo B; Blom, Nikolaj; Borruel, Natalia; Burgdorf, Kristoffer S; Boumezbeur, Fouad; Casellas, Francesc; Doré, Joël; Dworzynski, Piotr; Guarner, Francisco; Hansen, Torben; Hildebrand, Falk; Kaas, Rolf S; Kennedy, Sean; Kristiansen, Karsten; Kultima, Jens Roat; Léonard, Pierre; Levenez, Florence; Lund, Ole; Moumen, Bouziane; Le Paslier, Denis; Pons, Nicolas; Pedersen, Oluf; Prifti, Edi; Qin, Junjie; Raes, Jeroen; Sørensen, Søren; Tap, Julien; Tims, Sebastian; Ussery, David W; Yamada, Takuji; Renault, Pierre; Sicheritz-Ponten, Thomas; Bork, Peer; Wang, Jun; Brunak, Søren; Ehrlich, S Dusko

2014-08-01

Most current approaches for analyzing metagenomic data rely on comparisons to reference genomes, but the microbial diversity of many environments extends far beyond what is covered by reference databases. De novo segregation of complex metagenomic data into specific biological entities, such as particular bacterial strains or viruses, remains a largely unsolved problem. Here we present a method, based on binning co-abundant genes across a series of metagenomic samples, that enables comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities and aids assembly of microbial genomes without the need for reference sequences. We demonstrate the method on data from 396 human gut microbiome samples and identify 7,381 co-abundance gene groups (CAGs), including 741 metagenomic species (MGS). We use these to assemble 238 high-quality microbial genomes and identify affiliations between MGS and hundreds of viruses or genetic entities. Our method provides the means for comprehensive profiling of the diversity within complex metagenomic samples.

Rapid independent trait evolution despite a strong pleiotropic genetic correlation.

PubMed

Conner, Jeffrey K; Karoly, Keith; Stewart, Christy; Koelling, Vanessa A; Sahli, Heather F; Shaw, Frank H

2011-10-01

Genetic correlations are the most commonly studied of all potential constraints on adaptive evolution. We present a comprehensive test of constraints caused by genetic correlation, comparing empirical results to predictions from theory. The additive genetic correlation between the filament and the corolla tube in wild radish flowers is very high in magnitude, is estimated with good precision (0.85 ± 0.06), and is caused by pleiotropy. Thus, evolutionary changes in the relative lengths of these two traits should be constrained. Still, artificial selection produced rapid evolution of these traits in opposite directions, so that in one replicate relative to controls, the difference between them increased by six standard deviations in only nine generations. This would result in a 54% increase in relative fitness on the basis of a previous estimate of natural selection in this population, and it would produce the phenotypes found in the most extreme species in the family Brassicaceae in less than 100 generations. These responses were within theoretical expectations and were much slower than if the genetic correlation was zero; thus, there was evidence for constraint. These results, coupled with comparable results from other species, show that evolution can be rapid despite the constraints caused by genetic correlations.

Biological pathways and genetic mechanisms involved in social functioning.

PubMed

Ordoñana, Juan R; Bartels, Meike; Boomsma, Dorret I; Cella, David; Mosing, Miriam; Oliveira, Joao R; Patrick, Donald L; Veenhoven, Ruut; Wagner, Gert G; Sprangers, Mirjam A G

2013-08-01

To describe the major findings in the literature regarding associations between biological and genetic factors and social functioning, paying special attention to: (1) heritability studies on social functioning and related concepts; (2) hypothesized biological pathways and genetic variants that could be involved in social functioning, and (3) the implications of these results for quality-of-life research. A search of Web of Science and PubMed databases was conducted using combinations of the following keywords: genetics, twins, heritability, social functioning, social adjustment, social interaction, and social dysfunction. Variability in the definitions and measures of social functioning was extensive. Moderate to high heritability was reported for social functioning and related concepts, including prosocial behavior, loneliness, and extraversion. Disorders characterized by impairments in social functioning also show substantial heritability. Genetic variants hypothesized to be involved in social functioning are related to the network of brain structures and processes that are known to affect social cognition and behavior. Better knowledge and understanding about the impact of genetic factors on social functioning is needed to help us to attain a more comprehensive view of health-related quality-of-life (HRQOL) and will ultimately enhance our ability to identify those patients who are vulnerable to poor social functioning.

The Genetics of Urinary Tract Infections and the Innate Defense of the Kidney and Urinary tract

PubMed Central

Ambite, Ines; Rydstrom, Gustav; Schwaderer, Andrew L.; Hains, David S.

2015-01-01

The urinary tract is a sterile organ system. Urinary tract infections (UTIs) are common and often serious infections. Research has focused on uropathogen, environment, and host factors leading to UTI pathogenesis. A growing body of evidence exists implicating genetic factors that can contribute to UTI risks. In this review, we highlight genetic variations in aspects of the innate immune system critical to the host response to uropathogens. This overview includes genetic variations in pattern recognition receptor molecules, chemokines/cytokines, and neutrophil activation. We also comprehensively cover murine knockout models of UTI, genetic variations involved in renal scarring as a result of ascending UTIs, and asymptomatic bacteriuria. PMID:27617139

Dana-Farber Cancer Institute | Office of Cancer Genomics

Cancer.gov

Functional Annotation of Cancer Genomes Principal Investigator: William C. Hahn, M.D., Ph.D. The comprehensive characterization of cancer genomes has and will continue to provide an increasingly complete catalog of genetic alterations in specific cancers. However, most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability. Therefore, the functional consequences of the majority of mutations remain unclear.

A Comprehensive Analysis of High School Genetics Standards: Are States Keeping Pace with Modern Genetics?

ERIC Educational Resources Information Center

Dougherty, M. J.; Pleasants, C.; Solow, L.; Wong, A.; Zhang, H.

2011-01-01

Science education in the United States will increasingly be driven by testing and accountability requirements, such as those mandated by the No Child Left Behind Act, which rely heavily on learning outcomes, or "standards," that are currently developed on a state-by-state basis. Those standards, in turn, drive curriculum and instruction.…

Epigenetics and Epigenomics of Plants.

PubMed

Yadav, Chandra Bhan; Pandey, Garima; Muthamilarasan, Mehanathan; Prasad, Manoj

2018-01-23

The genetic material DNA in association with histone proteins forms the complex structure called chromatin, which is prone to undergo modification through certain epigenetic mechanisms including cytosine DNA methylation, histone modifications, and small RNA-mediated methylation. Alterations in chromatin structure lead to inaccessibility of genomic DNA to various regulatory proteins such as transcription factors, which eventually modulates gene expression. Advancements in high-throughput sequencing technologies have provided the opportunity to study the epigenetic mechanisms at genome-wide levels. Epigenomic studies using high-throughput technologies will widen the understanding of mechanisms as well as functions of regulatory pathways in plant genomes, which will further help in manipulating these pathways using genetic and biochemical approaches. This technology could be a potential research tool for displaying the systematic associations of genetic and epigenetic variations, especially in terms of cytosine methylation onto the genomic region in a specific cell or tissue. A comprehensive study of plant populations to correlate genotype to epigenotype and to phenotype, and also the study of methyl quantitative trait loci (QTL) or epiGWAS, is possible by using high-throughput sequencing methods, which will further accelerate molecular breeding programs for crop improvement. Graphical Abstract.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

PubMed

O'Mara, Tracy A; Glubb, Dylan M; Painter, Jodie N; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frederic; Zhao, Hui; Goode, Ellen L; Dowdy, Sean C; Fridley, Brooke L; Winham, Stacey J; Salvesen, Helga B; Njølstad, Tormund S; Trovik, Jone; Werner, Henrica M J; Tham, Emma; Liu, Tao; Mints, Miriam; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Thompson, Deborah J; Spurdle, Amanda B

2015-10-01

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types. © 2015 Society for Endocrinology.

Spatiotemporal Dynamics of Genetic Variation in the Iberian Lynx along Its Path to Extinction Reconstructed with Ancient DNA.

PubMed

Casas-Marce, Mireia; Marmesat, Elena; Soriano, Laura; Martínez-Cruz, Begoña; Lucena-Perez, Maria; Nocete, Francisco; Rodríguez-Hidalgo, Antonio; Canals, Antoni; Nadal, Jordi; Detry, Cleia; Bernáldez-Sánchez, Eloísa; Fernández-Rodríguez, Carlos; Pérez-Ripoll, Manuel; Stiller, Mathias; Hofreiter, Michael; Rodríguez, Alejandro; Revilla, Eloy; Delibes, Miguel; Godoy, José A

2017-11-01

There is the tendency to assume that endangered species have been both genetically and demographically healthier in the past, so that any genetic erosion observed today was caused by their recent decline. The Iberian lynx (Lynx pardinus) suffered a dramatic and continuous decline during the 20th century, and now shows extremely low genome- and species-wide genetic diversity among other signs of genomic erosion. We analyze ancient (N = 10), historical (N = 245), and contemporary (N = 172) samples with microsatellite and mitogenome data to reconstruct the species' demography and investigate patterns of genetic variation across space and time. Iberian lynx populations transitioned from low but significantly higher genetic diversity than today and shallow geographical differentiation millennia ago, through a structured metapopulation with varying levels of diversity during the last centuries, to two extremely genetically depauperate and differentiated remnant populations by 2002. The historical subpopulations show varying extents of genetic drift in relation to their recent size and time in isolation, but these do not predict whether the populations persisted or went finally extinct. In conclusion, current genetic patterns were mainly shaped by genetic drift, supporting the current admixture of the two genetic pools and calling for a comprehensive genetic management of the ongoing conservation program. This study illustrates how a retrospective analysis of demographic and genetic patterns of endangered species can shed light onto their evolutionary history and this, in turn, can inform conservation actions. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Phenotypic and genetic relations between the HEXACO dimensions and trait emotional intelligence.

PubMed

Veselka, Livia; Petrides, K V; Schermer, Julie Aitken; Cherkas, Lynn F; Spector, Tim D; Vernon, Philip A

2010-02-01

The present study investigated the location of trait emotional intelligence (trait EI or trait emotional self-efficacy) within the context of the HEXACO model - a more comprehensive personality framework than the conventional Big Five structure. A total of 666 MZ and 526 DZ adult twin pairs from the United Kingdom completed the short form of the Trait Emotional Intelligence Questionnaire (TEIQue-SF) and the short form of the HEXACO Personality Inventory (HEXACO-60). Many significant phenotypic correlations between the TEIQue-SF and the HEXACO-60 were obtained, which were strongest for HEXACO Extraversion, and weakest for HEXACO Honesty-Humility. As was expected, Emotionality was the only HEXACO dimension to correlate negatively with TEIQue-SF scores. Bivariate behavioral genetic analyses revealed that all phenotypic correlations were attributable to common genetic and common nonshared environmental factors. The study confirms the validity of trait EI as a constellation of emotional self-perceptions located at the lower levels of personality.

Heritability and molecular-genetic basis of the P3 event-related brain potential: A genome-wide association study

PubMed Central

MALONE, STEPHEN M.; VAIDYANATHAN, UMA; BASU, SAONLI; MILLER, MICHAEL B.; MCGUE, MATT; IACONO, WILLIAM G.

2014-01-01

P3 amplitude is a candidate endophenotype for disinhibitory psychopathology, psychosis, and other disorders. The present study is a comprehensive analysis of the behavioral- and molecular-genetic basis of P3 amplitude and a P3 genetic factor score in a large community sample (N = 4,211) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric models indicated that as much as 65% of the variance in each measure was due to additive genes. All SNPs in aggregate accounted for approximately 40% to 50% of the heritable variance. However, analyses of individual SNPs did not yield any significant associations. Analyses of individual genes did not confirm previous associations between P3 amplitude and candidate genes but did yield a novel association with myelin expression factor 2 (MYEF2). Main effects of individual variants may be too small to be detected by GWAS without larger samples. PMID:25387705

The influence of climatic niche preferences on the population genetic structure of a mistletoe species complex.

PubMed

Ramírez-Barahona, Santiago; González, Clementina; González-Rodríguez, Antonio; Ornelas, Juan Francisco

2017-06-01

The prevalent view on genetic structuring in parasitic plants is that host-race formation is caused by varying degrees of host specificity. However, the relative importance of ecological niche divergence and host specificity to population differentiation remains poorly understood. We evaluated the factors associated with population differentiation in mistletoes of the Psittacanthus schiedeanus complex (Loranthaceae) in Mexico. We used genetic data from chloroplast sequences and nuclear microsatellites to study population genetic structure and tested its association with host preferences and climatic niche variables. Pairwise genetic differentiation was associated with environmental and host preferences, independent of geography. However, environmental predictors appeared to be more important than host preferences to explain genetic structure, supporting the hypothesis that the occurrence of the parasite is largely determined by its own climatic niche and, to a lesser degree, by host specificity. Genetic structure is significant within this mistletoe species complex, but the processes associated with this structure appear to be more complex than previously thought. Although host specificity was not supported as the major determinant of population differentiation, we consider this to be part of a more comprehensive ecological model of mistletoe host-race formation that incorporates the effects of climatic niche evolution. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Arab gene geography: From population diversities to personalized medical genomics

PubMed Central

Tadmouri, Ghazi O.; Sastry, Konduru S.; Chouchane, Lotfi

2014-01-01

Genetic disorders are not equally distributed over the geography of the Arab region. While a number of disorders have a wide geographical presence encompassing 10 or more Arab countries, almost half of these disorders occur in a single Arab country or population. Nearly, one-third of the genetic disorders in Arabs result from congenital malformations and chromosomal abnormalities, which are also responsible for a significant proportion of neonatal and perinatal deaths in Arab populations. Strikingly, about two-thirds of these diseases in Arab patients follow an autosomal recessive mode of inheritance. High fertility rates together with increased consanguineous marriages, generally noticed in Arab populations, tend to increase the rates of genetic and congenital abnormalities. Many of the nearly 500 genes studied in Arab people revealed striking spectra of heterogeneity with many novel and rare mutations causing large arrays of clinical outcomes. In this review we provided an overview of Arab gene geography, and various genetic abnormalities in Arab populations, including disorders of blood, metabolic, circulatory and neoplasm, and also discussed their associated molecules or genes responsible for the cause of these disorders. Although studying Arab-specific genetic disorders resulted in a high value knowledge base, approximately 35% of genetic diseases in Arabs do not have a defined molecular etiology. This is a clear indication that comprehensive research is required in this area to understand the molecular pathologies causing diseases in Arab populations. PMID:25780794

Detection of genome-wide copy number variants in myeloid malignancies using next-generation sequencing.

PubMed

Shen, Wei; Paxton, Christian N; Szankasi, Philippe; Longhurst, Maria; Schumacher, Jonathan A; Frizzell, Kimberly A; Sorrells, Shelly M; Clayton, Adam L; Jattani, Rakhi P; Patel, Jay L; Toydemir, Reha; Kelley, Todd W; Xu, Xinjie

2018-04-01

Genetic abnormalities, including copy number variants (CNV), copy number neutral loss of heterozygosity (CN-LOH) and gene mutations, underlie the pathogenesis of myeloid malignancies and serve as important diagnostic, prognostic and/or therapeutic markers. Currently, multiple testing strategies are required for comprehensive genetic testing in myeloid malignancies. The aim of this proof-of-principle study was to investigate the feasibility of combining detection of genome-wide large CNVs, CN-LOH and targeted gene mutations into a single assay using next-generation sequencing (NGS). For genome-wide CNV detection, we designed a single nucleotide polymorphism (SNP) sequencing backbone with 22 762 SNP regions evenly distributed across the entire genome. For targeted mutation detection, 62 frequently mutated genes in myeloid malignancies were targeted. We combined this SNP sequencing backbone with a targeted mutation panel, and sequenced 9 healthy individuals and 16 patients with myeloid malignancies using NGS. We detected 52 somatic CNVs, 11 instances of CN-LOH and 39 oncogenic mutations in the 16 patients with myeloid malignancies, and none in the 9 healthy individuals. All CNVs and CN-LOH were confirmed by SNP microarray analysis. We describe a genome-wide SNP sequencing backbone which allows for sensitive detection of genome-wide CNVs and CN-LOH using NGS. This proof-of-principle study has demonstrated that this strategy can provide more comprehensive genetic profiling for patients with myeloid malignancies using a single assay. © 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.

Functional annotation of HOT regions in the human genome: implications for human disease and cancer

PubMed Central

Li, Hao; Chen, Hebing; Liu, Feng; Ren, Chao; Wang, Shengqi; Bo, Xiaochen; Shu, Wenjie

2015-01-01

Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy. PMID:26113264

Functional annotation of HOT regions in the human genome: implications for human disease and cancer.

PubMed

Li, Hao; Chen, Hebing; Liu, Feng; Ren, Chao; Wang, Shengqi; Bo, Xiaochen; Shu, Wenjie

2015-06-26

Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.

Understanding human DNA sequence variation.

PubMed

Kidd, K K; Pakstis, A J; Speed, W C; Kidd, J R

2004-01-01

Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an "out of Africa" hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.

The genetic architecture of economic and political preferences

PubMed Central

Benjamin, Daniel J.; Cesarini, David; van der Loos, Matthijs J. H. M.; Dawes, Christopher T.; Koellinger, Philipp D.; Magnusson, Patrik K. E.; Chabris, Christopher F.; Conley, Dalton; Laibson, David; Johannesson, Magnus; Visscher, Peter M.

2012-01-01

Preferences are fundamental building blocks in all models of economic and political behavior. We study a new sample of comprehensively genotyped subjects with data on economic and political preferences and educational attainment. We use dense single nucleotide polymorphism (SNP) data to estimate the proportion of variation in these traits explained by common SNPs and to conduct genome-wide association study (GWAS) and prediction analyses. The pattern of results is consistent with findings for other complex traits. First, the estimated fraction of phenotypic variation that could, in principle, be explained by dense SNP arrays is around one-half of the narrow heritability estimated using twin and family samples. The molecular-genetic–based heritability estimates, therefore, partially corroborate evidence of significant heritability from behavior genetic studies. Second, our analyses suggest that these traits have a polygenic architecture, with the heritable variation explained by many genes with small effects. Our results suggest that most published genetic association studies with economic and political traits are dramatically underpowered, which implies a high false discovery rate. These results convey a cautionary message for whether, how, and how soon molecular genetic data can contribute to, and potentially transform, research in social science. We propose some constructive responses to the inferential challenges posed by the small explanatory power of individual SNPs. PMID:22566634

A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.

PubMed

Weedon, Michael N; Clark, Vanessa J; Qian, Yudong; Ben-Shlomo, Yoav; Timpson, Nicholas; Ebrahim, Shah; Lawlor, Debbie A; Pembrey, Marcus E; Ring, Susan; Wilkin, Terry J; Voss, Linda D; Jeffery, Alison N; Metcalf, Brad; Ferrucci, Luigi; Corsi, Anna Maria; Murray, Anna; Melzer, David; Knight, Bridget; Shields, Bev; Smith, George Davey; Hattersley, Andrew T; Di Rienzo, Anna; Frayling, Tim M

2006-12-01

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

[Human origin and evolution. A review of advances in paleoanthropology, comparative genetics, and evolutionary psychology].

PubMed

Markov, A V

2009-01-01

In his main work, "On the origin of species", Darwin has refrained from discusion of the origin of man; be only mentioned that his theory would "throw light" on this problem. This famous Darwin's phrase turned out to be one of the most succesful scientific predictions. In the present paper some of the most important recent adavnces in paleoanthroplogy, comparative genetics and evolutionary psychology are reviewed. These three disciplines currently contribute most to our knowledge of anthropogenesis. The review demonstrates that Darwin's ideas not only "threw light" on human origin and evolution; they provided a comprehensive framework for a great variety of studies concerning different aspects of anthropogenesis.

Genetics of hereditary neurological disorders in children.

PubMed

Huang, Yue; Yu, Sui; Wu, Zhanhe; Tang, Beisha

2014-04-01

Hereditary neurological disorders (HNDs) are relatively common in children compared to those occurring in adulthood. Recognising clinical manifestations of HNDs is important for the selection of genetic testing, genetic testing results interpretation, and genetic consultation. Meanwhile, advances in next generation sequencing (NGS) technologies have significantly enabled the discovery of genetic causes of HNDs and also challenge paediatricians on applying genetic investigation. Combination of both clinical information and advanced technologies will enhance the genetic test yields in clinical setting. This review summarises the clinical presentations as well as genetic causes of paediatric neurological disorders in four major areas including movement disorders, neuropsychiatric disorders, neuron peripheral disorders and epilepsy. The aim of this review is to help paediatric neurologists not only to see the clinical features but also the complex genetic aspect of HNDs in order to utilise genetic investigation confidently in their clinical practice. A smooth transition from research based to clinical use of comprehensive genetic testing in HNDs in children could be foreseen in the near future while genetic testing, genetic counselling and genetic data interpretation are in place appropriately.

Population structure of elephant foot yams (Amorphophallus paeoniifolius (Dennst.) Nicolson) in Asia

PubMed Central

Misra, Raj Shekhar; Boonkorkaew, Patchareeya; Thanomchit, Kanokwan

2017-01-01

The corms and leaves of elephant foot yams (Amorphophallus paeoniifolius (Dennst.) Nicolson) are important foods in the local diet in many Asian regions. The crop has high productivity and wide agroecological adaptation and exhibits suitability for the agroforestry system. Although the plant is assumed to reproduce via panmixia, a comprehensive study on the genetic background across regions to enhance wider consumer palatability is still lacking. Here, ten informative microsatellites were analyzed in 29 populations across regions in India, Indonesia and Thailand to understand the genetic diversity, population structure and distribution to improve breeding and conservation programs. The genetic diversity was high among and within regions. Some populations exhibited excess heterozygosity and bottlenecking. Pairwise FST indicated very high genetic differentiation across regions (FST = 0.274), and the Asian population was unlikely to be panmictic. Phylogenetic tree construction grouped the populations according to country of origin with the exception of the Medan population from Indonesia. The current gene flow was apparent within the regions but was restricted among the regions. The present study revealed that Indonesia and Thailand populations could be alternative centers of the gene pool, together with India. Consequently, regional action should be incorporated in genetic conservation and breeding efforts to develop new varieties with global acceptance. PMID:28658282

Elaboration of the Reciprocal-Engagement Model of Genetic Counseling Practice: a Qualitative Investigation of Goals and Strategies.

PubMed

Redlinger-Grosse, Krista; Veach, Patricia McCarthy; LeRoy, Bonnie S; Zierhut, Heather

2017-12-01

As the genetic counseling field evolves, a comprehensive model of practice is critical. The Reciprocal-Engagement Model (REM) consists of 5 tenets and 17 goals. Lacking in the REM, however, are well-articulated counselor strategies and behaviors. The purpose of the present study was to further elaborate and provide supporting evidence for the REM by identifying and mapping genetic counseling strategies to the REM goals. A secondary, qualitative analysis was conducted on data from two prior studies: 1) focus group results of genetic counseling outcomes (Redlinger-Grosse et al., Journal of Genetic Counseling, 2015); and 2) genetic counselors' examples of successful and unsuccessful genetic counseling sessions (Geiser et al. 2009). Using directed content analysis, 337 unique strategies were extracted from focus group data. A Q-sort of the 337 strategies yielded 15 broader strategy domains that were then mapped to the successful and unsuccessful session examples. Differing prevalence of strategy domains identified in successful sessions versus the prevalence of domains identified as lacking in unsuccessful sessions provide further support for the REM goals. The most prevalent domains for successful sessions were Information Giving and Use Psychosocial Skills and Strategies; and for unsuccessful sessions, Information Giving and Establish Working Alliance. Identified strategies support the REM's reciprocal nature, especially with regard to addressing patients' informational and psychosocial needs. Patients' contributions to success (or lack thereof) of sessions was also noted, supporting a REM tenet that individual characteristics and the counselor-patient relationship are central to processes and outcomes. The elaborated REM could be used as a framework for certain graduate curricular objectives, and REM components could also inform process and outcomes research studies to document and further characterize genetic counselor strategies.

Host genetic variation impacts microbiome composition across human body sites.

PubMed

Blekhman, Ran; Goodrich, Julia K; Huang, Katherine; Sun, Qi; Bukowski, Robert; Bell, Jordana T; Spector, Timothy D; Keinan, Alon; Ley, Ruth E; Gevers, Dirk; Clark, Andrew G

2015-09-15

The composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While microbial communities are influenced by environmental factors, some degree of genetic influence of the host on the microbiome is also expected. This study is part of an expanding effort to comprehensively profile the interactions between human genetic variation and the composition of this microbial ecosystem on a genome- and microbiome-wide scale. Here, we jointly analyze the composition of the human microbiome and host genetic variation. By mining the shotgun metagenomic data from the Human Microbiome Project for host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using this dataset, we identify significant associations between host genetic variation and microbiome composition in 10 of the 15 body sites tested. These associations are driven by host genetic variation in immunity-related pathways, and are especially enriched in host genes that have been previously associated with microbiome-related complex diseases, such as inflammatory bowel disease and obesity-related disorders. Lastly, we show that host genomic regions associated with the microbiome have high levels of genetic differentiation among human populations, possibly indicating host genomic adaptation to environment-specific microbiomes. Our results highlight the role of host genetic variation in shaping the composition of the human microbiome, and provide a starting point toward understanding the complex interaction between human genetics and the microbiome in the context of human evolution and disease.

A bio-cultural approach to the study of food choice: The contribution of taste genetics, population and culture.

PubMed

Risso, Davide S; Giuliani, Cristina; Antinucci, Marco; Morini, Gabriella; Garagnani, Paolo; Tofanelli, Sergio; Luiselli, Donata

2017-07-01

The study of food choice, one of the most complex human traits, requires an integrated approach that takes into account environmental, socio-cultural and biological diversity. We recruited 183 volunteers from four geo-linguistic groups and highly diversified in terms of both genetic background and food habits from whom we collected genotypes and phenotypes tightly linked to taste perception. We confirmed previous genetic associations, in particular with stevioside perception, and noted significant differences in food consumption: in particular, broccoli, mustard and beer consumption scores were significantly higher (Adjusted P = 0.02, Adjusted P < 0.0001 and Adjusted P = 0.01, respectively) in North Europeans, when compared to the other groups. Licorice and Parmesan cheese showed lower consumption and liking scores in the Sri Lankan group (Adjusted P = 0.001 and Adjusted P < 0.001, respectively). We also highlighted how rs860170 (TAS2R16) strongly differentiated populations and was associated to salicin bitterness perception. Identifying genetic variants on chemosensory receptors that vary across populations and show associations with taste perception and food habits represents a step towards a better comprehension of this complex trait, aimed at improving the individual health status. This is the first study that concurrently explores the contribution of genetics, population diversity and cultural aspects in taste perception and food consumption. Published by Elsevier Ltd.

PGG.Population: a database for understanding the genomic diversity and genetic ancestry of human populations

PubMed Central

Zhang, Chao; Gao, Yang; Liu, Jiaojiao; Xue, Zhe; Lu, Yan; Deng, Lian; Tian, Lei; Feng, Qidi

2018-01-01

Abstract There are a growing number of studies focusing on delineating genetic variations that are associated with complex human traits and diseases due to recent advances in next-generation sequencing technologies. However, identifying and prioritizing disease-associated causal variants relies on understanding the distribution of genetic variations within and among populations. The PGG.Population database documents 7122 genomes representing 356 global populations from 107 countries and provides essential information for researchers to understand human genomic diversity and genetic ancestry. These data and information can facilitate the design of research studies and the interpretation of results of both evolutionary and medical studies involving human populations. The database is carefully maintained and constantly updated when new data are available. We included miscellaneous functions and a user-friendly graphical interface for visualization of genomic diversity, population relationships (genetic affinity), ancestral makeup, footprints of natural selection, and population history etc. Moreover, PGG.Population provides a useful feature for users to analyze data and visualize results in a dynamic style via online illustration. The long-term ambition of the PGG.Population, together with the joint efforts from other researchers who contribute their data to our database, is to create a comprehensive depository of geographic and ethnic variation of human genome, as well as a platform bringing influence on future practitioners of medicine and clinical investigators. PGG.Population is available at https://www.pggpopulation.org. PMID:29112749

Incidental and clinically actionable genetic variants in 1005 whole exomes and genomes from Qatar.

PubMed

Jain, Abhinav; Gandhi, Shrey; Koshy, Remya; Scaria, Vinod

2018-03-20

Incidental findings in genomic data have been studied in great detail in the recent years, especially from population-scale data sets. However, little is known about the frequency of such findings in ethnic groups, specifically the Middle East, which were not previously covered in global sequencing studies. The availability of whole exome and genome data sets for a highly consanguineous Arab population from Qatar motivated us to explore the incidental findings in this population-scale data. The sequence data of 1005 Qatari individuals were systematically analyzed for incidental genetic variants in the 59 genes suggested by the American College of Medical Genetics and Genomics. We identified four genetic variants which were pathogenic or likely pathogenic. These variants occurred in six individuals, suggesting a frequency of 0.59% in the population, much lesser than that previously reported from European and African populations. Our analysis identified a variant in RYR1 gene associated with Malignant Hyperthermia that has significantly higher frequency in the population compared to global frequencies. Evaluation of the allele frequencies of these variants suggested enrichment in sub-populations, especially in individuals of Sub-Saharan African ancestry. The present study thereby provides the information on pathogenicity and frequency, which could aid in genomic medicine. To the best of our knowledge, this is the first comprehensive analysis of incidental genetic findings in any Arab population and suggests ethnic differences in incidental findings.

Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil.

PubMed

Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; Santos, Patricia Koehler Dos; Ribeiro, Patricia Lisbôa Izetti; Oliveira, Cristina Brinkmann de Netto; Calvez-Kelm, Florence Le; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

2016-05-24

In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil.

Recommendations for Genetic Variation Data Capture in Developing Countries to Ensure a Comprehensive Worldwide Data Collection

PubMed Central

Patrinos, George P; Al Aama, Jumana; Al Aqeel, Aida; Al-Mulla, Fahd; Borg, Joseph; Devereux, Andrew; Felice, Alex E; Macrae, Finlay; Marafie, Makia J; Petersen, Michael B; Qi, Ming; Ramesar, Rajkumar S; Zlotogora, Joel; Cotton, Richard GH

2011-01-01

Developing countries have significantly contributed to the elucidation of the genetic basis of both common and rare disorders, providing an invaluable resource of cases due to large family sizes, consanguinity, and potential founder effects. Moreover, the recognized depth of genomic variation in indigenous African populations, reflecting the ancient origins of humanity on the African continent, and the effect of selection pressures on the genome, will be valuable in understanding the range of both pathological and nonpathological variations. The involvement of these populations in accurately documenting the extant genetic heterogeneity is more than essential. Developing nations are regarded as key contributors to the Human Variome Project (HVP; http://www.humanvariomeproject.org), a major effort to systematically collect mutations that contribute to or cause human disease and create a cyber infrastructure to tie databases together. However, biomedical research has not been the primary focus in these countries even though such activities are likely to produce economic and health benefits for all. Here, we propose several recommendations and guidelines to facilitate participation of developing countries in genetic variation data documentation, ensuring an accurate and comprehensive worldwide data collection. We also summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc. PMID:21089065

Initiative for standardization of reporting genetics of male infertility.

PubMed

Traven, Eva; Ogrinc, Ana; Kunej, Tanja

2017-02-01

The number of publications on research of male infertility is increasing. Technologies used in research of male infertility generate complex results and various types of data that need to be appropriately managed, arranged, and made available to other researchers for further use. In our previous study, we collected over 800 candidate loci for male fertility in seven mammalian species. However, the continuation of the work towards a comprehensive database of candidate genes associated with different types of idiopathic human male infertility is challenging due to fragmented information, obtained from a variety of technologies and various omics approaches. Results are published in different forms and usually need to be excavated from the text, which hinders the gathering of information. Standardized reporting of genetic anomalies as well as causative and risk factors of male infertility therefore presents an important issue. The aim of the study was to collect examples of diverse genomic loci published in association with human male infertility and to propose a standardized format for reporting genetic causes of male infertility. From the currently available data we have selected 75 studies reporting 186 representative genomic loci which have been proposed as genetic risk factors for male infertility. Based on collected and formatted data, we suggested a first step towards unification of reporting the genetics of male infertility in original and review studies. The proposed initiative consists of five relevant data types: 1) genetic locus, 2) race/ethnicity, number of participants (infertile/controls), 3) methodology, 4) phenotype (clinical data, disease ontology, and disease comorbidity), and 5) reference. The proposed form for standardized reporting presents a baseline for further optimization with additional genetic and clinical information. This data standardization initiative will enable faster multi-omics data integration, database development and sharing, establishing more targeted hypotheses, and facilitating biomarker discovery.

The Genetics of Osteosarcoma

PubMed Central

Martin, Jeff W.; Squire, Jeremy A.; Zielenska, Maria

2012-01-01

Osteosarcoma is a primary bone malignancy with a particularly high incidence rate in children and adolescents relative to other age groups. The etiology of this often aggressive cancer is currently unknown, because complicated structural and numeric genomic rearrangements in cancer cells preclude understanding of tumour development. In addition, few consistent genetic changes that may indicate effective molecular therapeutic targets have been reported. However, high-resolution techniques continue to improve knowledge of distinct areas of the genome that are more commonly associated with osteosarcomas. Copy number gains at chromosomes 1p, 1q, 6p, 8q, and 17p as well as copy number losses at chromosomes 3q, 6q, 9, 10, 13, 17p, and 18q have been detected by numerous groups, but definitive oncogenes or tumour suppressor genes remain elusive with respect to many loci. In this paper, we examine studies of the genetics of osteosarcoma to comprehensively describe the heterogeneity and complexity of this cancer. PMID:22685381

Complement dysregulation and disease: from genes and proteins to diagnostics and drugs.

PubMed

de Cordoba, Santiago Rodriguez; Tortajada, Agustin; Harris, Claire L; Morgan, B Paul

2012-11-01

During the last decade, numerous studies have associated genetic variations in complement components and regulators with a number of chronic and infectious diseases. The functional characterization of these complement protein variants, in addition to recent structural advances in understanding of the assembly, activation and regulation of the AP C3 convertase, have provided important insights into the pathogenic mechanisms involved in some of these complement related disorders. This knowledge has identified potential targets for complement inhibitory therapies which are demonstrating efficacy and generating considerable expectation in changing the natural history of these diseases. Comprehensive understanding of the genetic and non-genetic risk factors contributing to these disorders will also result in targeting of the right patient groups in a stratified medicine approach through better diagnostics and individually tailored treatments, thereby improving management of patients. Crown Copyright © 2012. Published by Elsevier GmbH. All rights reserved.

Molecular pathology and genetics of gastrointestinal neuroendocrine tumours.

PubMed

Lewis, Mark A; Yao, James C

2014-02-01

Neuroendocrine tumours (NETs) of the luminal gastrointestinal tract and pancreas are increasing in incidence and prevalence. Prior assumptions about the benign nature of 'carcinoids' and the clinical importance of distinguishing functional vs. nonfunctional tumours are being overturned through greater understanding of disease behaviour and heterogeneity. This review highlights the most contemporary genetic and molecular insights into gastroenteropancreatic NETs. Biomarkers such as neuron-specific enolase or chromogranin A could be supplemented or supplanted by PCR-based analysis of NET genes detectable in the blood transcriptome. Conventional pathology, including Ki67 testing, could be enhanced with immunohistochemistry and exome analysis. Prognostic markers and/or putative therapeutic targets uncovered through recent studies include heparanase, Id, ATM, SRC, EGFR, hsp90 and PDGFR. After a long-standing paucity of options for conventional cytotoxic therapy, the comprehension and treatment of gastroenteropancreatic NETs has been enriched by advancements in taxonomy, molecular pathology and genetic/epigenetic testing.

A new Notomastus (Annelida, Capitellidae) species from Korean waters, with genetic comparison based on three gene markers.

PubMed

Jeong, Man-Ki; Soh, Ho Young; Wi, Jin Hee; Suh, Hae-Lip

2018-01-01

Notomastus koreanus sp. n. , collected from the sublittoral muddy bottom of Korean waters, is described as a new species. The Korean new species closely resembles N. torquatus Hutchings & Rainer, 1979 in the chaetal arrangement and the details of abdominal segments, but differs in the position of genital pores and the absence of eyes. DNA sequences (mtCOI, 16S rRNA, and histone H3) of the new species were compared with all the available sequences of Notomastus species in the GenBank database. Three genes showed significant genetic differences between the new species and its congeners (COI: 51.2%, 16S: 38.1-47.3%, H3: 3.7-9.3%). This study also includes a comprehensive comparison of the new Korean Notomastus species with its most closely similar species, based on the morphological and genetic results.

Atopic Dermatitis and Comorbidities: Added Value of Comprehensive Dermatoepidemiology.

PubMed

Nijsten, Tamar

2017-05-01

Atopic dermatitis is common and in its severe form is devastating. This chronic inflammatory dermatosis is part of the atopic syndrome, which includes asthma, food allergies, and hay fever and is known to be associated with mental health disorders. In line with psoriasis, several recent observational studies using national survey and linkage data have suggested a link between atopic dermatitis and cardiovascular disease. The atopic dermatitis field can benefit from the past experiences in psoriasis research and should not follow the same path, but, rather, aim for a more comprehensive approach from the beginning. A recent German consortium studying links between atopic dermatitis and cardiovascular disease first screened a large claims database, followed by analyses of more deeply phenotyped (birth) cohorts with longitudinal data. In addition, genetic and metabolic analyses assessing the predisposition of patients with atopic dermatitis for cardiovascular disease were performed. Overall, the association between atopic dermatitis and cardiovascular disease was at most modest, but in more refined cohorts the cardiovascular risk profile and genetic architecture was comparable. A more integrated approach could create clarity about the clinical relevance of cardiovascular disease in individuals with atopic dermatitis sooner, avoid speculation that affects patient care, and save scientific resources. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Establishment of apoptotic regulatory network for genetic markers of colorectal cancer.

PubMed

Hao, Yibin; Shan, Guoyong; Nan, Kejun

2017-03-01

Our purpose is to screen out genetic markers applicable to early diagnosis for colorectal cancer and to establish apoptotic regulatory network model for colorectal cancer, thereby providing theoretical evidence and targeted therapy for early diagnosis of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers applied to early diagnosis of colorectal cancer were searched to perform comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to establish apoptotic regulatory network model based on screened genetic markers, and then verification experiment was conducted. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, p53, APC, DCC and PTEN, among which DCC shows highest diagnostic efficiency. GO analysis of genetic markers found that six genetic markers played role in biological process, molecular function and cellular component. It was indicated in apoptotic regulatory network built by KEGG analysis and verification experiment that WWOX could promote tumor cell apoptotic in colorectal cancer and elevate expression level of p53. The apoptotic regulatory model of colorectal cancer established in this study provides clinically theoretical evidence and targeted therapy for early diagnosis of colorectal cancer.

Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis.

PubMed

Taylor, Steven

2018-03-01

Catechol-O-methyltransferase (COMT) Val158Met is widely regarded as potentially important for understanding the genetic etiology of many different psychiatric disorders. The present study appears to be the first comprehensive meta-analysis of COMT genetic association studies to cover all psychiatric disorders for which there were available data, published in any language, and with an emphasis on investigating disorder subtypes (defined clinically or by demographic or other variables). Studies were included if they reported one or more datasets (i.e., some studies examined more than one clinical group) in which there were sufficient information to compute effect sizes. A total of 363 datasets were included, consisting of 56,998 cases and 74,668 healthy controls from case control studies, and 2,547 trios from family based studies. Fifteen disorders were included. Attention-deficit hyperactivity disorder and panic disorder were associated with the Val allele for Caucasian samples. Substance-use disorder, defined by DSM-IV criteria, was associated with the Val allele for Asian samples. Bipolar disorder was associated with the Met allele in Asian samples. Obsessive-compulsive disorder tended to be associated with the Met allele only for males. There was suggestive evidence that the Met allele is associated with an earlier age of onset of schizophrenia. Results suggest pleiotropy and underscore the importance of examining subgroups-defined by variables such as age of onset, sex, ethnicity, and diagnostic system-rather than examining disorders as monolithic constructs. © 2017 Wiley Periodicals, Inc.

Assessment of genetic diversity, population structure, and gene flow of tigers (Panthera tigris tigris) across Nepal's Terai Arc Landscape.

PubMed

Thapa, Kanchan; Manandhar, Sulochana; Bista, Manisha; Shakya, Jivan; Sah, Govind; Dhakal, Maheshwar; Sharma, Netra; Llewellyn, Bronwyn; Wultsch, Claudia; Waits, Lisette P; Kelly, Marcella J; Hero, Jean-Marc; Hughes, Jane; Karmacharya, Dibesh

2018-01-01

With fewer than 200 tigers (Panthera tigris tigris) left in Nepal, that are generally confined to five protected areas across the Terai Arc Landscape, genetic studies are needed to provide crucial information on diversity and connectivity for devising an effective country-wide tiger conservation strategy. As part of the Nepal Tiger Genome Project, we studied landscape change, genetic variation, population structure, and gene flow of tigers across the Terai Arc Landscape by conducting Nepal's first comprehensive and systematic scat-based, non-invasive genetic survey. Of the 770 scat samples collected opportunistically from five protected areas and six presumed corridors, 412 were tiger (57%). Out of ten microsatellite loci, we retain eight markers that were used in identifying 78 individual tigers. We used this dataset to examine population structure, genetic variation, contemporary gene flow, and potential population bottlenecks of tigers in Nepal. We detected three genetic clusters consistent with three demographic sub-populations and found moderate levels of genetic variation (He = 0.61, AR = 3.51) and genetic differentiation (FST = 0.14) across the landscape. We detected 3-7 migrants, confirming the potential for dispersal-mediated gene flow across the landscape. We found evidence of a bottleneck signature likely caused by large-scale land-use change documented in the last two centuries in the Terai forest. Securing tiger habitat including functional forest corridors is essential to enhance gene flow across the landscape and ensure long-term tiger survival. This requires cooperation among multiple stakeholders and careful conservation planning to prevent detrimental effects of anthropogenic activities on tigers.

Assessment of genetic diversity, population structure, and gene flow of tigers (Panthera tigris tigris) across Nepal's Terai Arc Landscape

PubMed Central

Manandhar, Sulochana; Bista, Manisha; Shakya, Jivan; Sah, Govind; Dhakal, Maheshwar; Sharma, Netra; Llewellyn, Bronwyn; Wultsch, Claudia; Waits, Lisette P.; Kelly, Marcella J.; Hero, Jean-Marc; Hughes, Jane

2018-01-01

With fewer than 200 tigers (Panthera tigris tigris) left in Nepal, that are generally confined to five protected areas across the Terai Arc Landscape, genetic studies are needed to provide crucial information on diversity and connectivity for devising an effective country-wide tiger conservation strategy. As part of the Nepal Tiger Genome Project, we studied landscape change, genetic variation, population structure, and gene flow of tigers across the Terai Arc Landscape by conducting Nepal’s first comprehensive and systematic scat-based, non-invasive genetic survey. Of the 770 scat samples collected opportunistically from five protected areas and six presumed corridors, 412 were tiger (57%). Out of ten microsatellite loci, we retain eight markers that were used in identifying 78 individual tigers. We used this dataset to examine population structure, genetic variation, contemporary gene flow, and potential population bottlenecks of tigers in Nepal. We detected three genetic clusters consistent with three demographic sub-populations and found moderate levels of genetic variation (He = 0.61, AR = 3.51) and genetic differentiation (FST = 0.14) across the landscape. We detected 3–7 migrants, confirming the potential for dispersal-mediated gene flow across the landscape. We found evidence of a bottleneck signature likely caused by large-scale land-use change documented in the last two centuries in the Terai forest. Securing tiger habitat including functional forest corridors is essential to enhance gene flow across the landscape and ensure long-term tiger survival. This requires cooperation among multiple stakeholders and careful conservation planning to prevent detrimental effects of anthropogenic activities on tigers. PMID:29561865

[Development, problems and results of specialty-specific genetic counseling at the Neurology Clinic of the Karl Marx University].

PubMed

Bachmann, H

1987-11-01

Genetic counselling for inherited neurological diseases has been established at the Clinic for Neurology of Karl Marx University. Comprehensive experiences have been got with the specific and sometimes markedly different problems and aims of counselling in Wilsons disease, X-linked recessive muscular dystrophies, myotonic dystrophy and other neuromuscular disorders, Huntingtons chorea and hereditary ataxias.

Diagnosing Autism in Individuals with Known Genetic Syndromes: Clinical Considerations and Implications for Intervention

PubMed Central

Hepburn, Susan L.; Moody, Eric J.

2015-01-01

Assessing symptoms of autism in persons with known genetic syndromes associated with intellectual and/or developmental disability is a complex clinical endeavor. We suggest that a developmental approach to evaluation is essential to reliably teasing apart global impairments from autism-specific symptomology. In this chapter, we discuss our assumptions about autism spectrum disorders, the process of conducting a family-focused, comprehensive evaluation with behaviorally complex children and some implications for intervention in persons with co-occurring autism and known genetic syndromes. PMID:26269783

A global interaction network maps a wiring diagram of cellular function

PubMed Central

Costanzo, Michael; VanderSluis, Benjamin; Koch, Elizabeth N.; Baryshnikova, Anastasia; Pons, Carles; Tan, Guihong; Wang, Wen; Usaj, Matej; Hanchard, Julia; Lee, Susan D.; Pelechano, Vicent; Styles, Erin B.; Billmann, Maximilian; van Leeuwen, Jolanda; van Dyk, Nydia; Lin, Zhen-Yuan; Kuzmin, Elena; Nelson, Justin; Piotrowski, Jeff S.; Srikumar, Tharan; Bahr, Sondra; Chen, Yiqun; Deshpande, Raamesh; Kurat, Christoph F.; Li, Sheena C.; Li, Zhijian; Usaj, Mojca Mattiazzi; Okada, Hiroki; Pascoe, Natasha; Luis, Bryan-Joseph San; Sharifpoor, Sara; Shuteriqi, Emira; Simpkins, Scott W.; Snider, Jamie; Suresh, Harsha Garadi; Tan, Yizhao; Zhu, Hongwei; Malod-Dognin, Noel; Janjic, Vuk; Przulj, Natasa; Troyanskaya, Olga G.; Stagljar, Igor; Xia, Tian; Ohya, Yoshikazu; Gingras, Anne-Claude; Raught, Brian; Boutros, Michael; Steinmetz, Lars M.; Moore, Claire L.; Rosebrock, Adam P.; Caudy, Amy A.; Myers, Chad L.; Andrews, Brenda; Boone, Charles

2017-01-01

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell. PMID:27708008

In vivo cell biology in zebrafish - providing insights into vertebrate development and disease.

PubMed

Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie; Mione, Marina; Knapik, Ela W; Sadler, Kirsten C

2014-02-01

Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease.

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

PubMed Central

Shaheen, Ranad; Faqeih, Eissa; Alshammari, Muneera J; Swaid, Abdulrahman; Al-Gazali, Lihadh; Mardawi, Elham; Ansari, Shinu; Sogaty, Sameera; Seidahmed, Mohammed Z; AlMotairi, Muhammed I; Farra, Chantal; Kurdi, Wesam; Al-Rasheed, Shatha; Alkuraya, Fowzan S

2013-01-01

Meckel–Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis–van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population. PMID:23169490

Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.

PubMed

Shapiro, Lucy; Chatterjee, Sumana; Ramadan, Dina G; Davies, Kate M; Savage, Martin O; Metherell, Louise A; Storr, Helen L

2017-12-01

GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres. © 2017 European Society of Endocrinology.

Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.

PubMed

Abou-El-Ardat, Khalil; Seifert, Michael; Becker, Kerstin; Eisenreich, Sophie; Lehmann, Matthias; Hackmann, Karl; Rump, Andreas; Meijer, Gerrit; Carvalho, Beatriz; Temme, Achim; Schackert, Gabriele; Schröck, Evelin; Krex, Dietmar; Klink, Barbara

2017-04-01

The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Comprehension and Data-Sharing Behavior of Direct-To-Consumer Genetic Test Customers.

PubMed

McGrath, Scott P; Coleman, Jason; Najjar, Lotfollah; Fruhling, Ann; Bastola, Dhundy R

2016-01-01

The aim of this study was to evaluate current direct-to-consumer (DTC) genetic customers' ability to interpret and comprehend test results and to determine if honest brokers are needed. One hundred and twenty-two customers of the DTC genetic testing company 23andMe were polled in an online survey. The subjects were asked about their personal test results and to interpret the results of two mock test cases (type 2 diabetes and multiple sclerosis), where results were translated into disease probability for an individual compared to the public. When asked to evaluate the risk, 72.1% correctly assessed the first case and 77% were correct on the second case. Only 23.8% of those surveyed were able to interpret both cases correctly. x03C7;2 and logistic regression were used to interpret the results. Participants who took the time to read the DTC test-provided supplemental material were 3.93 times (p = 0.040) more likely to correctly interpret the test results than those who did not. The odds for correctly interpreting the test cases were 3.289 times (p = 0.011) higher for those who made more than USD 50,000 than those who made less. Survey results were compared to the Health Information National Trends Survey (HINTS) phase 4 cycle 3 data to evaluate national trends. Most of the subjects were able to correctly interpret the test cases, yet a majority did not share their results with a health-care professional. As the market for DTC genetic testing grows, test comprehension will become more critical. Involving more health professionals in this process may be necessary to ensure proper interpretations. © 2016 S. Karger AG, Basel.

Reading Self-Perceived Ability, Enjoyment and Achievement: A Genetically Informative Study of Their Reciprocal Links Over Time

PubMed Central

2017-01-01

Extant literature has established a consistent association between aspects of reading motivation, such as enjoyment and self-perceived ability, and reading achievement, in that more motivated readers are generally more skilled readers. However, the developmental etiology of this relation is yet to be investigated. The present study explores the development of the motivation–achievement association and its genetic and environmental underpinnings. Applying cross-lagged design in a sample of 13,825 twins, we examined the relative contribution of genetic and environmental factors to the association between reading enjoyment and self-perceived ability and reading achievement. Children completed a reading comprehension task and self-reported their reading enjoyment and perceived ability twice in middle childhood: when they were 9–10 and 12 years old. Results showed a modest reciprocal association over time between reading motivation (enjoyment and perceived ability) and reading achievement. Reading motivation at age 9–10 statistically predicted the development of later achievement, and similarly, reading achievement at age 9–10 predicted the development of later motivation. This reciprocal association was observed beyond the stability of the variables and their contemporaneous correlation and was largely explained by genetic factors. PMID:28333527

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fahrenkrog, Annette M.; Neves, Leandro G.; Resende, Jr., Marcio F. R.

Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genesmore » in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. Lastly, these polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.« less

Potassium Channels in Epilepsy

PubMed Central

Köhling, Rüdiger; Wolfart, Jakob

2016-01-01

This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With ∼80 potassium channel types, of which ∼10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. PMID:27141079

NR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysis.

PubMed

Liu, Hongmei; Liu, Hongbo; Li, Ting; Cui, Jiayi; Fu, Yingmei; Ren, Juanjuan; Sun, Xiujia; Jiang, Ping; Yu, Shunying; Li, Chunbo

2017-05-22

The homo sapiens nuclear receptor subfamily 4, group A (NR4A2) genetic variation has been implicated as a risk factor for Parkinson's disease (PD). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-analysis to quantify the impact of NR4A2 variation on the risk of PD. All eligible case-control studies published up to June 2016 by searching Pubmed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of the association in fixed- or random-effects model. Eighteen studies reported 24 genetic variants with a total of 6150 cases and 5919 controls were included. Twelve studies for NR4A2 rs35479735 polymorphism and 4 studies for rs12803 were available for meta-analysis. A significant association was observed for rs35479735 under the homozygous model (OR=1.31, 95% CI: 1.10-1.56, P=0.003), whereas no significant association for rs12803 was detected. In subgroup analysis stratified by ethnicity, age onset and familial history, we found no significant association except one in sporadic PD subgroup under the recessive (OR=3.30, 95% CI: 1.23-8.84, P=0.02) and homozygous model (OR=3.43, 95% CI: 1.26-9.33, P=0.02) for rs35479735. The study comprehensively evaluated the association of NR4A2 variation with PD, and the results failed to demonstrate that the NR4A2 polymorphisms significantly associated with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

High-Level Genetic Diversity and Complex Population Structure of Siberian Apricot (Prunus sibirica L.) in China as Revealed by Nuclear SSR Markers

PubMed Central

Wang, Zhe; Kang, Ming; Liu, Huabo; Gao, Jiao; Zhang, Zhengdong; Li, Yingyue; Wu, Rongling; Pang, Xiaoming

2014-01-01

Siberian apricot (Prunus sibirica L.), an ecologically and economically important tree species with a high degree of tolerance to a variety of extreme environmental conditions, is widely distributed across the mountains of northeastern and northern China, eastern and southeastern regions of Mongolia, Eastern Siberia, and the Maritime Territory of Russia. However, few studies have examined the genetic diversity and population structure of this species. Using 31 nuclear microsatellites, we investigated the level of genetic diversity and population structure of Siberian apricot sampled from 22 populations across China. The number of alleles per locus ranged from 5 to 33, with an average of 19.323 alleles. The observed heterozygosity and expected heterozygosity ranged from 0.037 to 0.874 and 0.040 to 0.924 with average values of 0.639 and 0.774, respectively. A STRUCTURE-based analysis clustered all of the populations into four genetic clusters. Significant genetic differentiation was observed between all population pairs. A hierarchical analysis of molecular variance attributed about 94% of the variation to within populations. No significant difference was detected between the wild and semi-wild groups, indicating that recent cultivation practices have had little impact on the genetic diversity of Siberian apricot. The Mantel test showed that the genetic distance among the populations was not significantly correlated with geographic distance (r = 0.4651, p = 0.9940). Our study represents the most comprehensive investigation of the genetic diversity and population structure of Siberian apricot in China to date, and it provides valuable information for the collection of genetic resources for the breeding of Siberian apricot and related species. PMID:24516551

High-Risk Palliative Care Patients' Knowledge and Attitudes about Hereditary Cancer Testing and DNA Banking.

PubMed

Quillin, John M; Emidio, Oluwabunmi; Ma, Brittany; Bailey, Lauryn; Smith, Thomas J; Kang, In Guk; Yu, Brandon J; Owodunni, Oluwafemi Patrick; Abusamaan, Mohammed; Razzak, Rab; Bodurtha, Joann N

2017-12-04

Even at the end of life, testing cancer patients for inherited susceptibility may provide life-saving information to their relatives. Prior research suggests palliative care inpatients have suboptimal understanding of genetic importance, and testing may be underutilized in this clinical setting. These conclusions are based on limited research. This study aimed to estimate genetic testing prevalence among high-risk palliative care patients in a National Cancer Institute-designated comprehensive cancer center. We also aimed to understand these patients' understanding of, and attitudes toward, hereditary cancer testing and DNA banking. Palliative care in-patients with cancer completed structured interviews, and their medical records were reviewed. Among patients at high risk for hereditary cancer, we assessed history of genetic testing/DNA banking; and related knowledge and attitudes. Among 24 high-risk patients, 14 (58.3%) said they/their relatives had genetic testing or they had been referred for a genetics consultation. Of the remaining 10 patients, seven (70%) said they would "probably" or "definitely" get tested. Patients who had not had testing were least concerned about the impact of future testing on their family relationships; two (20%) said they were "extremely concerned" about privacy related to genetic testing. Of patients without prior testing, five (50%) said they had heard or read "a fair amount" about genetic testing. No high-risk patients had banked DNA. Overall, 23 (95.8%) said they had heard or read "almost nothing" or "relatively little" about DNA banking. Written materials and clinician discussion were most preferred ways to learn about genetic testing and DNA banking. Overall, this study demonstrates underutilization of genetics services at the end of life continues to be problematic, despite high patient interest.

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

PubMed Central

Fogel, Brent L.; Lee, Hane; Deignan, Joshua L.; Strom, Samuel P.; Kantarci, Sibel; Wang, Xizhe; Quintero-Rivera, Fabiola; Vilain, Eric; Grody, Wayne W.; Perlman, Susan; Geschwind, Daniel H.; Nelson, Stanley F.

2015-01-01

IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia. PMID:25133958

The current state of play on the molecular genetics of depression.

PubMed

Cohen-Woods, S; Craig, I W; McGuffin, P

2013-04-01

It has been well established that both genes and non-shared environment contribute substantially to the underlying aetiology of major depressive disorder (MDD). A comprehensive overview of genetic research in MDD is presented. Method Papers were retrieved from PubMed up to December 2011, using many keywords including: depression, major depressive disorder, genetics, rare variants, gene-environment, whole genome, epigenetics, and specific candidate genes and variants. These were combined in a variety of permutations. Linkage studies have yielded some promising chromosomal regions in MDD. However, there is a continued lack of consistency in association studies, in both candidate gene and genome-wide association studies (GWAS). Numerous factors may account for variable results including the use of different diagnostic approaches, small samples in early studies, population stratification, epigenetic phenomena, copy number variation (CNV), rare variation, and phenotypic and allelic heterogeneity. The conflicting results are also probably, in part, a consequence of environmental factors not being considered or controlled for. Each research group has to identify what issues their sample may best address. We suggest that, where possible, more emphasis should be placed on the environment in molecular behavioural genetics to identify individuals at environmental high risk in addition to genetic high risk. Sequencing should be used to identify rare and alternative variation that may act as a risk factor, and a systems biology approach including gene-gene interactions and pathway analyses would be advantageous. GWAS may require even larger samples with reliably defined (sub)phenotypes.

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach.

PubMed

Giardine, Belinda; Borg, Joseph; Higgs, Douglas R; Peterson, Kenneth R; Philipsen, Sjaak; Maglott, Donna; Singleton, Belinda K; Anstee, David J; Basak, A Nazli; Clark, Barnaby; Costa, Flavia C; Faustino, Paula; Fedosyuk, Halyna; Felice, Alex E; Francina, Alain; Galanello, Renzo; Gallivan, Monica V E; Georgitsi, Marianthi; Gibbons, Richard J; Giordano, Piero C; Harteveld, Cornelis L; Hoyer, James D; Jarvis, Martin; Joly, Philippe; Kanavakis, Emmanuel; Kollia, Panagoula; Menzel, Stephan; Miller, Webb; Moradkhani, Kamran; Old, John; Papachatzopoulou, Adamantia; Papadakis, Manoussos N; Papadopoulos, Petros; Pavlovic, Sonja; Perseu, Lucia; Radmilovic, Milena; Riemer, Cathy; Satta, Stefania; Schrijver, Iris; Stojiljkovic, Maja; Thein, Swee Lay; Traeger-Synodinos, Jan; Tully, Ray; Wada, Takahito; Waye, John S; Wiemann, Claudia; Zukic, Branka; Chui, David H K; Wajcman, Henri; Hardison, Ross C; Patrinos, George P

2011-03-20

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.

The genomic era and serious mental illness: a potential application for psychiatric genetic counseling.

PubMed

Austin, Jehannine C; Honer, William G

2007-02-01

Genetic counseling is an important clinical service that is routinely offered to families affected by genetic disorders or by complex disorders for which genetic testing is available. It is not yet routinely offered to individuals with serious mental illnesses and their families, but recent findings that beliefs about the cause of mental illness can affect an individual's adaptation to the illness suggest that genetic counseling may be a useful intervention for this population. In a genetic counseling session the counselor discusses genetic and environmental contributors to disease pathogenesis; helps individuals explore conceptions, fears, and adaptive strategies; and provides nondirective support for decision making. Expected outcomes may include reductions in fear, stigma, and guilt associated with a psychiatric diagnosis; improvements in adherence to prescribed medications; declines in risk behaviors; and reductions in misconceptions about the illness. The authors endorse a multidisciplinary approach in which a psychiatrist and genetic counselor collaborate to provide comprehensive psychiatric genetic counseling.

[Evolutionary process unveiled by the maximum genetic diversity hypothesis].

PubMed

Huang, Yi-Min; Xia, Meng-Ying; Huang, Shi

2013-05-01

As two major popular theories to explain evolutionary facts, the neutral theory and Neo-Darwinism, despite their proven virtues in certain areas, still fail to offer comprehensive explanations to such fundamental evolutionary phenomena as the genetic equidistance result, abundant overlap sites, increase in complexity over time, incomplete understanding of genetic diversity, and inconsistencies with fossil and archaeological records. Maximum genetic diversity hypothesis (MGD), however, constructs a more complete evolutionary genetics theory that incorporates all of the proven virtues of existing theories and adds to them the novel concept of a maximum or optimum limit on genetic distance or diversity. It has yet to meet a contradiction and explained for the first time the half-century old Genetic Equidistance phenomenon as well as most other major evolutionary facts. It provides practical and quantitative ways of studying complexity. Molecular interpretation using MGD-based methods reveal novel insights on the origins of humans and other primates that are consistent with fossil evidence and common sense, and reestablished the important role of China in the evolution of humans. MGD theory has also uncovered an important genetic mechanism in the construction of complex traits and the pathogenesis of complex diseases. We here made a series of sequence comparisons among yeasts, fishes and primates to illustrate the concept of limit on genetic distance. The idea of limit or optimum is in line with the yin-yang paradigm in the traditional Chinese view of the universal creative law in nature.

Genetic and Environmental Influences on Writing and their Relations to Language and Reading

PubMed Central

Olson, Richard K.; Hulslander, Jacqueline; Christopher, Micaela; Keenan, Janice M.; Wadsworth, Sally J.; Willcutt, Erik G.; Pennington, Bruce F.; DeFries, John C.

2011-01-01

Identical and fraternal twins (N = 540, age 8 to 18 years) were tested on three different measures of writing (Woodcock-Johnson III Tests of Achievement-Writing Samples and Writing Fluency; Handwriting Copy from the Group Diagnostic Reading and Aptitude Achievement Tests), three different language skills (Phonological Awareness, Rapid Naming, and Vocabulary), and three different reading skills (Word Recognition, Spelling, and Reading Comprehension). Substantial genetic influence was found on two of the writing measures, Writing Samples and Handwriting Copy, and all of the language and reading measures. Shared environment influences were generally not significant, except for vocabulary. Non-shared environment estimates, including measurement error, were significant for all variables. Genetic influences among the writing measures were significantly correlated (highest between the speeded measures Writing Fluency and Handwriting Copy), but there were also significant independent genetic influences between Copy and Samples and between Fluency and Samples. Genetic influences on writing were significantly correlated with genetic influences on all of the language and reading skills, but significant independent genetic influences were also found for Copy and Samples, whose genetic correlations were significantly less than 1.0 with the reading and language skills. The genetic correlations varied significantly in strength depending on the overlap between the writing, language, and reading task demands. We discuss implications of our results for education, limitations of the study, and new directions for research on writing and its relations to language and reading. PMID:21842316

From degeneration to genetic susceptibility, from eugenics to genethics, from Bezugsziffer to LOD score: the history of psychiatric genetics.

PubMed

Schulze, Thomas G; Fangerau, Heiner; Propping, Peter

2004-11-01

Reviewing the history of psychiatric genetics is a difficult task, since--in contrast to genetic research into most other disorders--it cannot simply be done by chronologically listing methodological achievements and major findings. Instead, it necessitates a comprehensive assessment of how the aetiological concept of mental disorders has developed since as early as the world of ancient Greece. Furthermore, it has to touch upon the sensitive issue of the eugenic movement that was closely linked to the study of heredity in mental disorders in the first half of the 20th century and, in Nazi Germany, led to the systematic mass murder of psychiatric patients. Finally, reviewing the scientific dimensions, history of psychiatric genetics is at the same time a walk through the history of complex genetics in general. In our review, we try to pay tribute to this complexity. We argue that psychiatric genetics has not only propelled our understanding of mental disorders but has significantly benefited genetic research into other complex disorders through the development of methodologically robust approaches (e.g., systematic phenotype characterisation, methods to control for ascertainment biases, age-correction). Given the recent reasons for new optimism, i.e., the identification of susceptibility genes for psychiatric phenotypes, a continued methodologically sound approach is needed more than ever to guarantee robust results. Finally, psychiatric genetic research should never again be performed in an environment void of ethical standards.

Genome-wide association study reveals putative regulators of bioenergy traits in Populus deltoides

DOE PAGES

Fahrenkrog, Annette M.; Neves, Leandro G.; Resende, Jr., Marcio F. R.; ...

2016-09-06

Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genesmore » in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. Lastly, these polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.« less

Insights to the Genetics of Diabetic Nephropathy through a Genome-wide Association Study of the GoKinD Collection

PubMed Central

Pezzolesi, Marcus G.; Skupien, Jan; Krolewski, Andrzej S.

2010-01-01

The Genetics of Kidneys in Diabetes (GoKinD) study was initiated to facilitate research aimed at identifying genes involved in diabetic nephropathy (DN) in type 1 diabetes (T1D). In this review, we present on overview of this study and the various reports that have utilized its collection. At the forefront of these efforts is the recent genome-wide association (GWA) scan implemented on the GoKinD collection. We highlight the results from our analysis of these data and describe compelling evidence from animal models that further support the potential role of associated loci in the susceptibility of DN. To enhance our analysis of genetic associations in GoKinD, using genome-wide imputation (GWI), we expanded our analysis of this collection to include genotype data from more than 2.4 million common SNPs. We illustrate the added utility of this enhanced dataset through the comprehensive fine-mapping of candidate genomic regions previously linked with DN and the targeted investigation of genes involved in candidate pathway implicated in its pathogenesis. Collectively, GWA and GWI data from the GoKinD collection will serve as a springboard for future investigations into the genetic basis of DN in T1D. PMID:20347642

Genome-wide genetic variation and comparison of fruit-associated traits between kumquat (Citrus japonica) and Clementine mandarin (Citrus clementina).

PubMed

Liu, Tian-Jia; Li, Yong-Ping; Zhou, Jing-Jing; Hu, Chun-Gen; Zhang, Jin-Zhi

2018-03-01

The comprehensive genetic variation of two citrus species were analyzed at genome and transcriptome level. A total of 1090 differentially expressed genes were found during fruit development by RNA-sequencing. Fruit size (fruit equatorial diameter) and weight (fresh weight) are the two most important components determining yield and consumer acceptability for many horticultural crops. However, little is known about the genetic control of these traits. Here, we performed whole-genome resequencing to reveal the comprehensive genetic variation of the fruit development between kumquat (Citrus japonica) and Clementine mandarin (Citrus clementina). In total, 5,865,235 single-nucleotide polymorphisms (SNPs) and 414,447 insertions/deletions (InDels) were identified in the two citrus species. Based on integrative analysis of genome and transcriptome of fruit, 640,801 SNPs and 20,733 InDels were identified. The features, genomic distribution, functional effect, and other characteristics of these genetic variations were explored. RNA-sequencing identified 1090 differentially expressed genes (DEGs) during fruit development of kumquat and Clementine mandarin. Gene Ontology revealed that these genes were involved in various molecular functional and biological processes. In addition, the genetic variation of 939 DEGs and 74 multiple fruit development pathway genes from previous reports were also identified. A global survey identified 24,237 specific alternative splicing events in the two citrus species and showed that intron retention is the most prevalent pattern of alternative splicing. These genome variation data provide a foundation for further exploration of citrus diversity and gene-phenotype relationships and for future research on molecular breeding to improve kumquat, Clementine mandarin and related species.

Targetable genetic features of primary testicular and primary central nervous system lymphomas

PubMed Central

Chapuy, Bjoern; Roemer, Margaretha G. M.; Stewart, Chip; Tan, Yuxiang; Abo, Ryan P.; Zhang, Liye; Dunford, Andrew J.; Meredith, David M.; Thorner, Aaron R.; Jordanova, Ekaterina S.; Liu, Gang; Feuerhake, Friedrich; Ducar, Matthew D.; Illerhaus, Gerald; Gusenleitner, Daniel; Linden, Erica A.; Sun, Heather H.; Homer, Heather; Aono, Miyuki; Pinkus, Geraldine S.; Ligon, Azra H.; Ligon, Keith L.; Ferry, Judith A.; Freeman, Gordon J.; van Hummelen, Paul; Golub, Todd R.; Getz, Gad; Rodig, Scott J.; de Jong, Daphne; Monti, Stefano

2016-01-01

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. PMID:26702065

Gene-Environment Interactions in Cardiovascular Disease

PubMed Central

Flowers, Elena; Froelicher, Erika Sivarajan; Aouizerat, Bradley E.

2011-01-01

Background Historically, models to describe disease were exclusively nature-based or nurture-based. Current theoretical models for complex conditions such as cardiovascular disease acknowledge the importance of both biologic and non-biologic contributors to disease. A critical feature is the occurrence of interactions between numerous risk factors for disease. The interaction between genetic (i.e. biologic, nature) and environmental (i.e. non-biologic, nurture) causes of disease is an important mechanism for understanding both the etiology and public health impact of cardiovascular disease. Objectives The purpose of this paper is to describe theoretical underpinnings of gene-environment interactions, models of interaction, methods for studying gene-environment interactions, and the related concept of interactions between epigenetic mechanisms and the environment. Discussion Advances in methods for measurement of genetic predictors of disease have enabled an increasingly comprehensive understanding of the causes of disease. In order to fully describe the effects of genetic predictors of disease, it is necessary to place genetic predictors within the context of known environmental risk factors. The additive or multiplicative effect of the interaction between genetic and environmental risk factors is often greater than the contribution of either risk factor alone. PMID:21684212

New Genetic and Linguistic Analyses Show Ancient Human Influence on Baobab Evolution and Distribution in Australia

PubMed Central

Rangan, Haripriya; Bell, Karen L.; Baum, David A.; Fowler, Rachael; McConvell, Patrick; Saunders, Thomas; Spronck, Stef; Kull, Christian A.; Murphy, Daniel J.

2015-01-01

This study investigates the role of human agency in the gene flow and geographical distribution of the Australian baobab, Adansonia gregorii. The genus Adansonia is a charismatic tree endemic to Africa, Madagascar, and northwest Australia that has long been valued by humans for its multiple uses. The distribution of genetic variation in baobabs in Africa has been partially attributed to human-mediated dispersal over millennia, but this relationship has never been investigated for the Australian species. We combined genetic and linguistic data to analyse geographic patterns of gene flow and movement of word-forms for A. gregorii in the Aboriginal languages of northwest Australia. Comprehensive assessment of genetic diversity showed weak geographic structure and high gene flow. Of potential dispersal vectors, humans were identified as most likely to have enabled gene flow across biogeographic barriers in northwest Australia. Genetic-linguistic analysis demonstrated congruence of gene flow patterns and directional movement of Aboriginal loanwords for A. gregorii. These findings, along with previous archaeobotanical evidence from the Late Pleistocene and Holocene, suggest that ancient humans significantly influenced the geographic distribution of Adansonia in northwest Australia. PMID:25830225

Large-scale discovery of novel genetic causes of developmental disorders.

PubMed

2015-03-12

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Differential detection of genetic Loci underlying stem and root lignin content in Populus.

PubMed

Yin, Tongming; Zhang, Xinye; Gunter, Lee; Priya, Ranjan; Sykes, Robert; Davis, Mark; Wullschleger, Stan D; Tuskan, Gerald A

2010-11-22

In this study, we established a comprehensive genetic map with a large number of progeny from a three-generation hybrid Populus intercross, and phenotyped the lignin content, S/G ratio and 28 cell wall subcomponents both in stems and roots for the mapping individuals. Phenotypic analysis revealed that lignin content and syringyl-to-guaiacyl (S/G) ratio using pyrolysis molecular beam mass spectroscopy (pyMBMS) varied among mapping individuals. Phenotypic analysis revealed that stem lignin content is significantly higher than that in root and the quantified traits can be classified into four distinct groups, with strong correlations observed among components within organs. Altogether, 179 coordinating QTLs were detected, and they were co-localized into 49 genetic loci, 27 of which appear to be pleiotropic. Many of the detected genetic loci were detected differentially in stem and root. This is the first report of separate genetic loci controlling cell wall phenotypes above and below ground. These results suggest that it may be possible to modify lignin content and composition via breed and/or engineer as a means of simultaneously improving Populus for cellulosic ethanol production and carbon sequestration.

The role of medical libraries in undergraduate education: a case study in genetics*

PubMed Central

Tennant, Michele R.; Miyamoto, Michael M.

2002-01-01

Between 1996 and 2001, the Health Science Center Libraries and Department of Zoology at the University of Florida partnered to provide a cohesive and comprehensive learning experience to undergraduate students in PCB3063, “Genetics.” During one semester each year, a librarian worked with up to 120 undergraduates, providing bibliographic and database instruction in the tools that practicing geneticists use (MEDLINE, GenBank, BLAST, etc.). Students learned to evaluate and synthesize the information that they retrieved, coupling it with information provided in classroom lectures, thus resulting in well-researched short papers on an assigned genetics topic. Exit surveys of students indicated that the majority found the library sessions and librarian's instruction to be useful. Responses also indicated that the project facilitated increased understanding of genetics concepts and appreciation for the scientific research process and the relevance of genetics to the real world. The library benefited from this partnership on a variety of fronts, including the development of skilled library users, pretrained future clientele, and increased visibility among campus research laboratories. The course and associated information instruction and assigned projects can be considered models for course-integrated instruction and the role of medical libraries in undergraduate education. PMID:11999176

Interactions between genetic variation and cellular environment in skeletal muscle gene expression.

PubMed

Taylor, D Leland; Knowles, David A; Scott, Laura J; Ramirez, Andrea H; Casale, Francesco Paolo; Wolford, Brooke N; Guan, Li; Varshney, Arushi; Albanus, Ricardo D'Oliveira; Parker, Stephen C J; Narisu, Narisu; Chines, Peter S; Erdos, Michael R; Welch, Ryan P; Kinnunen, Leena; Saramies, Jouko; Sundvall, Jouko; Lakka, Timo A; Laakso, Markku; Tuomilehto, Jaakko; Koistinen, Heikki A; Stegle, Oliver; Boehnke, Michael; Birney, Ewan; Collins, Francis S

2018-01-01

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.

Comprehensive view of the population history of Arabia as inferred by mtDNA variation.

PubMed

Černý, Viktor; Čížková, Martina; Poloni, Estella S; Al-Meeri, Ali; Mulligan, Connie J

2016-04-01

Genetic and archaeological research supports the theory that Arabia was the first region traversed by modern humans as they left Africa and dispersed throughout Eurasia. However, the role of Arabia from the initial migration out of Africa until more recent times is still unclear. We have generated 379 new hypervariable segment 1 (HVS-1) sequences from a range of geographic locations throughout Yemen. We compare these data to published HVS-1 sequences representing Arabia and neighboring regions to build a unique dataset of 186 populations and 14,290 sequences. We identify 4,563 haplotypes unevenly distributed across Arabia and neighboring regions. Arabia contains higher proportions of shared haplotypes than the regions with which it shares these haplotypes, suggesting high levels of migration through the region. Populations in Arabia show higher levels of population expansion than those in East Africa, but lower levels than the Near East, Middle East or India. Arabian populations also show very high levels of genetic variation that overlaps with variation from most other regions. We take a population genetics approach to provide a comprehensive view of the relationships of Arabian and neighboring populations. We show that Arabian populations share closest links to the Near East and North Africa, but have a more ancient origin with slower demographic growth and/or lower migration rates. Our conclusions are supported by phylogenetic studies but also suggest that recent migrations have erased signals of earlier events. © 2015 Wiley Periodicals, Inc.

Towards pathogenomics: a web-based resource for pathogenicity islands

PubMed Central

Yoon, Sung Ho; Park, Young-Kyu; Lee, Soohyun; Choi, Doil; Oh, Tae Kwang; Hur, Cheol-Goo; Kim, Jihyun F.

2007-01-01

Pathogenicity islands (PAIs) are genetic elements whose products are essential to the process of disease development. They have been horizontally (laterally) transferred from other microbes and are important in evolution of pathogenesis. In this study, a comprehensive database and search engines specialized for PAIs were established. The pathogenicity island database (PAIDB) is a comprehensive relational database of all the reported PAIs and potential PAI regions which were predicted by a method that combines feature-based analysis and similarity-based analysis. Also, using the PAI Finder search application, a multi-sequence query can be analyzed onsite for the presence of potential PAIs. As of April 2006, PAIDB contains 112 types of PAIs and 889 GenBank accessions containing either partial or all PAI loci previously reported in the literature, which are present in 497 strains of pathogenic bacteria. The database also offers 310 candidate PAIs predicted from 118 sequenced prokaryotic genomes. With the increasing number of prokaryotic genomes without functional inference and sequenced genetic regions of suspected involvement in diseases, this web-based, user-friendly resource has the potential to be of significant use in pathogenomics. PAIDB is freely accessible at . PMID:17090594

State of the art discovery with tumor profiling in pediatric oncology.

PubMed

Carroll, William L; Raetz, Elizabeth; Meyer, Julia

2015-01-01

It is an exciting era in pediatric oncology with the advent of new technologies to comprehensively characterize cancer genomes in childhood tumors. Defining the genetic landscape of pediatric tumors has not only provided critical insight into tumor evolution, but it has also offered promise for more effective treatment in some cases, such as Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) and anaplastic lymphoma kinase (ALK)-mutated tumors. However, several challenges remain as the field of genomic tumor profiling emerges. This new technology is costly, and the overall impact on survival has yet to be determined. Tumor heterogeneity and clonal evolution have also presented challenges in the development of targeted therapy. In this article, we review breakthroughs in gene sequencing methodology and discuss examples where genomic discoveries have resulted in the recognition of tumor susceptibility as well as incorporation of targeted therapy. We also discuss how broad scale comprehensive tumor analyses have demonstrated the convergence of individual genetic alterations on common relevant pathways. Although the impact of tumor profiling is best studied within the context of rigorously designed clinical trials, there is promise that there will be growing opportunities for the adaption of precision medicine in pediatric oncology in the future.

Establishment of apoptotic regulatory network for genetic markers of colorectal cancer and optimal selection of traditional Chinese medicine target.

PubMed

Tian, Tongde; Chen, Chuanliang; Yang, Feng; Tang, Jingwen; Pei, Junwen; Shi, Bian; Zhang, Ning; Zhang, Jianhua

2017-03-01

The paper aimed to screen out genetic markers applicable to early diagnosis for colorectal cancer and establish apoptotic regulatory network model for colorectal cancer, and to analyze the current situation of traditional Chinese medicine (TCM) target, thereby providing theoretical evidence for early diagnosis and targeted therapy of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers that are applied to early diagnosis of colorectal cancer were searched and performed comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. KEGG analysis was employed to establish apoptotic regulatory network model based on screened genetic markers, and optimization was conducted on TCM targets. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, P53, APC, DCC and PTEN, among which DCC has the highest diagnostic efficiency. Apoptotic regulatory network was built by KEGG analysis. Currently, it was reported that TCM has regulatory function on gene locus in apoptotic regulatory network. The apoptotic regulatory model of colorectal cancer established in this study provides theoretical evidence for early diagnosis and TCM targeted therapy of colorectal cancer in clinic.

Date Palm Genetic Diversity Analysis Using Microsatellite Polymorphism.

PubMed

Khierallah, Hussam S M; Bader, Saleh M; Hamwieh, Alladin; Baum, Michael

2017-01-01

Date palm (Phoenix dactylifera L.) is considered one of the great socioeconomic resources in the Middle East and the Arab regions. The tree has been and still is at the center of the comprehensive agricultural development. The number of known date palm cultivars, distributed worldwide, is approximately 3000. The success of genetic diversity conservation or any breeding program depends on an understanding of the amount and distribution of the genetic variation already in existence in the genetic pool. Development of suitable DNA molecular markers for this tree may allow researchers to estimate genetic diversity, which will ultimately lead to the genetic conservation of date palm. Simple sequence repeats (SSRs) are DNA strands, consisting of tandemly repeated mono-, di-, tri-, tetra-, or penta-nucleotide units that are arranged throughout the genomes of most eukaryotic species. Microsatellite markers, developed from genomic libraries, belong to either the transcribed region or the non-transcribed region of the genome, and there is rarely available information on their functions. Microsatellite sequences are especially suited to distinguish closely related genotypes due to a high degree of variability making them ideally suitable in population studies and the identification of closely related cultivars. This chapter focuses on the methods employed to characterize date palm genotypes using SSR markers.

The influence of the arid Andean high plateau on the phylogeography and population genetics of guanaco (Lama guanicoe) in South America

PubMed Central

MARIN, JUAN C.; GONZÁLEZ, BENITO A.; POULIN, ELIE; CASEY, CIARA S.; JOHNSON, WARREN E.

2012-01-01

A comprehensive study of the phylogeography and population genetics of the largest wild artiodactyl in the arid and cold-temperate South American environments, the guanaco (Lama guanicoe) was conducted. Patterns of molecular genetic structure were described using 514 bp of mtDNA sequence and 14 biparentally-inherited microsatellite markers from 314 samples. These individuals originated from 17 localities throughout the current distribution across Peru, Bolivia, Argentina and Chile. This confirmed well-defined genetic differentiation and subspecies designation of populations geographically separated to the northwest (L. g. cacsilensis) and southeast (L. g. guanicoe) of the central Andes plateau. However, these populations are not completely isolated, as shown by admixture prevalent throughout a limited contact zone, and a strong signal of expansion from north to south in the beginning of the Holocene. Microsatellite analyses differentiated 3 northwestern and 4-5 southeastern populations, suggesting patterns of genetic contact among these populations. Possible genetic refuges were identified, as were source-sink patterns of gene flow at historical and recent time scales. Conservation and management of guanaco should be implemented with an understanding of these local population dynamics while also considering the preservation of broader adaptive variation and evolutionary processes. PMID:23206254

Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family.

PubMed

Yahalom, Claudia; Sharon, Dror; Dalia, Eli; Simhon, Shiran Ben; Shemesh, Efrat; Blumenfeld, Anat

2015-06-01

To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling.

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

PubMed

Morgan, Sarah; Shatunov, Aleksey; Sproviero, William; Jones, Ashley R; Shoai, Maryam; Hughes, Deborah; Al Khleifat, Ahmad; Malaspina, Andrea; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Sidle, Katie; Orrell, Richard W; Fratta, Pietro; Hardy, John; Pittman, Alan; Al-Chalabi, Ammar

2017-06-01

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Testing the effects of educational strategies on comprehension of a genomic concept using virtual reality technology.

PubMed

Kaphingst, Kimberly A; Persky, Susan; McCall, Cade; Lachance, Christina; Loewenstein, Johanna; Beall, Andrew C; Blascovich, Jim

2009-11-01

Applying genetic susceptibility information to improve health will likely require educating patients about abstract concepts, for which there is little existing research. This experimental study examined the effect of learning mode on comprehension of a genomic concept. 156 individuals aged 18-40 without specialized knowledge were randomly assigned to either a virtual reality active learning or didactic learning condition. The outcome was comprehension (recall, transfer, mental models). Change in recall was greater for didactic learning than for active learning (p<0.001). Mean transfer and change in mental models were also higher for didactic learning (p<0.0001 and p<0.05, respectively). Believability was higher for didactic learning (p<0.05), while ratings for motivation (p<0.05), interest (p<0.0001), and enjoyment (p<0.0001) were higher for active learning, but these variables did not mediate the association between learning mode and comprehension. These results show that learning mode affects comprehension, but additional research is needed regarding how and in what contexts different approaches are best for educating patients about abstract concepts. Didactic, interpersonal health education approaches may be more effective than interactive games in educating patients about abstract, unfamiliar concepts. These findings indicate the importance of traditional health education approaches in emerging areas like genomics.

Comprehensive Genetic Characterization of Intraprostatic Chronic Inflammation and Prostate Cancer in African American Men

DTIC Science & Technology

2016-09-01

history. 23 CONCLUSION: Various alternative finger length ratios show strong differences between African-American and white men in this study. The...African American Men PRINCIPAL INVESTIGATOR: Elisa Marie Ledet, PhD CONTRACTING ORGANIZATION: Administrators of the Tulane University New Orleans...Intraprostatic Chronic Inflammation and Prostate Cancer in African American Men 5b. GRANT NUMBER W81XWH-15-1-0379 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

Trepanation and enlarged parietal foramen on skulls from the Loyalty Islands (Melanesia).

PubMed

Vasilyev, Sergey V; Sviridov, Alexey A

2017-06-01

The goal of this study is a comprehensive examination of openings discovered on two skulls in the collection of skeletal remains from the Loyalty Islands (Melanesia). The skull No. 1524 displayed an evidence of successful trepanation, and the skull No. 7985 revealed openings that were reminiscent of a trepanation, however, we are inclined to believe that in the latter case we are dealing with a rare genetic anomaly - enlarged parietal foramen.

Genotype-by-Environment Interactions for Female Mate Choice of Male Cuticular Hydrocarbons in Drosophila simulans

PubMed Central

Ingleby, Fiona C.; Hunt, John; Hosken, David J.

2013-01-01

Recent research has highlighted the potential importance of environmental and genotype-by-environment (G×E) variation in sexual selection, but most studies have focussed on the expression of male sexual traits. Consequently, our understanding of genetic variation for plasticity in female mate choice is extremely poor. In this study we examine the genetics of female mate choice in Drosophila simulans using isolines reared across two post-eclosion temperatures. There was evidence for G×Es in female choosiness and preference, which suggests that the evolution of female mate choice behaviour could differ across environments. However, the ranked order of preferred males was consistent across females and environments, so the same males are favoured by mate choice in spite of G×Es. Our study highlights the importance of taking cross-environment perspectives in order to gain a more comprehensive understanding of the operation of sexual selection. PMID:23825675

Genetic incorporation of Nε-acetyllysine reveals a novel acetylation-sumoylation switch in yeast.

PubMed

Kim, Sang-Woo; Lee, Kyung Jin; Kim, Sinil; Kim, Jihyo; Cho, Kyukwang; Ro, Hyeon-Su; Park, Hee-Sung

2017-11-01

The lysine acetylation of proteins plays a key role in regulating protein functions, thereby controlling a wide range of cellular processes. Despite the prevalence and significance of lysine acetylation in eukaryotes, however, its systematic study has been challenged by the technical limitations of conventional approaches for selective lysine acetylation in vivo. Here, we report the in vivo study of lysine acetylation via the genetic incorporation of N ε -acetyllysine in yeast. We demonstrate that a newly discovered acetylation-sumoylation switch precisely controls the localization and cellular function of the yeast septin protein, Cdc11, during the cell cycle. This approach should facilitate the comprehensive in vivo study of lysine acetylation across a wide range of proteins in eukaryotic organisms. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic polymorphism and chronic obstructive pulmonary disease.

PubMed

Yuan, Cunhua; Chang, De; Lu, Guangming; Deng, Xiaowei

2017-01-01

Chronic obstructive pulmonary disease (COPD) is a common chronic disease, and its morbidity and mortality are increasing. There are many studies that have tried to explain the pathogenesis of COPD from genetic susceptibility, to identify the susceptibility of COPD factors, which play a role in early prevention, early detection and the early treatment. However, it is well known that COPD is an inflammatory disease characterized by incomplete reversible airflow limitation in which genes interact with the environment. In recent years, many studies have proved gene polymorphisms and COPD correlation. However, there is less research on the relationship between COPD and genome-wide association study (GWAS), epigenetics and apoptosis. In this paper, we summarized the correlation between gene level and COPD from the following four aspects: the GWAS, the gene polymorphism, the epigenetics and the apoptosis, and the relationship between COPD and gene is summarized comprehensively.

Challenges of Identifying Clinically Actionable Genetic Variants for Precision Medicine

PubMed Central

2016-01-01

Advances in genomic medicine have the potential to change the way we treat human disease, but translating these advances into reality for improving healthcare outcomes depends essentially on our ability to discover disease- and/or drug-associated clinically actionable genetic mutations. Integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a big data infrastructure can provide an efficient and effective way to identify clinically actionable genetic variants for personalized treatments and reduce healthcare costs. We review bioinformatics processing of next-generation sequencing (NGS) data, bioinformatics infrastructures for implementing precision medicine, and bioinformatics approaches for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs. PMID:27195526

76 FR 26751 - Prime Hook National Wildlife Refuge, Sussex County, DE; Comprehensive Conservation Plan and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-09

... the planting of genetically modified organisms until the refuge completed compatibility determinations... to wildlife, plant, and habitat conservation, while providing for wildlife-dependent recreation...

Seborrheic Dermatitis and Dandruff: A Comprehensive Review

PubMed Central

Borda, Luis J.; Wikramanayake, Tongyu C.

2016-01-01

Seborrheic Dermatitis (SD) and dandruff are of a continuous spectrum of the same disease that affects the seborrheic areas of the body. Dandruff is restricted to the scalp, and involves itchy, flaking skin without visible inflammation. SD can affect the scalp as well as other seborrheic areas, and involves itchy and flaking or scaling skin, inflammation and pruritus. Various intrinsic and environmental factors, such as sebaceous secretions, skin surface fungal colonization, individual susceptibility, and interactions between these factors, all contribute to the pathogenesis of SD and dandruff. In this review, we summarize the current knowledge on SD and dandruff, including epidemiology, burden of disease, clinical presentations and diagnosis, treatment, genetic studies in humans and animal models, and predisposing factors. Genetic and biochemical studies and investigations in animal models provide further insight on the pathophysiology and strategies for better treatment. PMID:27148560

Clinically relevant lessons from Family HealthLink: a cancer and coronary heart disease familial risk assessment tool.

PubMed

Sweet, Kevin; Sturm, Amy C; Rettig, Amy; McElroy, Joseph; Agnese, Doreen

2015-06-01

A descriptive retrospective study was performed using two separate user cohorts to determine the effectiveness of Family HealthLink as a clinical triage tool. Cohort 1 consisted of 2,502 users who accessed the public website. Cohort 2 consisted of 194 new patients in a Comprehensive Breast Center setting. For patient users, we assessed documentation of family history and genetics referral. For all users seen in a genetics clinic, the Family HealthLink assessment was compared with that performed by genetic counselors and genetic testing outcomes. For general public users, the percentage meeting high-risk criteria were: for cancer only, 22.2%; for coronary heart disease only, 24.3%; and for both diseases, 10.4%. These risk stratification percentages were similar for the patient users. For the patient users, there often was documentation of family history of certain cancer types by oncology professionals, but age of onset and coronary heart disease family history were less complete. Of 142 with high-risk assignments seen in a genetics clinic, 130 (91.5%) of these assignments were corroborated. Forty-two underwent genetic testing and 17 (40.5%) had new molecular diagnoses established. A significant percentage of individuals are at high familial risk and may require more intensive screening and referral. Interactive family history triage tools can aid this process.Genet Med 17 6, 493-500.

The role of pharmacogenetics and advances in gene therapy in the treatment of diabetic retinopathy.

PubMed

Agarwal, Aniruddha; Ingham, Sally A; Harkins, Keegan A; Do, Diana V; Nguyen, Quan Dong

2016-02-01

Diabetic retinopathy (DR) and its complications such as diabetic macular edema continue to remain a major cause for legal blindness in the developed world. While the introduction of anti-tVEGF agents has significantly improved visual outcomes of patients with DR, unpredictable response, largely due to genetic polymorphisms, appears to be a challenge with this therapy. With advances in identification of various genetic biomarkers, novel therapeutic strategies consisting of gene transfer are being developed and tested for patients with DR. Application of pharmacogenetic principles appears to be a promising futuristic strategy to attenuate diabetes-mediated retinal vasculopathy. In this comprehensive review, data from recent studies in the field of pharmacogenomics for the treatment of DR have been provided.

Medical genetic issues in clinical of pediatric neurology practice:a history of pediatrics in Peking University First Hospital.

PubMed

Wu, Xi-ru

2006-02-18

The Department of Pediatrics of Peking University First Hospital has a long term of outstanding history. It was established about 60 years ago. After the division of pediatric neurology (DPN) had been established in 1960s, it had been assigned to cover genetic disorders. During the recent 20 years, efforts have been put on three aspects: (1) Pediatric neurology clinical service and education; (2) research studies of childhood epilepsies and pediatric neurogenetic disorders; and (3) development of a strong DPN team to establish a comprehensive pediatric neurological program. In this paper, we reviewed the history of the pediatric neurology division in our department, our clinical and research work and achievements for neurogenetic diseases.

Modeling Gene-Environment Interactions With Quasi-Natural Experiments.

PubMed

Schmitz, Lauren; Conley, Dalton

2017-02-01

This overview develops new empirical models that can effectively document Gene × Environment (G×E) interactions in observational data. Current G×E studies are often unable to support causal inference because they use endogenous measures of the environment or fail to adequately address the nonrandom distribution of genes across environments, confounding estimates. Comprehensive measures of genetic variation are incorporated into quasi-natural experimental designs to exploit exogenous environmental shocks or isolate variation in environmental exposure to avoid potential confounders. In addition, we offer insights from population genetics that improve upon extant approaches to address problems from population stratification. Together, these tools offer a powerful way forward for G×E research on the origin and development of social inequality across the life course. © 2015 Wiley Periodicals, Inc.

Gene flow among wild and domesticated almond species: insights from chloroplast and nuclear markers

PubMed Central

Delplancke, Malou; Alvarez, Nadir; Espíndola, Anahí; Joly, Hélène; Benoit, Laure; Brouck, Elise; Arrigo, Nils

2012-01-01

Hybridization has played a central role in the evolutionary history of domesticated plants. Notably, several breeding programs relying on gene introgression from the wild compartment have been performed in fruit tree species within the genus Prunus but few studies investigated spontaneous gene flow among wild and domesticated Prunus species. Consequently, a comprehensive understanding of genetic relationships and levels of gene flow between domesticated and wild Prunus species is needed. Combining nuclear and chloroplastic microsatellites, we investigated the gene flow and hybridization among two key almond tree species, the cultivated Prunus dulcis and one of the most widespread wild relative Prunus orientalis in the Fertile Crescent. We detected high genetic diversity levels in both species along with substantial and symmetric gene flow between the domesticated P. dulcis and the wild P. orientalis. These results were discussed in light of the cultivated species diversity, by outlining the frequent spontaneous genetic contributions of wild species to the domesticated compartment. In addition, crop-to-wild gene flow suggests that ad hoc transgene containment strategies would be required if genetically modified cultivars were introduced in the northwestern Mediterranean. PMID:25568053

LISTA, a comprehensive compilation of nucleotide sequences encoding proteins from the yeast Saccharomyces.

PubMed Central

Linder, P; Dölz, R; Mossé, M O; Lazowska, J; Slonimski, P P

1993-01-01

The amount of nucleotide sequence data is increasing exponentially. We therefore made an effort to make a comprehensive database (LISTA) for the yeast Saccharomyces cerevisiae. Each sequence has been attributed a single genetic name and in the case of allelic duplicated sequences, synonyms are given, if necessary. For the nomenclature we have introduced a standard principle for naming gene sequences based on priority rules. We have also applied a simple method to distinguish duplicated sequences of one and the same gene from non-allelic sequences of duplicated genes. By using these principles we have sorted out a lot of confusion in the literature and databanks. Along with the genetic name, the mnemonic from the EMBL databank, the codon bias, reference of the publication of the sequence and the EMBL accession numbers are included in each entry. PMID:8332521

Spatial Genetic Structure and Mitochondrial DNA Phylogeography of Argentinean Populations of the Grasshopper Dichroplus elongatus

PubMed Central

Rosetti, Natalia; Remis, Maria Isabel

2012-01-01

Many grasshopper species are considered of agronomical importance because they cause damage to pastures and crops. Comprehension of pest population dynamics requires a clear understanding of the genetic diversity and spatial structure of populations. In this study we report on patterns of genetic variation in the South American grasshopper Dichroplus elongatus which is an agricultural pest of crops and forage grasses of great economic significance in Argentina. We use Direct Amplification of Minisatellite Regions (DAMD) and partial sequences of the cytochrome oxydase 1 (COI) mitochondrial gene to investigate intraspecific structure, demographic history and gene flow patterns in twenty Argentinean populations of this species belonging to different geographic and biogeographic regions. DAMD data suggest that, although genetic drift and migration occur within and between populations, measurable relatedness among neighbouring populations declines with distance and dispersal over distances greater than 200 km is not typical, whereas effective gene flow may occur for populations separated by less than 100 km. Landscape analysis was useful to detect genetic discontinuities associated with environmental heterogeneity reflecting the changing agroecosystem. The COI results indicate the existence of strong genetic differentiation between two groups of populations located at both margins of the Paraná River which became separated during climate oscillations of the Middle Pleistocene, suggesting a significant restriction in effective dispersion mediated by females and large scale geographic differentiation. The number of migrants between populations estimated through mitochondrial and DAMD markers suggest that gene flow is low prompting a non-homogeneous spatial structure and justifying the variation through space. Moreover, the genetic analysis of both markers allows us to conclude that males appear to disperse more than females, reducing the chance of the genetic loss associated with recent anthropogenic fragmentation of the D. elongatus studied range. PMID:22859953

An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population.

PubMed

Lu, Timothy Tehua; Lao, Oscar; Nothnagel, Michael; Junge, Olaf; Freitag-Wolf, Sandra; Caliebe, Amke; Balascakova, Miroslava; Bertranpetit, Jaume; Bindoff, Laurence Albert; Comas, David; Holmlund, Gunilla; Kouvatsi, Anastasia; Macek, Milan; Mollet, Isabelle; Nielsen, Finn; Parson, Walther; Palo, Jukka; Ploski, Rafal; Sajantila, Antti; Tagliabracci, Adriano; Gether, Ulrik; Werge, Thomas; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, André Gerardus; Gieger, Christian; Wichmann, Heinz-Erich; Ruether, Andreas; Schreiber, Stefan; Becker, Christian; Nürnberg, Peter; Nelson, Matthew Roberts; Kayser, Manfred; Krawczak, Michael

2009-07-01

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309,790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.

Cohort Profile: Generation Scotland: Scottish Family Health Study (GS:SFHS). The study, its participants and their potential for genetic research on health and illness.

PubMed

Smith, Blair H; Campbell, Archie; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Kerr, Shona M; Deary, Ian J; Macintyre, Donald J; Campbell, Harry; McGilchrist, Mark; Hocking, Lynne J; Wisely, Lucy; Ford, Ian; Lindsay, Robert S; Morton, Robin; Palmer, Colin N A; Dominiczak, Anna F; Porteous, David J; Morris, Andrew D

2013-06-01

GS:SFHS is a family-based genetic epidemiology study with DNA and socio-demographic and clinical data from about 24 000 volunteers across Scotland aged 18-98 years, from February 2006 to March 2011. Biological samples and anonymized data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Specific and important features of GS:SFHS include the family-based recruitment, with the intent of obtaining family groups; the breadth and depth of phenotype information, including detailed data on cognitive function, personality traits and mental health; consent and mechanisms for linkage of all data to comprehensive routine health-care records; and 'broad' consent from participants to use their data and samples for a wide range of medical research, including commercial research, and for re-contact for the potential collection of other data or samples, or for participation in related studies and the design and review of the protocol in parallel with in-depth sociological research on (potential) participants and users of the research outcomes. These features were designed to maximize the power of the resource to identify, replicate or control for genetic factors associated with a wide spectrum of illnesses and risk factors, both now and in the future.

Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate

PubMed Central

Ortega, Ángeles; Berná, Genoveva; Rojas, Anabel; Martín, Franz; Soria, Bernat

2017-01-01

Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM. PMID:28574454

Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1.

PubMed

Kim, Ahlee; Fujimoto, Masanobu; Hwa, Vivian; Backeljauw, Philippe; Dauber, Andrew

2018-01-01

Cholesterol side-chain cleavage enzyme (P450scc) deficiency is a rare genetic disorder causing primary adrenal insufficiency with or without a 46,XY disorder of sexual development (DSD). Herein, we report a case of the combination of primary adrenal insufficiency, a DSD (testes with female external genitalia in a setting of a 47,XXY karyotype), and Angelman syndrome. Comprehensive genetic analyses were performed, including a single nucleotide polymorphism microarray and whole-exome sequencing. In vitro studies were performed to evaluate the pathogenicity of the novel mutation that was identified by whole-exome sequencing. The patient was found to have segmental uniparental disomy (UPD) of chromosome 15 explaining her diagnosis of Angelman syndrome. Whole-exome sequencing further revealed a novel homozygous intronic variant in CYP11A1, the gene encoding P450scc, found within the region of UPD. In vitro studies confirmed that this variant led to decreased efficiency of CYP11A1 splicing. We report the first case of the combination of 2 rare genetic disorders, Angelman syndrome, and P450scc deficiency. After 20 years of diagnostic efforts, significant advances in genetic diagnostic technology allowed us to determine that these 2 disorders originate from a unified genetic etiology, segmental UPD unmasking a novel recessive mutation in CYP11A1. © 2018 S. Karger AG, Basel.

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

PubMed

Okada, Yukinori; Wu, Di; Trynka, Gosia; Raj, Towfique; Terao, Chikashi; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Suzuki, Akari; Yoshida, Shinji; Graham, Robert R; Manoharan, Arun; Ortmann, Ward; Bhangale, Tushar; Denny, Joshua C; Carroll, Robert J; Eyler, Anne E; Greenberg, Jeffrey D; Kremer, Joel M; Pappas, Dimitrios A; Jiang, Lei; Yin, Jian; Ye, Lingying; Su, Ding-Feng; Yang, Jian; Xie, Gang; Keystone, Ed; Westra, Harm-Jan; Esko, Tõnu; Metspalu, Andres; Zhou, Xuezhong; Gupta, Namrata; Mirel, Daniel; Stahl, Eli A; Diogo, Dorothée; Cui, Jing; Liao, Katherine; Guo, Michael H; Myouzen, Keiko; Kawaguchi, Takahisa; Coenen, Marieke J H; van Riel, Piet L C M; van de Laar, Mart A F J; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Bridges, S Louis; Zhernakova, Alexandra; Toes, Rene E M; Tak, Paul P; Miceli-Richard, Corinne; Bang, So-Young; Lee, Hye-Soon; Martin, Javier; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Rantapää-Dahlqvist, Solbritt; Arlestig, Lisbeth; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Eyre, Steve; Bowes, John; Barton, Anne; de Vries, Niek; Moreland, Larry W; Criswell, Lindsey A; Karlson, Elizabeth W; Taniguchi, Atsuo; Yamada, Ryo; Kubo, Michiaki; Liu, Jun S; Bae, Sang-Cheol; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Gregersen, Peter K; Raychaudhuri, Soumya; Stranger, Barbara E; De Jager, Philip L; Franke, Lude; Visscher, Peter M; Brown, Matthew A; Yamanaka, Hisashi; Mimori, Tsuneyo; Takahashi, Atsushi; Xu, Huji; Behrens, Timothy W; Siminovitch, Katherine A; Momohara, Shigeki; Matsuda, Fumihiko; Yamamoto, Kazuhiko; Plenge, Robert M

2014-02-20

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Genetic Risk Prediction of Atrial Fibrillation

PubMed Central

Lubitz, Steven A.; Yin, Xiaoyan; Lin, Henry J.; Kolek, Matthew; Smith, J. Gustav; Trompet, Stella; Rienstra, Michiel; Rost, Natalia S.; Teixeira, Pedro L.; Almgren, Peter; Anderson, Christopher D.; Chen, Lin Y.; Engström, Gunnar; Ford, Ian; Furie, Karen L.; Guo, Xiuqing; Larson, Martin G.; Lunetta, Kathryn L.; Macfarlane, Peter W.; Psaty, Bruce M.; Soliman, Elsayed Z.; Sotoodehnia, Nona; Stott, David J.; Taylor, Kent D.; Weng, Lu-Chen; Yao, Jie; Geelhoed, Bastiaan; Verweij, Niek; Siland, Joylene E.; Kathiresan, Sekar; Roselli, Carolina; Roden, Dan; van der Harst, Pim; Darbar, Dawood; Jukema, J. Wouter; Melander, Olle; Rosand, Jonathan; Rotter, Jerome I.; Heckbert, Susan R.; Ellinor, Patrick T.; Alonso, Alvaro; Benjamin, Emelia J.

2017-01-01

Background Atrial fibrillation (AF) is common and has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 controls. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1×10−3 to <1×10−8 in a prior independent genetic association study. Results Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13–1.46; P=1.5×10−4) to 1.67 (25 variants; 95%CI, 1.47–1.90; P=9.3×10−15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke, versus those in the lowest quartile (95%CI, 1.39–4.58; P=2.7×10−3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20–4.40; P=0.01). Conclusions Comprehensive AF genetic risk scores were associated with incident AF beyond clinical AF risk factors, with magnitudes of risk comparable to other clinical risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts to determine whether AF genetic risk may improve identification of subclinical AF or distinguish stroke mechanisms are warranted. PMID:27793994

Genetic Population Structure of the Coral Reef Sea Star Linckia laevigata in the Western Indian Ocean and Indo-West Pacific.

PubMed

Otwoma, Levy Michael; Kochzius, Marc

2016-01-01

The coral reef sea star Linckia laevigata is common on shallow water coral reefs of the Indo-West Pacific. Its large geographic distribution and comprehensive data from previous studies makes it suitable to examine genetic differentiation and connectivity over large geographical scales. Based on partial sequences of the mitochondrial cytochrome oxidase I (COI) gene this study investigates the genetic population structure and connectivity of L. laevigata in the Western Indian Ocean (WIO) and compares it to previous studies in the Indo-Malay-Philippines Archipelago (IMPA). A total of 138 samples were collected from nine locations in the WIO. AMOVA revealed a low but significant ΦST-value of 0.024 for the WIO populations. In the hierarchical AMOVA, the following grouping rejected the hypothesis of panmixia: (1) Kenya (Watamu, Mombasa, Diani) and Tanzanian Island populations (Misali and Jambiani) and (2) the rest of the WIO sites (mainland Tanzania and Madagascar; ΦCT = 0.03). The genetic population structure was stronger and more significant (ΦST = 0.13) in the comparative analysis of WIO and IMPA populations. Three clades were identified in the haplotype network. The strong genetic differentiation (ΦCT = 0.199, P < 0.001) suggests that Indo-West Pacific populations of L. laevigata can be grouped into four biogeographic regions: (1) WIO (2) Eastern Indian Ocean (3) IMPA and (4) Western Pacific. The findings of this study support the existence of a genetic break in the Indo-West Pacific consistent with the effect of lowered sea level during the Pleistocene, which limited gene flow between the Pacific and Indian Ocean.

Genetic Population Structure of the Coral Reef Sea Star Linckia laevigata in the Western Indian Ocean and Indo-West Pacific

PubMed Central

Kochzius, Marc

2016-01-01

The coral reef sea star Linckia laevigata is common on shallow water coral reefs of the Indo-West Pacific. Its large geographic distribution and comprehensive data from previous studies makes it suitable to examine genetic differentiation and connectivity over large geographical scales. Based on partial sequences of the mitochondrial cytochrome oxidase I (COI) gene this study investigates the genetic population structure and connectivity of L. laevigata in the Western Indian Ocean (WIO) and compares it to previous studies in the Indo-Malay-Philippines Archipelago (IMPA). A total of 138 samples were collected from nine locations in the WIO. AMOVA revealed a low but significant ΦST-value of 0.024 for the WIO populations. In the hierarchical AMOVA, the following grouping rejected the hypothesis of panmixia: (1) Kenya (Watamu, Mombasa, Diani) and Tanzanian Island populations (Misali and Jambiani) and (2) the rest of the WIO sites (mainland Tanzania and Madagascar; ΦCT = 0.03). The genetic population structure was stronger and more significant (ΦST = 0.13) in the comparative analysis of WIO and IMPA populations. Three clades were identified in the haplotype network. The strong genetic differentiation (ΦCT = 0.199, P < 0.001) suggests that Indo-West Pacific populations of L. laevigata can be grouped into four biogeographic regions: (1) WIO (2) Eastern Indian Ocean (3) IMPA and (4) Western Pacific. The findings of this study support the existence of a genetic break in the Indo-West Pacific consistent with the effect of lowered sea level during the Pleistocene, which limited gene flow between the Pacific and Indian Ocean. PMID:27798700

PGG.Population: a database for understanding the genomic diversity and genetic ancestry of human populations.

PubMed

Zhang, Chao; Gao, Yang; Liu, Jiaojiao; Xue, Zhe; Lu, Yan; Deng, Lian; Tian, Lei; Feng, Qidi; Xu, Shuhua

2018-01-04

There are a growing number of studies focusing on delineating genetic variations that are associated with complex human traits and diseases due to recent advances in next-generation sequencing technologies. However, identifying and prioritizing disease-associated causal variants relies on understanding the distribution of genetic variations within and among populations. The PGG.Population database documents 7122 genomes representing 356 global populations from 107 countries and provides essential information for researchers to understand human genomic diversity and genetic ancestry. These data and information can facilitate the design of research studies and the interpretation of results of both evolutionary and medical studies involving human populations. The database is carefully maintained and constantly updated when new data are available. We included miscellaneous functions and a user-friendly graphical interface for visualization of genomic diversity, population relationships (genetic affinity), ancestral makeup, footprints of natural selection, and population history etc. Moreover, PGG.Population provides a useful feature for users to analyze data and visualize results in a dynamic style via online illustration. The long-term ambition of the PGG.Population, together with the joint efforts from other researchers who contribute their data to our database, is to create a comprehensive depository of geographic and ethnic variation of human genome, as well as a platform bringing influence on future practitioners of medicine and clinical investigators. PGG.Population is available at https://www.pggpopulation.org. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

PubMed Central

Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; dos Santos, Patricia Koehler; Ribeiro, Patricia Lisbôa Izetti; de Oliveira, Cristina Brinkmann; Kelm, Florence Le Calvez; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

2016-01-01

Abstract In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil. PMID:27223485

A Model Program for Translational Medicine in Epilepsy Genetics

PubMed Central

Smith, Lacey A.; Ullmann, Jeremy F. P.; Olson, Heather E.; El Achkar, Christelle M.; Truglio, Gessica; Kelly, McKenna; Rosen-Sheidley, Beth; Poduri, Annapurna

2017-01-01

Recent technological advances in gene sequencing have led to a rapid increase in gene discovery in epilepsy. However, the ability to assess pathogenicity of variants, provide functional analysis, and develop targeted therapies has not kept pace with rapid advances in sequencing technology. Thus, although clinical genetic testing may lead to a specific molecular diagnosis for some patients, test results often lead to more questions than answers. As the field begins to focus on therapeutic applications of genetic diagnoses using precision medicine, developing processes that offer more than equivocal test results is essential. The success of precision medicine in epilepsy relies on establishing a correct genetic diagnosis, analyzing functional consequences of genetic variants, screening potential therapeutics in the preclinical laboratory setting, and initiating targeted therapy trials for patients. We describe the structure of a comprehensive, pediatric Epilepsy Genetics Program that can serve as a model for translational medicine in epilepsy. PMID:28056630

Current Evidence and Insights about Genetics in Thoracic Aorta Disease

PubMed Central

Muneretto, Claudio

2013-01-01

Thoracic aortic aneurysms have been historically considered to be caused by etiologic factors similar to those implied in abdominal aortic aneurysms. However, during the past decade, there has been increasing evidence that almost 20% of thoracic aortic aneurysms may be associated with a genetic disease, often within a syndromic or familial disorder. Moreover, the presence of congenital anomalies, such as bicuspid aortic valve, may have a unique common genetic underlying cause. Finally, also sporadic forms have been found to be potentially associated with genetic disorders, as highlighted by the analysis of rare variants and expression of specific microRNAs. We therefore sought to perform a comprehensive review of the role of genetic causes in the development of thoracic aortic aneurysms, by analyzing in detail the current evidence of genetic alterations in syndromes such as Marfan, Loeys-Dietz, and Ehler-Danlos, familial or sporadic forms, or forms associated with bicuspid aortic valve. PMID:24453931

Role of the Neddylation Enzyme Uba3, a New Estrogen Receptor Corepressor, in Breast Cancer

DTIC Science & Technology

2005-09-01

downstream targets Cancer Res 64:8184-8192 (cover article ). *This DOD award is acknowledged in these publications. Presentations 1. Fan M, Park A...www.endoiournals.org/. The final copy edited article can be found at 15 http://www.endojoumals.org/. The Endocrine Society disclaims any responsibility or...8217Hutnan Cancer Genetics Program, Departtent of Molecular Virology, Inmunology , and Medical Genetics, Comprehensive Cancer Center, The Ohio State Universit

Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design.

PubMed

Cho, Alex H; Killeya-Jones, Ley A; O'Daniel, Julianne M; Kawamoto, Kensaku; Gallagher, Patrick; Haga, Susanne; Lucas, Joseph E; Trujillo, Gloria M; Joy, Scott V; Ginsburg, Geoffrey S

2012-01-18

Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. ClinicalTrials.gov: NCT00849563.

Pathophysiology of diverticular disease.

PubMed

Schieffer, Kathleen M; Kline, Bryan P; Yochum, Gregory S; Koltun, Walter A

2018-06-07

Inflammation of diverticula, or outpouchings of the colonic mucosa and submucosa through the muscularis layer, leads to diverticulitis. The development of diverticular disease, encompassing both diverticulosis and diverticulitis, is a result of genetic predisposition, lifestyle, and environmental factors, including the microbiome. Areas covered: Previous reports implicated genetic predisposition, environmental factors, and colonic dysmotility in diverticular disease. Recent studies have associated specific host immune responses and the microbiome as contributors to diverticulitis. To review pertinent literature describing pathophysiological factors associated with diverticulosis or diverticulitis, we searched the PubMed database (March 2018) for articles considering the role of colonic architecture, genetic predisposition, environment, colonic motility, immune response, and the microbiome. Expert commentary: In the recent years, research into the molecular underpinnings of diverticular disease has enhanced our understanding of diverticular disease pathogenesis. Although acute uncomplicated diverticulitis is treated with broad spectrum antibiotics, evaluation of the microbiome has been limited and requires further comprehensive studies. Evidence suggests that a deregulation of the host immune response is associated with both diverticulosis and diverticulitis. Further examining these pathways may reveal proteins that can be therapeutic targets or aid in identifying biological determinants of clinical or surgical decision making.

Systematic review and meta-analysis of genetic risk factors for neuropathic pain.

PubMed

Veluchamy, Abirami; Hébert, Harry L; Meng, Weihua; Palmer, Colin N A; Smith, Blair H

2018-05-01

Neuropathic pain (NP) is an increasingly common chronic pain state and a major health burden, affecting approximately 7% to 10% of the general population. Emerging evidence suggests that genetic factors could partially explain individual susceptibility to NP and the estimated heritability in twins is 37%. The aim of this study was to systematically review and summarize the studies in humans that have investigated the influence of genetic factors associated with NP. We conducted a comprehensive literature search and performed meta-analyses of all the potential genetic variants associated with NP. We reviewed 29 full-text articles and identified 28 genes that were significantly associated with NP, mainly involved in neurotransmission, immune response, and metabolism. Genetic variants in HLA genes, COMT, OPRM1, TNFA, IL6, and GCH1, were found to have an association with NP in more than one study. In the meta-analysis, polymorphisms in HLA-DRB1*13 (odds ratio [OR], 2.96; confidence interval [CI], 1.93-4.56), HLA-DRB1*04 (OR, 1.40; CI, 1.02-1.93), HLA-DQB1*03 (OR, 2.86; CI, 1.57-5.21), HLA-A*33 (OR, 2.32; CI, 1.42-3.80), and HLA-B*44 (OR, 3.17; CI, 2.22-4.55) were associated with significantly increased risk of developing NP, whereas HLA-A*02 (OR, 0.64; CI, 0.47-0.87) conferred reduced risk and neither rs1799971 in OPRM1 (OR, 0.55; CI, 0.27-1.11) nor rs4680 in COMT (OR, 0.95; CI, 0.81-1.13) were significantly associated with NP. These findings demonstrate an important and specific contribution of genetic factors to the risk of developing NP. However, large-scale replication studies are required to validate these candidate genes. Our review also highlights the need for genome-wide association studies with consistent case definition to elucidate the genetic architecture underpinning NP.

Comprehensive Analyses of Molecules with Altered Expression in the Brain of a Mouse Model of Down Syndrome for Identification of Pharmacotherapeutic Targets.

PubMed

Ishihara, Keiichi

2017-01-01

Down syndrome, caused by the triplication of human chromosome 21, is the most frequent genetic cause of mental retardation. Mice with a segmental trisomy for mouse chromosome 16, which is orthologous to human chromosome 21, exhibit abnormalities similar to those in individuals with Down syndrome and therefore offer the opportunity for a genotype-phenotype correlation. In the current review, I present several mouse lines with trisomic regions of various lengths and discuss their usefulness for elucidating the mechanisms underlying Down syndrome-associated developmental cognitive disabilities. In addition, our recent comprehensive study attempting to identify molecules with disturbed expression in the brain of a mouse model of Down syndrome in order to develop a pharmacologic therapy for Down syndrome is described.

A comprehensive review of amyotrophic lateral sclerosis

PubMed Central

Zarei, Sara; Carr, Karen; Reiley, Luz; Diaz, Kelvin; Guerra, Orleiquis; Altamirano, Pablo Fernandez; Pagani, Wilfredo; Lodin, Daud; Orozco, Gloria; Chinea, Angel

2015-01-01

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5–10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease. PMID:26629397

Genetic diversity and population structure of an extremely endangered species: the world's largest Rhododendron.

PubMed

Wu, Fu Qin; Shen, Shi Kang; Zhang, Xin Jun; Wang, Yue Hua; Sun, Wei Bang

2014-12-04

Comprehensive studies on the genetic diversity and structure of endangered species are urgently needed to promote effective conservation and management activities. The big tree rhododendron, Rhododendron protistum var. giganteum, is a highly endangered species with only two known endemic populations in a small area in the southern part of Yunnan Province in China. Unfortunately, limited information is available regarding the population genetics of this species. Therefore, we conducted amplified fragment length polymorphism (AFLP) analysis to characterize the genetic diversity and variation of this species within and between remaining populations. Twelve primer combinations of AFLP produced 447 unambiguous and repetitious bands. Among these bands, 298 (66.67 %) were polymorphic. We found high genetic diversity at the species level (percentage of polymorphic loci = 66.67 %, h = 0.240, I = 0.358) and low genetic differentiation (Gst = 0.110) between the two populations. Gene flow between populations (Nm) was relatively high at 4.065. Analysis of molecular variance results revealed that 22 % of the genetic variation was partitioned between populations and 78 % of the genetic variation was within populations. The presence of moderate to high genetic diversity and low genetic differentiation in the two populations can be explained by life history traits, pollen dispersal and high gene flow (Nm = 4.065). Bayesian structure and principal coordinate analysis revealed that 56 sampled trees were clustered into two groups. Our results suggest that some rare and endangered species are able to maintain high levels of genetic diversity even at small population sizes. These results will assist with the design of conservation and management programmes, such as in situ and ex situ conservation, seed collection for germplasm conservation and reintroduction. Published by Oxford University Press on behalf of the Annals of Botany Company.

Extensive genetic diversity, unique population structure and evidence of genetic exchange in the sexually transmitted parasite Trichomonas vaginalis.

PubMed

Conrad, Melissa D; Gorman, Andrew W; Schillinger, Julia A; Fiori, Pier Luigi; Arroyo, Rossana; Malla, Nancy; Dubey, Mohan Lal; Gonzalez, Jorge; Blank, Susan; Secor, William E; Carlton, Jane M

2012-01-01

Trichomonas vaginalis is the causative agent of human trichomoniasis, the most common non-viral sexually transmitted infection world-wide. Despite its prevalence, little is known about the genetic diversity and population structure of this haploid parasite due to the lack of appropriate tools. The development of a panel of microsatellite makers and SNPs from mining the parasite's genome sequence has paved the way to a global analysis of the genetic structure of the pathogen and association with clinical phenotypes. Here we utilize a panel of T. vaginalis-specific genetic markers to genotype 235 isolates from Mexico, Chile, India, Australia, Papua New Guinea, Italy, Africa and the United States, including 19 clinical isolates recently collected from 270 women attending New York City sexually transmitted disease clinics. Using population genetic analysis, we show that T. vaginalis is a genetically diverse parasite with a unique population structure consisting of two types present in equal proportions world-wide. Parasites belonging to the two types (type 1 and type 2) differ significantly in the rate at which they harbor the T. vaginalis virus, a dsRNA virus implicated in parasite pathogenesis, and in their sensitivity to the widely-used drug, metronidazole. We also uncover evidence of genetic exchange, indicating a sexual life-cycle of the parasite despite an absence of morphologically-distinct sexual stages. Our study represents the first robust and comprehensive evaluation of global T. vaginalis genetic diversity and population structure. Our identification of a unique two-type structure, and the clinically relevant phenotypes associated with them, provides a new dimension for understanding T. vaginalis pathogenesis. In addition, our demonstration of the possibility of genetic exchange in the parasite has important implications for genetic research and control of the disease.

Education and certification of genetic counselors.

PubMed

Katsichti, L; Hadzipetros-Bardanis, M; Bartsocas, C S

1999-01-01

Genetic counseling is defined by the American Society of Human Genetics as a communication process which deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. The first graduate program (Master's degree) in genetic counseling started in 1969 at Sarah Lawrence College, NY, USA, while in 1979 the National Society of Genetic Counseling (NSGC) was established. Today, there are 29 programs in U.S.A. offering a Master's degree in Genetic Counseling, five programs in Canada, one in Mexico, one in England and one in S. Africa. Most of these graduate programs offer two year training, consisting of graduate courses, seminars, research and practical training. Emphasis is given in human physiology, biochemistry, clinical genetics, cytogenetics, molecular and biochemical genetics, population genetics and statistics, prenatal diagnosis, teratology and genetic counseling in relation to psychosocial and ethical issues. Certification for eligible candidates is available through the American Board of Medical Genetics (ABMG). Requirements for certification include a master's degree in human genetics, training at sites accredited by the ABMG, documentation of genetic counseling experience, evidence of continuing education and successful completion of a comprehensive ABMG certification examination. As professionals, genetic counselors should maintain expertise, should insure mechanisms for professional advancement and should always maintain the ability to approach their patients.

A Comparative Study on Multifactor Dimensionality Reduction Methods for Detecting Gene-Gene Interactions with the Survival Phenotype

PubMed Central

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

Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India.

PubMed

Mohan, Viswanathan; Radha, Venkatesan; Nguyen, Thong T; Stawiski, Eric W; Pahuja, Kanika Bajaj; Goldstein, Leonard D; Tom, Jennifer; Anjana, Ranjit Mohan; Kong-Beltran, Monica; Bhangale, Tushar; Jahnavi, Suresh; Chandni, Radhakrishnan; Gayathri, Vijay; George, Paul; Zhang, Na; Murugan, Sakthivel; Phalke, Sameer; Chaudhuri, Subhra; Gupta, Ravi; Zhang, Jingli; Santhosh, Sam; Stinson, Jeremy; Modrusan, Zora; Ramprasad, V L; Seshagiri, Somasekar; Peterson, Andrew S

2018-02-13

Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed. We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6-1 that may contribute to development of MODY. Functional assessment of the NKX6-1 variants showed that they are functionally impaired. Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6-1, and these require further validation.

End-Stage Kidney Failure in Oman: An Analysis of Registry Data with an Emphasis on Congenital and Inherited Renal Diseases

PubMed Central

Al Mawali, Adhra; Al Maimani, Yacoub

2017-01-01

Globally, end-stage kidney disease (ESKD) is a huge burden on health care systems. The aims of this study were to perform a comprehensive epidemiological and etiological report of ESKD patients commencing RRT in Oman with an emphasis on genetic causes and inherited kidney disease. All newly registered Omani patients with ESKD commencing RRT from 2001 until 2015 (n = 2,922) were analysed using the RRT register in Oman. All potentially genetic or inherited causes of ESKD were reviewed. In Oman, ESKD is more prevalent in males (57.1%) than females (42.9%) with a median age of incident ESKD of 53 years. Diabetic nephropathy was the most prevalent cause of ESKD (46%), followed by hypertensive nephropathy (19%), glomerulonephritis (15%), and inherited kidney disease (5%). For patients less than 20 years of age inherited kidney disease accounted for 32.5% of cases. Of this cohort with inherited renal disease, 40.3% had autosomal dominant polycystic kidney disease, 11.5% had congenital anomalies of the kidney and urinary tract, 9.4% had Alport syndrome, and 7.2% had autosomal recessive polycystic kidney disease. This study represents a comprehensive population-based epidemiological and etiological report of ESKD patients in Oman commencing RRT. Inherited kidney disease was the leading cause of paediatric ESKD. PMID:28685101

Landscape genomics in Atlantic salmon (Salmo salar): searching for gene-environment interactions driving local adaptation.

PubMed

Vincent, Bourret; Dionne, Mélanie; Kent, Matthew P; Lien, Sigbjørn; Bernatchez, Louis

2013-12-01

A growing number of studies are examining the factors driving historical and contemporary evolution in wild populations. By combining surveys of genomic variation with a comprehensive assessment of environmental parameters, such studies can increase our understanding of the genomic and geographical extent of local adaptation in wild populations. We used a large-scale landscape genomics approach to examine adaptive and neutral differentiation across 54 North American populations of Atlantic salmon representing seven previously defined genetically distinct regional groups. Over 5500 genome-wide single nucleotide polymorphisms were genotyped in 641 individuals and 28 bulk assays of 25 pooled individuals each. Genome scans, linkage map, and 49 environmental variables were combined to conduct an innovative landscape genomic analysis. Our results provide valuable insight into the links between environmental variation and both neutral and potentially adaptive genetic divergence. In particular, we identified markers potentially under divergent selection, as well as associated selective environmental factors and biological functions with the observed adaptive divergence. Multivariate landscape genetic analysis revealed strong associations of both genetic and environmental structures. We found an enrichment of growth-related functions among outlier markers. Climate (temperature-precipitation) and geological characteristics were significantly associated with both potentially adaptive and neutral genetic divergence and should be considered as candidate loci involved in adaptation at the regional scale in Atlantic salmon. Hence, this study significantly contributes to the improvement of tools used in modern conservation and management schemes of Atlantic salmon wild populations. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.

PubMed

Hamosh, Ada; Scott, Alan F; Amberger, Joanna S; Bocchini, Carol A; McKusick, Victor A

2005-01-01

Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support human genetics research and education and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim/) is now distributed electronically by the National Center for Biotechnology Information, where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, HUGO nomenclature, MapViewer, GeneTests, patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.

Cohort profile: the Western Australian Sleep Health Study.

PubMed

Mukherjee, Sutapa; Hillman, David; Lee, Jessica; Fedson, Annette; Simpson, Laila; Ward, Kim; Love, Gregory; Edwards, Cass; Szegner, Bernadett; Palmer, Lyle John

2012-03-01

Epidemiologic and genetic studies of obstructive sleep apnoea (OSA) are limited by a lack of large-scale, well-characterized OSA cohorts. These studies require large sample size to provide adequate power to detect differences between groups. This study describes the development of such a cohort (The Western Australian Sleep Health Study) in OSA patients of Caucasian-European origin attending the only public sleep clinic in Western Australia (WA). The main aim of the study is to phenotype 4,000 OSA patients in order to define the genetics of OSA and its co-morbidities. Almost all underwent laboratory-based attended polysomnography (PSG). Currently complete data (questionnaire, biochemistry, DNA, and PSG) has been obtained on over 3,000 individuals and will reach the target of 4,000 individuals by the end of 2010. In a separate but related study, we have developed a sleep study database containing data from all patients who have undergone PSG at the sleep laboratory since its inception in 1988 until the present day (over 30,000 PSG studies representing data from approximately 20,000 individuals). In addition, data from both cohorts have been linked prospectively to statutory health data collected by the WA Department of Health. This study will be the largest sleep clinic cohort database internationally with access to genetic and epidemiological data. It is unique among sleep clinic cohorts because of its size, the breadth of data collected and the ability to link prospectively to statutory health data. It will be a major tool to comprehensively assess genetic and epidemiologic factors determining OSA and its co-morbidities.

Worldwide phylogenetic relationship of avian poxviruses

USGS Publications Warehouse

Gyuranecz, Miklós; Foster, Jeffrey T.; Dán, Ádám; Ip, Hon S.; Egstad, Kristina F.; Parker, Patricia G.; Higashiguchi, Jenni M.; Skinner, Michael A.; Höfle, Ursula; Kreizinger, Zsuzsa; Dorrestein, Gerry M.; Solt, Szabolcs; Sós, Endre; Kim, Young Jun; Uhart, Marcela; Pereda, Ariel; González-Hein, Gisela; Hidalgo, Hector; Blanco, Juan-Manuel; Erdélyi, Károly

2013-01-01

Poxvirus infections have been found in 230 species of wild and domestic birds worldwide in both terrestrial and marine environments. This ubiquity raises the question of how infection has been transmitted and globally dispersed. We present a comprehensive global phylogeny of 111 novel poxvirus isolates in addition to all available sequences from GenBank. Phylogenetic analysis of Avipoxvirus genus has traditionally relied on one gene region (4b core protein). In this study we have expanded the analyses to include a second locus (DNA polymerase gene), allowing for a more robust phylogenetic framework, finer genetic resolution within specific groups and the detection of potential recombination. Our phylogenetic results reveal several major features of avipoxvirus evolution and ecology and propose an updated avipoxvirus taxonomy, including three novel subclades. The characterization of poxviruses from 57 species of birds in this study extends the current knowledge of their host range and provides the first evidence of the phylogenetic effect of genetic recombination of avipoxviruses. The repeated occurrence of avian family or order-specific grouping within certain clades (e.g. starling poxvirus, falcon poxvirus, raptor poxvirus, etc.) indicates a marked role of host adaptation, while the sharing of poxvirus species within prey-predator systems emphasizes the capacity for cross-species infection and limited host adaptation. Our study provides a broad and comprehensive phylogenetic analysis of the Avipoxvirus genus, an ecologically and environmentally important viral group, to formulate a genome sequencing strategy that will clarify avipoxvirus taxonomy.

Worldwide Phylogenetic Relationship of Avian Poxviruses

PubMed Central

Foster, Jeffrey T.; Dán, Ádám; Ip, Hon S.; Egstad, Kristina F.; Parker, Patricia G.; Higashiguchi, Jenni M.; Skinner, Michael A.; Höfle, Ursula; Kreizinger, Zsuzsa; Dorrestein, Gerry M.; Solt, Szabolcs; Sós, Endre; Kim, Young Jun; Uhart, Marcela; Pereda, Ariel; González-Hein, Gisela; Hidalgo, Hector; Blanco, Juan-Manuel; Erdélyi, Károly

2013-01-01

Poxvirus infections have been found in 230 species of wild and domestic birds worldwide in both terrestrial and marine environments. This ubiquity raises the question of how infection has been transmitted and globally dispersed. We present a comprehensive global phylogeny of 111 novel poxvirus isolates in addition to all available sequences from GenBank. Phylogenetic analysis of the Avipoxvirus genus has traditionally relied on one gene region (4b core protein). In this study we expanded the analyses to include a second locus (DNA polymerase gene), allowing for a more robust phylogenetic framework, finer genetic resolution within specific groups, and the detection of potential recombination. Our phylogenetic results reveal several major features of avipoxvirus evolution and ecology and propose an updated avipoxvirus taxonomy, including three novel subclades. The characterization of poxviruses from 57 species of birds in this study extends the current knowledge of their host range and provides the first evidence of the phylogenetic effect of genetic recombination of avipoxviruses. The repeated occurrence of avian family or order-specific grouping within certain clades (e.g., starling poxvirus, falcon poxvirus, raptor poxvirus, etc.) indicates a marked role of host adaptation, while the sharing of poxvirus species within prey-predator systems emphasizes the capacity for cross-species infection and limited host adaptation. Our study provides a broad and comprehensive phylogenetic analysis of the Avipoxvirus genus, an ecologically and environmentally important viral group, to formulate a genome sequencing strategy that will clarify avipoxvirus taxonomy. PMID:23408635

In vivo cell biology in zebrafish – providing insights into vertebrate development and disease

PubMed Central

Vacaru, Ana M.; Unlu, Gokhan; Spitzner, Marie; Mione, Marina; Knapik, Ela W.; Sadler, Kirsten C.

2014-01-01

ABSTRACT Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease. PMID:24481493

I feel you-monitoring environmental variables related to asthma in an integrated real-time frame.

PubMed

Berenguer, Anabela Gonçalves

2015-09-11

The study of asthma and other complex diseases has proven to be a "moving target" for researchers due to its complex aetiology, difficulty in definition, and immeasurable environmental effects. A large number of studies regarding the contribution of both genetic and environmental factors often result in contradictory results, in part due to the highly heterogeneous nature of asthma. Recent literature has focused on the epigenetic signatures of asthma caused by environmental factors, highlighting the importance of environment. However, unlike the genetic techniques, environmental assessment still lacks accuracy. A plausible solution for this problem would be an individual-based environmental exposure assessment, relying on new technologies such as personal real-time environmental sensors. This could prove to enable the assessment of the whole environmental exposure-or exposome-matching in terms of precision the genome that is emphasized in most studies so far. In addition, the measurement of the whole array of biological molecules, in response to the environment action, could help understand the context of the disease. The current perspective comprises a beyond-genetics integrated vision of omics technology coupled with real-time environmental measures targeting to enhance our comprehension of the disease genesis.

A Systematic Review of Genetic Testing and Lifestyle Behaviour Change: Are We Using High-Quality Genetic Interventions and Considering Behaviour Change Theory?

PubMed

Horne, Justine; Madill, Janet; O'Connor, Colleen; Shelley, Jacob; Gilliland, Jason

2018-04-10

Studying the impact of genetic testing interventions on lifestyle behaviour change has been a priority area of research in recent years. Substantial heterogeneity exists in the results and conclusions of this literature, which has yet to be explained using validated behaviour change theory and an assessment of the quality of genetic interventions. The theory of planned behaviour (TPB) helps to explain key contributors to behaviour change. It has been hypothesized that personalization could be added to this theory to help predict changes in health behaviours. This systematic review provides a detailed, comprehensive identification, assessment, and summary of primary research articles pertaining to lifestyle behaviour change (nutrition, physical activity, sleep, and smoking) resulting from genetic testing interventions. The present review further aims to provide in-depth analyses of studies conducted to date within the context of the TPB and the quality of genetic interventions provided to participants while aiming to determine whether or not genetic testing facilitates changes in lifestyle habits. This review is timely in light of a recently published "call-to-action" paper, highlighting the need to incorporate the TPB into personalized healthcare behaviour change research. Three bibliographic databases, one key website, and article reference lists were searched for relevant primary research articles. The PRISMA Flow Diagram and PRISMA Checklist were used to guide the search strategy and manuscript preparation. Out of 32,783 titles retrieved, 26 studies met the inclusion criteria. Three quality assessments were conducted and included: (1) risk of bias, (2) quality of genetic interventions, and (3) consideration of theoretical underpinnings - primarily the TPB. Risk of bias in studies was overall rated to be "fair." Consideration of the TPB was "poor," with no study making reference to this validated theory. While some studies (n = 11; 42%) made reference to other behaviour change theories, these theories were generally mentioned briefly, and were not thoroughly incorporated into the study design or analyses. The genetic interventions provided to participants were overall of "poor" quality. However, a separate analysis of studies using controlled intervention research methods demonstrated the use of higher-quality genetic interventions (overall rated to be "fair"). The provision of actionable recommendations informed by genetic testing was more likely to facilitate behaviour change than the provision of genetic information without actionable lifestyle recommendations. Several studies of good quality demonstrated changes in lifestyle habits arising from the provision of genetic interventions. The most promising lifestyle changes were changes in nutrition. It is possible to facilitate behaviour change using genetic testing as the catalyst. Future research should ensure that high-quality genetic interventions are provided to participants, and should consider validated theories such as the TPB in their study design and analyses. Further recommendations for future research are provided. © 2018 S. Karger AG, Basel.

Genetic characterization, molecular epidemiology, and phylogenetic relationships of insect-specific viruses in the taxon Negevirus

PubMed Central

Nunes, Marcio R.T.; Contreras-Gutierrez, María Angélica; Guzman, Hilda; Martins, Livia C.; Barbirato, Mayla Feitoza; Savit, Chelsea; Balta, Victoria; Uribe, Sandra; Vivero, Rafael; Suaza, Juan David; Oliveira, Hamilton; Nunes Neto, Joaquin P.; Carvalho, Valeria L.; da Silva, Sandro Patroca; Cardoso, Jedson F.; de Oliveira, Rodrigo Santo; da Silva Lemos, Poliana; Wood, Thomas G.; Widen, Steven G.; Vasconcelos, Pedro F.C.; Fish, Durland; Vasilakis, Nikos; Tesh, Robert B.

2017-01-01

The recently described taxon Negevirus is comprised of a diverse group of insect-specific viruses isolated from mosquitoes and phlebotomine sandflies. In this study, a comprehensive genetic characterization, molecular, epidemiological and evolutionary analyses were conducted on nearly full-length sequences of 91 new negevirus isolates obtained in Brazil, Colombia, Peru, Panama, USA and Nepal. We demonstrated that these arthropod restricted viruses are clustered in two major phylogenetic groups with origins related to three plant virus genera (Cilevirus, Higrevirus and Blunevirus). Molecular analyses demonstrated that specific host correlations are not present with most negeviruses; instead, high genetic variability, wide host-range, and cross-species transmission were noted. The data presented here also revealed the existence of five novel insect-specific viruses falling into two arthropod-restrictive virus taxa, previously proposed as distinct genera, designated Nelorpivirus and Sandewavirus. Our results provide a better understanding of the molecular epidemiology, evolution, taxonomy and stability of this group of insect-restricted viruses. PMID:28193550

How I manage patients with Fanconi anaemia.

PubMed

Dufour, Carlo

2017-07-01

Fanconi Anaemia is a rare, genetic heterogeneous multisystem disease that is the most common congenital syndrome of marrow failure. Twenty genes have been reported to cause the disease. Remarkable progress has been made over the last 20 years in the understanding of the genetic and pathophysiological mechanisms. Unfortunately, these advances have not been completely paralleled by advances in medical treatment, where the most important component remains stem cell transplantation. This therapy, although contributing to long-term negative effects, such as increased occurrence of late malignancies, is the only current option capable of prolonging the survival of patients. In spite of relevant recent progress in matched unrelated donor transplants, the largest studies with longer follow-up still show a superiority of matched sibling donor transplants with a success rate, in selected cohorts, of over 90%. This article reviews different aspects of the disease, including genetics, diagnosis and treatment options, with special focus on stem cell transplantation, comprehensive post-diagnosis management, decision-making processes and long-term follow-up. © 2017 John Wiley & Sons Ltd.

Genetic characterization, molecular epidemiology, and phylogenetic relationships of insect-specific viruses in the taxon Negevirus.

PubMed

Nunes, Marcio R T; Contreras-Gutierrez, María Angélica; Guzman, Hilda; Martins, Livia C; Barbirato, Mayla Feitoza; Savit, Chelsea; Balta, Victoria; Uribe, Sandra; Vivero, Rafael; Suaza, Juan David; Oliveira, Hamilton; Nunes Neto, Joaquin P; Carvalho, Valeria L; da Silva, Sandro Patroca; Cardoso, Jedson F; de Oliveira, Rodrigo Santo; da Silva Lemos, Poliana; Wood, Thomas G; Widen, Steven G; Vasconcelos, Pedro F C; Fish, Durland; Vasilakis, Nikos; Tesh, Robert B

2017-04-01

The recently described taxon Negevirus is comprised of a diverse group of insect-specific viruses isolated from mosquitoes and phlebotomine sandflies. In this study, a comprehensive genetic characterization, molecular, epidemiological and evolutionary analyses were conducted on nearly full-length sequences of 91 new negevirus isolates obtained in Brazil, Colombia, Peru, Panama, USA and Nepal. We demonstrated that these arthropod restricted viruses are clustered in two major phylogenetic groups with origins related to three plant virus genera (Cilevirus, Higrevirus and Blunevirus). Molecular analyses demonstrated that specific host correlations are not present with most negeviruses; instead, high genetic variability, wide host-range, and cross-species transmission were noted. The data presented here also revealed the existence of five novel insect-specific viruses falling into two arthropod-restrictive virus taxa, previously proposed as distinct genera, designated Nelorpivirus and Sandewavirus. Our results provide a better understanding of the molecular epidemiology, evolution, taxonomy and stability of this group of insect-restricted viruses. Copyright © 2017 Elsevier Inc. All rights reserved.

Common genetic variation drives molecular heterogeneity in human iPSCs.

PubMed

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.

Common genetic variation drives molecular heterogeneity in human iPSCs

PubMed Central

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

Applying Biometric Growth Curve Models to Developmental Synchronies in Cognitive Development: The Louisville Twin Study.

PubMed

Finkel, Deborah; Davis, Deborah Winders; Turkheimer, Eric; Dickens, William T

2015-11-01

Biometric latent growth curve models were applied to data from the LTS in order to replicate and extend Wilson's (Child Dev 54:298-316, 1983) findings. Assessments of cognitive development were available from 8 measurement occasions covering the period 4-15 years for 1032 individuals. Latent growth curve models were fit to percent correct for 7 subscales: information, similarities, arithmetic, vocabulary, comprehension, picture completion, and block design. Models were fit separately to WPPSI (ages 4-6 years) and WISC-R (ages 7-15). Results indicated the expected increases in heritability in younger childhood, and plateaus in heritability as children reached age 10 years. Heritability of change, per se (slope estimates), varied dramatically across domains. Significant genetic influences on slope parameters that were independent of initial levels of performance were found for only information and picture completion subscales. Thus evidence for both genetic continuity and genetic innovation in the development of cognitive abilities in childhood were found.

Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

PubMed Central

Pendergrass, Sarah A.; Brown-Gentry, Kristin; Dudek, Scott; Frase, Alex; Torstenson, Eric S.; Goodloe, Robert; Ambite, Jose Luis; Avery, Christy L.; Buyske, Steve; Bůžková, Petra; Deelman, Ewa; Fesinmeyer, Megan D.; Haiman, Christopher A.; Heiss, Gerardo; Hindorff, Lucia A.; Hsu, Chu-Nan; Jackson, Rebecca D.; Kooperberg, Charles; Le Marchand, Loic; Lin, Yi; Matise, Tara C.; Monroe, Kristine R.; Moreland, Larry; Park, Sungshim L.; Reiner, Alex; Wallace, Robert; Wilkens, Lynn R.; Crawford, Dana C.; Ritchie, Marylyn D.

2013-01-01

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype–phenotype associations, 26 represented phenotypes closely related to previously known genotype–phenotype associations, and 33 represented potentially novel genotype–phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits. PMID:23382687

Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an institute of child neuropsychiatry.

PubMed

Battaglia, A; Bianchini, E; Carey, J C

1999-01-01

The Consensus Conference of the American College of Medical Genetics has established guidelines regarding the evaluation of patients with mental retardation (MR) [Curry et al., Am. J. Med. Genet. 72:468-477, 1997]. They emphasized the high diagnostic utility of cytogenetic studies and of neuroimaging in certain clinical settings. However, data on the diagnostic yield of these studies in well-characterized populations of individuals with MR are scant. Majnemer and Shevell [J. Pediatr. 127:193-199, 1995] attained a diagnostic yield of 63%. However, this study included only 60 patients and the classification included pathogenetic and causal groups. The Stella Maris Institute has evaluated systematically patients with developmental delay (DD)/MR and performed various laboratory studies and neuroimaging in almost all patients. We report a retrospective analysis of the diagnostic yield of 120 consecutive patients observed at our Institute during the first 6 months of 1996. There were 77 males and 43 females; 47 were mildly delayed (IQ 70-50), 31 were moderately delayed (IQ 50-35), and 42 were severely delayed (IQ 35-20). Diagnostic studies (history, physical examination, standard cytogenetics, fragile X testing, molecular studies, electroencephalography, electromyography, nerve conduction studies, neuroimaging, and metabolic screening tests) yielded a causal diagnosis in 50 (41.6%) and a pathogenetic diagnosis in 47 (39.2%) of the 120 patients. Causal categories included chromosomal abnormalities (14), Fra(X) syndromes (4), known MCA/MR syndromes (19), fetal environmental syndromes (1), neurometabolic (3) disorders, neurocutaneous (3) disorders, hypoxic-ischemic encephalopathy (3), other encephalopathies (1), and congenital bilateral perisylvian syndrome (2). Pathogenetic categories included idiopathic MCA/MR syndromes (35), epileptic syndromes (10), and isolated lissencephaly sequence (2). Diagnostic yield did not differ across categories and degree of DD. Our results, while confirming the diagnostic utility of cytogenetic/molecular genetic, and neuroimaging studies, suggest the usefulness of accurate electroencephalogram recordings, and stress the importance of a thorough physical examination. Referral to a university child neurology and psychiatry service, where a comprehensive assessment with a selected battery of investigations is possible, yields etiologic findings in a high percentage of DD/MR patients, with important implications for management, prognosis and recurrence risk estimate.

Childhood Midline Tract Carcinoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

NUT midline carcinoma is an aggressive malignancy genetically defined by rearrangements of the NUT gene. Get comprehensive information about childhood NUT midline carcinoma, molecular features, clinical presentation, prognosis, and treatment in this summary for clinicians.

Stakeholder Conference on Bee Health

EPA Pesticide Factsheets

USDA and EPA released a comprehensive scientific report on honey bee health in May 2013. The report points to multiple factors playing a role in honey bee colony declines, including parasites and disease, genetics, poor nutrition, and pesticide exposure.

Anaconda: AN automated pipeline for somatic COpy Number variation Detection and Annotation from tumor exome sequencing data.

PubMed

Gao, Jianing; Wan, Changlin; Zhang, Huan; Li, Ao; Zang, Qiguang; Ban, Rongjun; Ali, Asim; Yu, Zhenghua; Shi, Qinghua; Jiang, Xiaohua; Zhang, Yuanwei

2017-10-03

Copy number variations (CNVs) are the main genetic structural variations in cancer genome. Detecting CNVs in genetic exome region is efficient and cost-effective in identifying cancer associated genes. Many tools had been developed accordingly and yet these tools lack of reliability because of high false negative rate, which is intrinsically caused by genome exonic bias. To provide an alternative option, here, we report Anaconda, a comprehensive pipeline that allows flexible integration of multiple CNV-calling methods and systematic annotation of CNVs in analyzing WES data. Just by one command, Anaconda can generate CNV detection result by up to four CNV detecting tools. Associated with comprehensive annotation analysis of genes involved in shared CNV regions, Anaconda is able to deliver a more reliable and useful report in assistance with CNV-associate cancer researches. Anaconda package and manual can be freely accessed at http://mcg.ustc.edu.cn/bsc/ANACONDA/ .

Prospective investigation of FOXP1 syndrome.

PubMed

Siper, Paige M; De Rubeis, Silvia; Trelles, Maria Del Pilar; Durkin, Allison; Di Marino, Daniele; Muratet, François; Frank, Yitzchak; Lozano, Reymundo; Eichler, Evan E; Kelly, Morgan; Beighley, Jennifer; Gerdts, Jennifer; Wallace, Arianne S; Mefford, Heather C; Bernier, Raphael A; Kolevzon, Alexander; Buxbaum, Joseph D

2017-01-01

Haploinsufficiency of the forkhead-box protein P1 ( FOXP1 ) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1 . Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.

A transcriptome-based examination of blood group expression

PubMed Central

Noh, S.-J.; Lee, Y.T.; Byrnes, C.; Miller, J.L.

2011-01-01

Over the last two decades, red cell biologists witnessed a vast expansion of genetic-based information pertaining to blood group antigens and their carrier molecules. Genetic progress has led to a better comprehension of the associated antigens. To assist with studies concerning the integrated regulation and function of blood groups, transcript levels for each of the 36 associated genes were studied. Profiles using mRNA from directly sampled reticulocytes and cultured primary erythroblasts are summarized in this report. Transcriptome profiles suggest a highly regulated pattern of blood group gene expression during erythroid differentiation and ontogeny. Approximately one-third of the blood group carrier genes are transcribed in an erythroid-specific fashion. Low-level and indistinct expression was noted for most of the carbohydrate-associated genes. Methods are now being developed to further explore and manipulate expression of the blood group genes at all stages of human erythropoiesis. PMID:20685146

Evolutionary domestication in Drosophila subobscura.

PubMed

Simões, P; Rose, M R; Duarte, A; Gonçalves, R; Matos, M

2007-03-01

The domestication of plants and animals is historically one of the most important topics in evolutionary biology. The evolutionary genetic changes arising from human cultivation are complex because of the effects of such varied processes as continuing natural selection, artificial selection, deliberate inbreeding, genetic drift and hybridization of different lineages. Despite the interest of domestication as an evolutionary process, few studies of multicellular sexual species have approached this topic using well-replicated experiments. Here we present a comprehensive study in which replicated evolutionary trajectories from several Drosophila subobscura populations provide a detailed view of the evolutionary dynamics of domestication in an outbreeding animal species. Our results show a clear evolutionary response in fecundity traits, but no clear pattern for adult starvation resistance and juvenile traits such as development time and viability. These results supply new perspectives on the confounding of adaptation with other evolutionary mechanisms in the process of domestication.

Identification of Five Novel Variants in Chinese Oculocutaneous Albinism by Targeted Next-Generation Sequencing.

PubMed

Qiu, Biyuan; Ma, Tao; Peng, Chunyan; Zheng, Xiaoqin; Yang, Jiyun

2018-04-01

The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic. To develop and validate a more comprehensive, targeted, next-generation-sequencing-based diagnostic for the identification of OCA-causing variants. The genomic DNA samples from 28 OCA probands were analyzed by targeted next-generation sequencing (NGS), and the candidate variants were confirmed through Sanger sequencing. We observed mutations in the TYR, OCA2, and SLC45A2 genes in 25/28 (89%) patients with OCA. We identified 38 pathogenic variants among these three genes, including 5 novel variants: c.1970G>T (p.Gly657Val), c.1669A>C (p.Thr557Pro), c.2339-2A>C, and c.1349C>G (p.Thr450Arg) in OCA2; c.459_470delTTTTGCTGCCGA (p.Ala155_Phe158del) in SLC45A2. Our findings expand the mutational spectrum of OCA in the Chinese population, and the assay we developed should be broadly useful as a molecular diagnostic, and as an aid for genetic counseling for OCA patients.

The power of projectomes: genetic mosaic labeling in the larval zebrafish brain reveals organizing principles of sensory circuits.

PubMed

Robles, Estuardo

2017-09-01

In no vertebrate species do we possess an accurate, comprehensive tally of neuron types in the brain. This is in no small part due to the vast diversity of neuronal types that comprise complex vertebrate nervous systems. A fundamental goal of neuroscience is to construct comprehensive catalogs of cell types defined by structure, connectivity, and physiological response properties. This type of information will be invaluable for generating models of how assemblies of neurons encode and distribute sensory information and correspondingly alter behavior. This review summarizes recent efforts in the larval zebrafish to construct sensory projectomes, comprehensive analyses of axonal morphologies in sensory axon tracts. Focusing on the olfactory and optic tract, these studies revealed principles of sensory information processing in the olfactory and visual systems that could not have been directly quantified by other methods. In essence, these studies reconstructed the optic and olfactory tract in a virtual manner, providing insights into patterns of neuronal growth that underlie the formation of sensory axon tracts. Quantitative analysis of neuronal diversity revealed organizing principles that determine information flow through sensory systems in the zebrafish that are likely to be conserved across vertebrate species. The generation of comprehensive cell type classifications based on structural, physiological, and molecular features will lead to testable hypotheses on the functional role of individual sensory neuron subtypes in controlling specific sensory-evoked behaviors.

Genetic Diversity and Domestication Footprints of Chinese Cherry [Cerasus pseudocerasus (Lindl.) G.Don] as Revealed by Nuclear Microsatellites

PubMed Central

Zhang, Jing; Chen, Tao; Wang, Yan; Chen, Qing; Sun, Bo; Luo, Ya; Zhang, Yong; Tang, Haoru; Wang, Xiaorong

2018-01-01

Chinese cherry [Cerasus pseudocerasus (Lindl.) G.Don] is a commercially important fruit crop in China, but its structure patterns and domestication history remain imprecise. To address these questions, we estimated the genetic structure and domestication history of Chinese cherry using 19 nuclear microsatellite markers and 650 representative accessions (including 118 Cerasus relatives) selected throughout their natural eco-geographical distributions. Our structure analyses detected no genetic contribution from Cerasus relatives to the evolution history of Chinese cherry. A separate genetic structure was detected in wild Chinese cherries and rough geographical structures were observed in cultivated Chinese cherries. One wild (wild Chinese cherry, WC) and two cultivated (cultivated Chinese cherry, CC1 and CC2) genetic clusters were defined. Our approximate Bayesian computation analyses supported an independent domestication history with two domestication events for CC1 and CC2, happening about 3900 and 2200 years ago, respectively. Moderate loss of genetic diversity, over 1000-year domestication bottlenecks and divergent domestication in fruit traits were also detected in cultivated Chinese cherries, which is highly correlated to long-term clonal propagation and different domestication trends and preferences. Our study is the first to comprehensively and systematically investigate the structure patterns and domestication history for Chinese cherry, providing important references for revealing the evolution and domestication history of perennial woody fruit trees. PMID:29535750

Congruence of Additive and Non-Additive Effects on Gene Expression Estimated from Pedigree and SNP Data

PubMed Central

Powell, Joseph E.; Henders, Anjali K.; McRae, Allan F.; Kim, Jinhee; Hemani, Gibran; Martin, Nicholas G.; Dermitzakis, Emmanouil T.; Gibson, Greg

2013-01-01

There is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted—in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects. PMID:23696747

Congruence of additive and non-additive effects on gene expression estimated from pedigree and SNP data.

PubMed

Powell, Joseph E; Henders, Anjali K; McRae, Allan F; Kim, Jinhee; Hemani, Gibran; Martin, Nicholas G; Dermitzakis, Emmanouil T; Gibson, Greg; Montgomery, Grant W; Visscher, Peter M

2013-05-01

There is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted--in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects.

Ethical and practical challenges surrounding genetic and genomic research in developing countries.

PubMed

Nyika, Aceme

2009-11-01

The nature of some potential benefits and risks associated with genetic research is different from the types of potential benefits and risks associated with other types of health research such as clinical trials and biomedical research involving humans. Whereas most potential risks associated with biomedical research or clinical trials are mainly biological in nature, potential risks associated with genetic research are mainly of socioeconomic nature. Although the peculiarity of some of the aspects of genetic research and the complexity of the science involved are acknowledged, the extent to which these characteristics hinder firstly disclosure of information to participants and their communities and secondly comprehension of the disclosed information is a practical challenge that tends to be exaggerated in some cases. In this article, a brief overview of the various types of genetic research will be given in order to set the scene for some ethical and practical issues surrounding the research in developing countries that will be discussed subsequently. Case studies that illustrate some of the ethical and practical issues flagged will be given, followed by suggestions on possible ways of tackling some of the challenges in developing country settings. Nevertheless, genetic and genomic research could go a long way in providing knowledge that could be useful in the development of drugs and vaccines for many diseases affecting the developing countries.

A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients.

PubMed

Masson, Emmanuelle; Chen, Jian-Min; Audrézet, Marie-Pierre; Cooper, David N; Férec, Claude

2013-01-01

Idiopathic chronic pancreatitis (ICP) has traditionally been defined as chronic pancreatitis in the absence of any obvious precipitating factors (e.g. alcohol abuse) and family history of the disease. Studies over the past 15 years have revealed that ICP has a highly complex genetic architecture involving multiple gene loci. Here, we have attempted to provide a conservative assessment of the major genetic causes of ICP in a sample of 253 young French ICP patients. For the first time, conventional types of mutation (comprising coding sequence variants and variants at intron/exon boundaries) and gross genomic rearrangements were screened for in all four major pancreatitis genes, PRSS1, SPINK1, CTRC and CFTR. For the purposes of the study, synonymous, intronic and 5'- or 3'-untranslated region variants were excluded from the analysis except where there was persuasive evidence of functional consequences. The remaining sequence variants/genotypes were classified into causative, contributory or neutral categories by consideration of (i) their allele frequencies in patient and normal control populations, (ii) their presumed or experimentally confirmed functional effects, (iii) the relative importance of their associated genes in the pathogenesis of chronic pancreatitis and (iv) gene-gene interactions wherever applicable. Adoption of this strategy allowed us to assess the pathogenic relevance of specific variants/genotypes to their respective carriers to an unprecedented degree. The genetic cause of ICP could be assigned in 23.7% of individuals in the study group. A strong genetic susceptibility factor was also present in an additional 24.5% of cases. Taken together, up to 48.2% of the studied ICP patients were found to display evidence of a genetic basis for their pancreatitis. Whereas these particular proportions may not be extrapolable to all ICP patients, the approach employed should serve as a useful framework for acquiring a better understanding of the role of genetic factors in causing this oligogenic disease.

Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity.

PubMed

Pigeyre, Marie; Yazdi, Fereshteh T; Kaur, Yuvreet; Meyre, David

2016-06-01

In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy

PubMed Central

Ng, Andrea K.; Allan, James M.; Pui, Ching-Hon; Kennedy, Ann R.; Xu, X. George; Purdy, James A.; Applegate, Kimberly; Yahalom, Joachim; Constine, Louis S.; Gilbert, Ethel S.; Boice, John D.

2012-01-01

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose–response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose–response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies. PMID:22312134

Toxoplasma and Africa: One Parasite, Two Opposite Population Structures.

PubMed

Galal, Lokman; Ajzenberg, Daniel; Hamidović, Azra; Durieux, Marie-Fleur; Dardé, Marie-Laure; Mercier, Aurélien

2018-02-01

Exploring the genetic diversity of Toxoplasma gondii is essential for an understanding of its worldwide distribution and the determinants of its evolution. Africa remains one of the least studied areas of the world regarding T. gondii genetic diversity. This review has compiled published data on T. gondii strains from Africa to generate a comprehensive map of their continent-wide geographical distribution. The emerging picture about T. gondii strain distribution in Africa suggests a geographical separation of the parasite populations across the continent. We discuss the potential role of a number of factors in shaping this structure. We finally suggest the next steps towards a better understanding of Toxoplasma epidemiology in Africa in light of the strains circulating on this continent. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic dissection of the α-globin super-enhancer in vivo

PubMed Central

Hay, Deborah; Hughes, Jim R.; Rode, Christina; Li, Pik-Shan; Pennacchio, Len A.; Sloane-Stanley, Jacqueline A.; Ayyub, Helena; Butler, Sue; Sauka-Spengler, Tatjana; Gibbons, Richard J.; Smith, Andrew J.H.; Wood, William G.; Higgs, Douglas R.

2016-01-01

Many genes determining cell identity are regulated by clusters of mediator-bound enhancer elements collectively referred to as super-enhancers. These have been proposed to manifest higher-order properties important in development and disease. Here, we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer singly and in informative combinations, we demonstrate that each constituent enhancer appears to act independently and in an additive fashion with respect to hematologic phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation. PMID:27376235

Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population.

PubMed

Hu, Guo-Xin; Dai, Da-Peng; Wang, Hao; Huang, Xiang-Xin; Zhou, Xiao-Yang; Cai, Jie; Chen, Hao; Cai, Jian-Ping

2017-03-01

To systematically investigate the genetic polymorphisms of the CYP3A4 gene in a Han Chinese population. The promoter and exons of CYP3A4 gene in 1114 unrelated, healthy Han Chinese subjects were amplified and genotyped by direct sequencing. In total, five previously reported alleles (*1G, *4, *5, *18B and *23) were detected, of which one allele (*23) was reported for the first time in Han Chinese population. Additionally, seven novel exonic variants were also identified and designated as new alleles CYP3A4*28-*34. This study provides the most comprehensive data of CYP3A4 polymorphisms in Han Chinese population and detects the largest number of novel CYP3A4 alleles in one ethnic group.

GGDonto ontology as a knowledge-base for genetic diseases and disorders of glycan metabolism and their causative genes.

PubMed

Solovieva, Elena; Shikanai, Toshihide; Fujita, Noriaki; Narimatsu, Hisashi

2018-04-18

Inherited mutations in glyco-related genes can affect the biosynthesis and degradation of glycans and result in severe genetic diseases and disorders. The Glyco-Disease Genes Database (GDGDB), which provides information about these diseases and disorders as well as their causative genes, has been developed by the Research Center for Medical Glycoscience (RCMG) and released in April 2010. GDGDB currently provides information on about 80 genetic diseases and disorders caused by single-gene mutations in glyco-related genes. Many biomedical resources provide information about genetic disorders and genes involved in their pathogenesis, but resources focused on genetic disorders known to be related to glycan metabolism are lacking. With the aim of providing more comprehensive knowledge on genetic diseases and disorders of glycan biosynthesis and degradation, we enriched the content of the GDGDB database and improved the methods for data representation. We developed the Genetic Glyco-Diseases Ontology (GGDonto) and a RDF/SPARQL-based user interface using Semantic Web technologies. In particular, we represented the GGDonto content using Semantic Web languages, such as RDF, RDFS, SKOS, and OWL, and created an interactive user interface based on SPARQL queries. This user interface provides features to browse the hierarchy of the ontology, view detailed information on diseases and related genes, and find relevant background information. Moreover, it provides the ability to filter and search information by faceted and keyword searches. Focused on the molecular etiology, pathogenesis, and clinical manifestations of genetic diseases and disorders of glycan metabolism and developed as a knowledge-base for this scientific field, GGDonto provides comprehensive information on various topics, including links to aid the integration with other scientific resources. The availability and accessibility of this knowledge will help users better understand how genetic defects impact the metabolism of glycans as well as how this impaired metabolism affects various biological functions and human health. In this way, GGDonto will be useful in fields related to glycoscience, including cell biology, biotechnology, and biomedical, and pharmaceutical research.

How the Effects of Aging and Stresses of Life Are Integrated in Mortality Rates: Insights for Genetic Studies of Human Health and Longevity

PubMed Central

Yashin, Anatoliy I.; Arbeev, Konstantin G.; Arbeeva, Liubov S.; Wu, Deqing; Akushevich, Igor; Kovtun, Mikhail; Yashkin, Arseniy; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V.

2015-01-01

Background Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. Data and methods We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. Results The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. Conclusion The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field. PMID:26280653

Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes.

PubMed

Alshogran, Osama Y

2017-10-01

Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice.

Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol).

PubMed

Richardson, Marty; Kirkham, Jamie; Dwan, Kerry; Sloan, Derek; Davies, Geraint; Jorgensen, Andrea

2017-07-13

Tuberculosis patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions, such as hepatotoxicity. Genetic risk factors, such as polymorphisms of the NAT2, CYP2E1 and GSTM1 genes, may increase the risk of experiencing such toxicity events. Many pharmacogenetic studies have investigated the association between genetic variants and anti-tuberculosis drug-related toxicity events, and several meta-analyses have synthesised data from these studies, although conclusions from these meta-analyses are conflicting. Many meta-analyses also have serious methodological limitations, such as applying restrictive inclusion criteria, or not assessing the quality of included studies. Most also only consider hepatotoxicity outcomes and specific genetic variants. The purpose of this systematic review and meta-analysis is to give a comprehensive evaluation of the evidence base for associations between any genetic variant and anti-tuberculosis drug-related toxicity. We will search for studies in MEDLINE, EMBASE, BIOSIS and Web of Science. We will also hand search reference lists from relevant studies and contact experts in the field. We will include cohort studies, case-control studies and randomised controlled trials that recruited patients with tuberculosis who were either already established on anti-tuberculosis treatment or were commencing treatment and who were genotyped to investigate the effect of genetic variants on any anti-tuberculosis drug-related toxicity outcome. One author will screen abstracts to identify potentially relevant studies and will then obtain the full text for each potentially relevant study in order to assess eligibility. At each of these stages, a second author will independently screen/assess 10% of studies. Two authors will independently extract data and assess the quality of studies using a pre-piloted data extraction form. If appropriate, we will pool estimates of effect for each genotype on each outcome using meta-analyses stratified by ethnicity. Our review and meta-analysis will update and add to the existing research in this field. By not restricting the scope of the review to a specific drug, genetic variant, or toxicity outcome, we hope to synthesise data for associations between genetic variants and anti-tuberculosis drug-related toxicity outcomes that have previously not been summarised in systematic reviews, and consequently, add to the knowledge base of the pharmacogenetics of anti-tuberculosis drugs. PROSPERO CRD42017068448.

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

PubMed Central

Fernández-Falgueras, Anna; Sarquella-Brugada, Georgia; Cesar, Sergi; Mademont, Irene; Mates, Jesus; Pérez-Serra, Alexandra; Coll, Monica; Pico, Ferran; Iglesias, Anna; Tirón, Coloma; Allegue, Catarina; Carro, Esther; Gallego, María Ángeles; Ferrer-Costa, Carles; Hospital, Anna; Bardalet, Narcís; Borondo, Juan Carlos; Vingut, Albert; Arbelo, Elena; Brugada, Josep; Castellà, Josep; Medallo, Jordi; Brugada, Ramon

2016-01-01

Background Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases. Methods and Findings Our cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively. Conclusions Cardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk. PMID:27930701

Which BRCA genetic testing programs are ready for implementation in health care? A systematic review of economic evaluations.

PubMed

D'Andrea, Elvira; Marzuillo, Carolina; De Vito, Corrado; Di Marco, Marco; Pitini, Erica; Vacchio, Maria Rosaria; Villari, Paolo

2016-12-01

There is considerable evidence regarding the efficacy and effectiveness of BRCA genetic testing programs, but whether they represent good use of financial resources is not clear. Therefore, we aimed to identify the main health-care programs for BRCA testing and to evaluate their cost-effectiveness. We performed a systematic review of full economic evaluations of health-care programs involving BRCA testing. Nine economic evaluations were included, and four main categories of BRCA testing programs were identified: (i) population-based genetic screening of individuals without cancer, either comprehensive or targeted based on ancestry; (ii) family history (FH)-based genetic screening, i.e., testing individuals without cancer but with FH suggestive of BRCA mutation; (iii) familial mutation (FM)-based genetic screening, i.e., testing individuals without cancer but with known familial BRCA mutation; and (iv) cancer-based genetic screening, i.e., testing individuals with BRCA-related cancers. Currently BRCA1/2 population-based screening represents good value for the money among Ashkenazi Jews only. FH-based screening is potentially very cost-effective, although further studies that include costs of identifying high-risk women are needed. There is no evidence of cost-effectiveness for BRCA screening of all newly diagnosed cases of breast/ovarian cancers followed by cascade testing of relatives, but programs that include tools for identifying affected women at higher risk for inherited forms are promising. Cost-effectiveness is highly sensitive to the cost of BRCA1/2 testing.Genet Med 18 12, 1171-1180.

Relieving the Bottleneck: An Investigation of Barriers to Expansion of Supervision Networks at Genetic Counseling Training Programs.

PubMed

Berg, Jordan; Hoskovec, Jennifer; Hashmi, S Shahrukh; McCarthy Veach, Patricia; Ownby, Allison; Singletary, Claire N

2018-02-01

Rapid growth in the demand for genetic counselors has led to a workforce shortage. There is a prevailing assumption that the number of training slots for genetic counseling students is linked to the availability of clinical supervisors. This study aimed to determine and compare barriers to expansion of supervision networks at genetic counseling training programs as perceived by supervisors, non-supervisors, and Program Directors. Genetic counselors were recruited via National Society of Genetic Counselors e-blast; Program Directors received personal emails. Online surveys were completed by 216 supervisors, 98 non-supervisors, and 23 Program Directors. Respondents rated impact of 35 barriers; comparisons were made using Kruskal-Wallis and Wilcoxon ranked sum tests. Half of supervisors (51%) indicated willingness to increase supervision. All non-supervisors were willing to supervise. However, all agreed that being too busy impacted ability to supervise, highlighted by supervisors' most impactful barriers: lack of time, other responsibilities, intensive nature of supervision, desire for breaks, and unfilled positions. Non-supervisors noted unique barriers: distance, institutional barriers, and non-clinical roles. Program Directors' perceptions were congruent with those of genetic counselors with three exceptions they rated as impactful: lack of money, prefer not to supervise, and never been asked. In order to expand supervision networks and provide comprehensive student experiences, the profession must examine service delivery models to increase workplace efficiency, reconsider the supervision paradigm, and redefine what constitutes a countable case or place value on non-direct patient care experiences.

Testing the Effects of Educational Strategies on Comprehension of a Genomic Concept Using Virtual Reality Technology

PubMed Central

Kaphingst, Kimberly A.; Persky, Susan; McCall, Cade; Lachance, Christina; Loewenstein, Johanna; Beall, Andrew C.; Blascovich, Jim

2009-01-01

Objective Applying genetic susceptibility information to improve health will likely require educating patients about abstract concepts, for which there is little existing research. This experimental study examined the effect of learning mode on comprehension of a genomic concept. Methods 156 individuals aged 18–40 without specialized knowledge were randomly assigned to either a virtual reality active learning or didactic learning condition. The outcome was comprehension (recall, transfer, mental models). Results Change in recall was greater for didactic learning than active learning (p<0.001). Mean transfer and change in mental models were also higher for didactic learning (p<0.0001 and p<0.05, respectively). Believability was higher for didactic learning (p<0.05), while ratings for motivation (p<0.05), interest (p<0.0001), and enjoyment (p<0.0001) were higher for active learning, but these variables did not mediate the association between learning mode and comprehension. Conclusion These results show that learning mode affects comprehension, but additional research is needed regarding how and in what contexts different approaches are best for educating patients about abstract concepts. Practice implications Didactic, interpersonal health education approaches may be more effective than interactive games in educating patients about abstract, unfamiliar concepts. These findings indicate the importance of traditional health education approaches in emerging areas like genomics. PMID:19409749

Evaluation of the Informational Content, Readability and Comprehensibility of Online Health Information on Monogenic Diabetes.

PubMed

Guan, Yue; Maloney, Kristin A; Roter, Debra L; Pollin, Toni I

2018-06-01

The purpose of this study was to assess the informational content, readability, suitability and comprehensibility of websites offering educational information about monogenic diabetes available to patients. The top 20 results from 15 queries in four search engines were screened. Content analysis was performed by two independent coders. Readability was determined using Flesch-Kincaid grade level (FKGL) and Simplified Measure of Goobledygook (SMOG). The Comprehensibility Assessment of Materials (SAM + CAM) scale was utilized to evaluate website suitability and comprehensibility. Only 2% (N = 29) of 1200 screened websites met inclusion criteria. Content analysis showed that 16 websites presented information on at least the most common forms of MODY (1, 2 and 3), four addressed the utility of genetic counseling, and none included support resources for patients. All websites exceeded the consensus readability level (6th grade) as assessed by FKGL (10.1 grade) and SMOG (12.8 ± 1.5 grades). Although the majority (N = 20) of websites had an overall "adequate" to "superior" quality score (SAM + CAM score > = 40%), more than one-third scored "not suitable" in categories of content, literacy demand, graphics, and learning motivation. The online educational resources for monogenic diabetes have a high readability level and require improvement in ease of use and comprehensibility for patients with diabetes.

Network for Early Onset Cystic Kidney Diseases—A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood

PubMed Central

König, Jens Christian; Titieni, Andrea; Konrad, Martin; Bergmann, C.

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype–phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing “revolution” in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress. PMID:29497606

Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood.

PubMed

König, Jens Christian; Titieni, Andrea; Konrad, Martin

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.

Adverse life events, psychiatric history, and biological predictors of postpartum depression in an ethnically diverse sample of postpartum women.

PubMed

Guintivano, J; Sullivan, P F; Stuebe, A M; Penders, T; Thorp, J; Rubinow, D R; Meltzer-Brody, S

2018-05-01

Race, psychiatric history, and adverse life events have all been independently associated with postpartum depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case-control study of PPD, including comprehensive assessments of symptoms and biomarkers, while examining the effects of genetic ancestry. We recruited our sample (549 cases, 968 controls) at 6 weeks postpartum from obstetrical clinics in North Carolina. PPD status was determined using the MINI-plus. Psychiatric history was extracted from medical records. Participants were administered self-report instruments to assess depression (Edinburgh Postnatal Depression Scale) and adverse life events. Levels of estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanalone were assayed. Principal components from genotype data were used to estimate genetic ancestry and logistic regression was used to identify predictors of PPD. This population was racially diverse (68% Black, 13% Latina, 18% European). Genetic ancestry was not a predictor of PPD. Case status was predicted by a history of major depression (p = 4.01E-14), lifetime anxiety disorder diagnosis (p = 1.25E-34), and adverse life events (p = 6.06E-06). There were no significant differences between groups in any hormones or neurosteroids. Psychiatric history and multiple exposures to adverse life events were significant predictors of PPD in a population of minority and low-income women. Genetic ancestry and hormone levels were not predictive of case status. Increased genetic vulnerability in conjunction with risk factors may predict the onset of PPD, whereas genetic ancestry does not appear predictive.

Large-scale phylogeography of the disjunct Neotropical tree species Schizolobium parahyba (Fabaceae-Caesalpinioideae).

PubMed

Turchetto-Zolet, Andreia C; Cruz, Fernanda; Vendramin, Giovanni G; Simon, Marcelo F; Salgueiro, Fabiano; Margis-Pinheiro, Marcia; Margis, Rogerio

2012-10-01

Neotropical rainforests exhibit high levels of endemism and diversity. Although the evolutionary genetics of plant diversification has garnered increased interest, phylogeographic studies of widely distributed species remain scarce. Here we describe chloroplast and nuclear variation patterns in Schizolobium parahyba (Fabaceae), a widespread tree in Neotropical rainforests that harbor two varieties with a disjunct distribution. Chloroplast and nuclear sequence analyses yielded 21 and 4 haplotypes, respectively. Two genetic diversity centers that correlate with the two known varieties were identified: the Southeastern Atlantic forest and the Amazonian basin. In contrast, the populations from southern and northeastern Atlantic forests and Andean-Central American forests exhibited low levels of genetic diversity and divergent haplotypes, likely related to historical processes that impact the flora and fauna in these regions, such as a founder's effect after dispersion and demographic expansion. Phylogeographic and demographic patterns suggest that episodes of genetic isolation and dispersal events have shaped the evolutionary history for this species, and different patterns have guided the evolution of S. parahyba. Moreover, the results of this study suggest that the dry corridor formed by Cerrado and Caatinga ecoregions and the Andean uplift acted as barriers to this species' gene flow, a picture that may be generalized to most of the plant biodiversity tropical woodlands and forests. These results also reinforce the importance of evaluating multiple genetic markers for a more comprehensive understanding of population structure and history. Our results provide insight into the conservation efforts and ongoing work on the genetics of population divergence and speciation in these Neotropical rainforests. Copyright © 2012 Elsevier Inc. All rights reserved.

Mobile Genome Express (MGE): A comprehensive automatic genetic analyses pipeline with a mobile device.

PubMed

Yoon, Jun-Hee; Kim, Thomas W; Mendez, Pedro; Jablons, David M; Kim, Il-Jin

2017-01-01

The development of next-generation sequencing (NGS) technology allows to sequence whole exomes or genome. However, data analysis is still the biggest bottleneck for its wide implementation. Most laboratories still depend on manual procedures for data handling and analyses, which translates into a delay and decreased efficiency in the delivery of NGS results to doctors and patients. Thus, there is high demand for developing an automatic and an easy-to-use NGS data analyses system. We developed comprehensive, automatic genetic analyses controller named Mobile Genome Express (MGE) that works in smartphones or other mobile devices. MGE can handle all the steps for genetic analyses, such as: sample information submission, sequencing run quality check from the sequencer, secured data transfer and results review. We sequenced an Actrometrix control DNA containing multiple proven human mutations using a targeted sequencing panel, and the whole analysis was managed by MGE, and its data reviewing program called ELECTRO. All steps were processed automatically except for the final sequencing review procedure with ELECTRO to confirm mutations. The data analysis process was completed within several hours. We confirmed the mutations that we have identified were consistent with our previous results obtained by using multi-step, manual pipelines.

The nature of individual differences in inhibited temperament and risk for psychiatric disease: a review and meta-analysis

PubMed Central

Clauss, J. A.; Avery, S. N.; Blackford, J. U.

2015-01-01

What makes us different from one another? Why does one person jump out of airplanes for fun while another prefers to stay home and read? Why are some babies born with a predisposition to become anxious? Questions about individual differences in temperament have engaged the minds of scientists, psychologists, and philosophers for centuries. Recent technological advances in neuroimaging and genetics provide an unprecedented opportunity to answer these questions. Here we review the literature on the neurobiology of one of the most basic individual differences—the tendency to approach or avoid novelty. This trait, called inhibited temperament, is innate, heritable, and observed across species. Importantly, inhibited temperament also confers risk for psychiatric disease. Here, we provide a comprehensive review of inhibited temperament including neuroimaging and genetic studies in human and non-human primates. We conducted a meta-analysis of neuroimaging findings in inhibited humans that points to alterations in a fronto-limbic-basal ganglia circuit; these findings provide the basis of a model of inhibited temperament neurocircuitry. Lesion and neuroimaging studies in non-human primate models of inhibited temperament highlight roles for the amygdala, hippocampus, orbitofrontal cortex, and dorsal prefrontal cortex. Genetic studies highlight a role for genes that regulate neurotransmitter function, such as the serotonin transporter polymorphisms (5-HTTLPR), as well as genes that regulate stress response, such as corticotropin-releasing hormone (CRH). Together these studies provide a foundation of knowledge about the genetic and neural substrates of this most basic of temperament traits. Future studies using novel imaging methods and genetic approaches promise to expand upon these biological bases of inhibited temperament and inform our understanding of risk for psychiatric disease. PMID:25784645

The nature of individual differences in inhibited temperament and risk for psychiatric disease: A review and meta-analysis.

PubMed

Clauss, J A; Avery, S N; Blackford, J U

2015-04-01

What makes us different from one another? Why does one person jump out of airplanes for fun while another prefers to stay home and read? Why are some babies born with a predisposition to become anxious? Questions about individual differences in temperament have engaged the minds of scientists, psychologists, and philosophers for centuries. Recent technological advances in neuroimaging and genetics provide an unprecedented opportunity to answer these questions. Here we review the literature on the neurobiology of one of the most basic individual differences-the tendency to approach or avoid novelty. This trait, called inhibited temperament, is innate, heritable, and observed across species. Importantly, inhibited temperament also confers risk for psychiatric disease. Here, we provide a comprehensive review of inhibited temperament, including neuroimaging and genetic studies in human and non-human primates. We conducted a meta-analysis of neuroimaging findings in inhibited humans that points to alterations in a fronto-limbic-basal ganglia circuit; these findings provide the basis of a model of inhibited temperament neurocircuitry. Lesion and neuroimaging studies in non-human primate models of inhibited temperament highlight roles for the amygdala, hippocampus, orbitofrontal cortex, and dorsal prefrontal cortex. Genetic studies highlight a role for genes that regulate neurotransmitter function, such as the serotonin transporter polymorphisms (5-HTTLPR), as well as genes that regulate stress response, such as corticotropin-releasing hormone (CRH). Together these studies provide a foundation of knowledge about the genetic and neural substrates of this most basic of temperament traits. Future studies using novel imaging methods and genetic approaches promise to expand upon these biological bases of inhibited temperament and inform our understanding of risk for psychiatric disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chromatin Challenges during DNA Replication: A Systems Representation

PubMed Central

Aladjem, Mirit I.; Weinstein, John N.; Pommier, Yves

2008-01-01

In a recent review, A. Groth and coworkers presented a comprehensive account of nucleosome disassembly in front of a DNA replication fork, assembly behind the replication fork, and the copying of epigenetic information onto the replicated chromatin. Understanding those processes however would be enhanced by a comprehensive graphical depiction analogous to a circuit diagram. Accordingly, we have constructed a molecular interaction map (MIM) that preserves in essentially complete detail the processes described by Groth et al. The MIM organizes and elucidates the information presented by Groth et al. on the complexities of chromatin replication, thereby providing a tool for system-level comprehension of the effects of genetic mutations, altered gene expression, and pharmacologic intervention. PMID:17959828

Western redcedar—a literature review.

Treesearch

Don Minore

1983-01-01

This report is a comprehensive compilation of information on western redcedar (Thuja plicata Donn) - its occurrence and abundance; associated plant species; morphology and anatomy; products; medical aspects; diseases; insect, bird, and mammal. pests; genetics; horticulture; physiology; ecology; mensuration; and silviculture. Management...

Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

PubMed Central

Stavropoulos, Dimitri J; Merico, Daniele; Jobling, Rebekah; Bowdin, Sarah; Monfared, Nasim; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Yuen, Ryan K C; Szego, Michael J; Hayeems, Robin Z; Shaul, Randi Zlotnik; Brudno, Michael; Girdea, Marta; Frey, Brendan; Alipanahi, Babak; Ahmed, Sohnee; Babul-Hirji, Riyana; Porras, Ramses Badilla; Carter, Melissa T; Chad, Lauren; Chaudhry, Ayeshah; Chitayat, David; Doust, Soghra Jougheh; Cytrynbaum, Cheryl; Dupuis, Lucie; Ejaz, Resham; Fishman, Leona; Guerin, Andrea; Hashemi, Bita; Helal, Mayada; Hewson, Stacy; Inbar-Feigenberg, Michal; Kannu, Peter; Karp, Natalya; Kim, Raymond H; Kronick, Jonathan; Liston, Eriskay; MacDonald, Heather; Mercimek-Mahmutoglu, Saadet; Mendoza-Londono, Roberto; Nasr, Enas; Nimmo, Graeme; Parkinson, Nicole; Quercia, Nada; Raiman, Julian; Roifman, Maian; Schulze, Andreas; Shugar, Andrea; Shuman, Cheryl; Sinajon, Pierre; Siriwardena, Komudi; Weksberg, Rosanna; Yoon, Grace; Carew, Chris; Erickson, Raith; Leach, Richard A; Klein, Robert; Ray, Peter N; Meyn, M Stephen; Scherer, Stephen W; Cohn, Ronald D; Marshall, Christian R

2016-01-01

The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis. PMID:28567303

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

PubMed

Stavropoulos, Dimitri J; Merico, Daniele; Jobling, Rebekah; Bowdin, Sarah; Monfared, Nasim; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Yuen, Ryan K C; Szego, Michael J; Hayeems, Robin Z; Shaul, Randi Zlotnik; Brudno, Michael; Girdea, Marta; Frey, Brendan; Alipanahi, Babak; Ahmed, Sohnee; Babul-Hirji, Riyana; Porras, Ramses Badilla; Carter, Melissa T; Chad, Lauren; Chaudhry, Ayeshah; Chitayat, David; Doust, Soghra Jougheh; Cytrynbaum, Cheryl; Dupuis, Lucie; Ejaz, Resham; Fishman, Leona; Guerin, Andrea; Hashemi, Bita; Helal, Mayada; Hewson, Stacy; Inbar-Feigenberg, Michal; Kannu, Peter; Karp, Natalya; Kim, Raymond; Kronick, Jonathan; Liston, Eriskay; MacDonald, Heather; Mercimek-Mahmutoglu, Saadet; Mendoza-Londono, Roberto; Nasr, Enas; Nimmo, Graeme; Parkinson, Nicole; Quercia, Nada; Raiman, Julian; Roifman, Maian; Schulze, Andreas; Shugar, Andrea; Shuman, Cheryl; Sinajon, Pierre; Siriwardena, Komudi; Weksberg, Rosanna; Yoon, Grace; Carew, Chris; Erickson, Raith; Leach, Richard A; Klein, Robert; Ray, Peter N; Meyn, M Stephen; Scherer, Stephen W; Cohn, Ronald D; Marshall, Christian R

2016-01-13

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.

PubMed

Tóth, Beáta; Volokha, Alla; Mihas, Alexander; Pac, Malgorzata; Bernatowska, Ewa; Kondratenko, Irina; Polyakov, Alexander; Erdos, Melinda; Pasic, Srdjan; Bataneant, Michaela; Szaflarska, Anna; Mironska, Kristina; Richter, Darko; Stavrik, Katarina; Avcin, Tadej; Márton, Gabriella; Nagy, Kálmán; Dérfalvi, Beáta; Szolnoky, Miklós; Kalmár, Agnes; Belevtsev, Michael; Guseva, Marina; Rugina, Aurica; Kriván, Gergely; Timár, László; Nyul, Zoltán; Mosdósi, Bernadett; Kareva, Lidija; Peova, Sonja; Chernyshova, Liudmyla; Gherghina, Ioan; Serban, Margit; Conley, Mary Ellen; Notarangelo, Luigi D; Smith, C I Edvard; van Dongen, Jacques; van der Burg, Mirjam; Maródi, László

2009-06-01

Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.

Micropropagation and genetic transformation of Tylophora indica (Burm. f.) Merr.: a review.

PubMed

Teixeira da Silva, Jaime A; Jha, Sumita

2016-11-01

This review provides an in-depth and comprehensive overview of the in vitro culture of Tylophora species, which have medicinal properties. Tylophora indica (Burm. f.) Merr. is a climbing perennial vine with medicinal properties. The tissue culture and genetic transformation of T. indica, which has been extensively studied, is reviewed. Micropropagation using nodal explants has been reported in 25 % of all publications. Leaf explants from field-grown plants has been the explant of choice of independent research groups, which reported direct and callus-mediated organogenesis as well as callus-mediated somatic embryogenesis. Protoplast-mediated regeneration and callus-mediated shoot organogenesis has also been reported from stem explants, and to a lesser degree from root explants of micropropagated plants in vitro. Recent studies that used HPLC confirmed the potential of micropropagated plants to synthesize the major T. indica alkaloid tylophorine prior to and after transfer to field conditions. The genetic integrity of callus-regenerated plants was confirmed by RAPD in a few reports. Tissue culture is an essential base for genetic transformation studies. Hairy roots and transgenic T. indica plants have been shown to accumulate tylophorine suggesting that in vitro biology and transgenic methods are viable ways of clonally producing valuable germplasm and mass producing compounds of commercial value. Further studies that investigate the factors affecting the biosynthesis of Tylophora alkaloids and other secondary metabolites need to be conducted using non-transformed as well as transformed cell and organ cultures.

Comprehensive high-resolution genomic profiling and cytogenetics of human chondrocyte cultures by GTG-banding, locus-specific FISH, SKY and SNP array.

PubMed

Wallenborn, M; Petters, O; Rudolf, D; Hantmann, H; Richter, M; Ahnert, P; Rohani, L; Smink, J J; Bulwin, G C; Krupp, W; Schulz, R M; Holland, H

2018-04-23

In the development of cell-based medicinal products, it is crucial to guarantee that the application of such an advanced therapy medicinal product (ATMP) is safe for the patients. The consensus of the European regulatory authorities is: "In conclusion, on the basis of the state of art, conventional karyotyping can be considered a valuable and useful technique to analyse chromosomal stability during preclinical studies". 408 chondrocyte samples (84 monolayers and 324 spheroids) from six patients were analysed using trypsin-Giemsa staining, spectral karyotyping and fluorescence in situ hybridisation, to evaluate the genetic stability of chondrocyte samples from non-clinical studies. Single nucleotide polymorphism (SNP) array analysis was performed on chondrocyte spheroids from five of the six donors. Applying this combination of techniques, the genetic analyses performed revealed no significant genetic instability until passage 3 in monolayer cells and interphase cells from spheroid cultures at different time points. Clonal occurrence of polyploid metaphases and endoreduplications were identified associated with prolonged cultivation time. Also, gonosomal losses were observed in chondrocyte spheroids, with increasing passage and duration of the differentiation phase. Interestingly, in one of the donors, chromosomal aberrations that are also described in extraskeletal myxoid chondrosarcoma were identified. The SNP array analysis exhibited chromosomal aberrations in two donors and copy neutral losses of heterozygosity regions in four donors. This study showed the necessity of combined genetic analyses at defined cultivation time points in quality studies within the field of cell therapy.

A Review of Selected Genes with Known Effects on Performance and Health of Cattle

PubMed Central

Casas, Eduardo; Kehrli, Marcus E.

2016-01-01

There are genetic conditions that influence production in dairy and beef cattle. The objective of this review was to describe relevant genetic conditions that have been associated with productivity and health in cattle. Genes or genomic regions that have been identified as a candidate for the condition will be included, and the genetic basis of the condition will be defined. Genes and genetic conditions included in this review are bovine leukocyte adhesion deficiency, deficiency of the uridine monophosphate synthase, bovine chronic interstitial nephritis, horn development, myostatin, complex vertebral malformation, leptin, osteopetrosis, apoptosis peptide activating factor 1, chondrodysplastic dwarfism, caseins, calpastatin, umbilical hernia, lactoglobulin, citrullinemia, cholesterol deficiency, prions, thyroglobulin, diacylglycerol acyltransferase, syndactyly, maple syrup urine disease, slick hair, Factor XI deficiency, and μ-Calpain. This review is not meant to be comprehensive, and relevant information is provided to ascertain genetic markers associated with the conditions. PMID:28018909

The impact of Alzheimer disease genetics on expert and advanced gerontological nursing practice.

PubMed

Schutte, D L

1998-11-01

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the United States, affecting as many as 4 million people. Extensive research is under way to identify environmental and genetic risk factors for this complex disease. Currently, four genes are associated with an increased risk for AD: the amyloid precursor protein gene on chromosome 21, the Presenilin I gene on chromosome 14, the Presenilin II gene on chromosome 1, and the apolipoprotein E gene on chromosome 19. Expert and advanced practice gerontological nurses are faced with new challenges as a result of these gene discoveries. Gerontological nurses should assess for relevant environmental and genetic risk factors; obtain comprehensive family health histories recorded as pedigrees; integrate genetic information into diagnosis, intervention, and evaluation strategies; initiate and coordinate referrals to genetic specialists; and provide ongoing emotional and decision-making support for patients and families experiencing AD.

Development of genic-SSR markers by deep transcriptome sequencing in pigeonpea [Cajanus cajan (L.) Millspaugh].

PubMed

Dutta, Sutapa; Kumawat, Giriraj; Singh, Bikram P; Gupta, Deepak K; Singh, Sangeeta; Dogra, Vivek; Gaikwad, Kishor; Sharma, Tilak R; Raje, Ranjeet S; Bandhopadhya, Tapas K; Datta, Subhojit; Singh, Mahendra N; Bashasab, Fakrudin; Kulwal, Pawan; Wanjari, K B; K Varshney, Rajeev; Cook, Douglas R; Singh, Nagendra K

2011-01-20

Pigeonpea [Cajanus cajan (L.) Millspaugh], one of the most important food legumes of semi-arid tropical and subtropical regions, has limited genomic resources, particularly expressed sequence based (genic) markers. We report a comprehensive set of validated genic simple sequence repeat (SSR) markers using deep transcriptome sequencing, and its application in genetic diversity analysis and mapping. In this study, 43,324 transcriptome shotgun assembly unigene contigs were assembled from 1.696 million 454 GS-FLX sequence reads of separate pooled cDNA libraries prepared from leaf, root, stem and immature seed of two pigeonpea varieties, Asha and UPAS 120. A total of 3,771 genic-SSR loci, excluding homopolymeric and compound repeats, were identified; of which 2,877 PCR primer pairs were designed for marker development. Dinucleotide was the most common repeat motif with a frequency of 60.41%, followed by tri- (34.52%), hexa- (2.62%), tetra- (1.67%) and pentanucleotide (0.76%) repeat motifs. Primers were synthesized and tested for 772 of these loci with repeat lengths of ≥ 18 bp. Of these, 550 markers were validated for consistent amplification in eight diverse pigeonpea varieties; 71 were found to be polymorphic on agarose gel electrophoresis. Genetic diversity analysis was done on 22 pigeonpea varieties and eight wild species using 20 highly polymorphic genic-SSR markers. The number of alleles at these loci ranged from 4-10 and the polymorphism information content values ranged from 0.46 to 0.72. Neighbor-joining dendrogram showed distinct separation of the different groups of pigeonpea cultivars and wild species. Deep transcriptome sequencing of the two parental lines helped in silico identification of polymorphic genic-SSR loci to facilitate the rapid development of an intra-species reference genetic map, a subset of which was validated for expected allelic segregation in the reference mapping population. We developed 550 validated genic-SSR markers in pigeonpea using deep transcriptome sequencing. From these, 20 highly polymorphic markers were used to evaluate the genetic relationship among species of the genus Cajanus. A comprehensive set of genic-SSR markers was developed as an important genomic resource for diversity analysis and genetic mapping in pigeonpea.

Development of genic-SSR markers by deep transcriptome sequencing in pigeonpea [Cajanus cajan (L.) Millspaugh

PubMed Central

2011-01-01

Background Pigeonpea [Cajanus cajan (L.) Millspaugh], one of the most important food legumes of semi-arid tropical and subtropical regions, has limited genomic resources, particularly expressed sequence based (genic) markers. We report a comprehensive set of validated genic simple sequence repeat (SSR) markers using deep transcriptome sequencing, and its application in genetic diversity analysis and mapping. Results In this study, 43,324 transcriptome shotgun assembly unigene contigs were assembled from 1.696 million 454 GS-FLX sequence reads of separate pooled cDNA libraries prepared from leaf, root, stem and immature seed of two pigeonpea varieties, Asha and UPAS 120. A total of 3,771 genic-SSR loci, excluding homopolymeric and compound repeats, were identified; of which 2,877 PCR primer pairs were designed for marker development. Dinucleotide was the most common repeat motif with a frequency of 60.41%, followed by tri- (34.52%), hexa- (2.62%), tetra- (1.67%) and pentanucleotide (0.76%) repeat motifs. Primers were synthesized and tested for 772 of these loci with repeat lengths of ≥18 bp. Of these, 550 markers were validated for consistent amplification in eight diverse pigeonpea varieties; 71 were found to be polymorphic on agarose gel electrophoresis. Genetic diversity analysis was done on 22 pigeonpea varieties and eight wild species using 20 highly polymorphic genic-SSR markers. The number of alleles at these loci ranged from 4-10 and the polymorphism information content values ranged from 0.46 to 0.72. Neighbor-joining dendrogram showed distinct separation of the different groups of pigeonpea cultivars and wild species. Deep transcriptome sequencing of the two parental lines helped in silico identification of polymorphic genic-SSR loci to facilitate the rapid development of an intra-species reference genetic map, a subset of which was validated for expected allelic segregation in the reference mapping population. Conclusion We developed 550 validated genic-SSR markers in pigeonpea using deep transcriptome sequencing. From these, 20 highly polymorphic markers were used to evaluate the genetic relationship among species of the genus Cajanus. A comprehensive set of genic-SSR markers was developed as an important genomic resource for diversity analysis and genetic mapping in pigeonpea. PMID:21251263

Unraveling the Tangled Skein: The Evolution of Transcriptional Regulatory Networks in Development.

PubMed

Rebeiz, Mark; Patel, Nipam H; Hinman, Veronica F

2015-01-01

The molecular and genetic basis for the evolution of anatomical diversity is a major question that has inspired evolutionary and developmental biologists for decades. Because morphology takes form during development, a true comprehension of how anatomical structures evolve requires an understanding of the evolutionary events that alter developmental genetic programs. Vast gene regulatory networks (GRNs) that connect transcription factors to their target regulatory sequences control gene expression in time and space and therefore determine the tissue-specific genetic programs that shape morphological structures. In recent years, many new examples have greatly advanced our understanding of the genetic alterations that modify GRNs to generate newly evolved morphologies. Here, we review several aspects of GRN evolution, including their deep preservation, their mechanisms of alteration, and how they originate to generate novel developmental programs.

Homophila: human disease gene cognates in Drosophila

PubMed Central

Chien, Samson; Reiter, Lawrence T.; Bier, Ethan; Gribskov, Michael

2002-01-01

Although many human genes have been associated with genetic diseases, knowing which mutations result in disease phenotypes often does not explain the etiology of a specific disease. Drosophila melanogaster provides a powerful system in which to use genetic and molecular approaches to investigate human genetic diseases. Homophila is an intergenomic resource linking the human and fly genomes in order to stimulate functional genomic investigations in Drosophila that address questions about genetic disease in humans. Homophila provides a comprehensive linkage between the disease genes compiled in Online Mendelian Inheritance in Man (OMIM) and the complete Drosophila genomic sequence. Homophila is a relational database that allows searching based on human disease descriptions, OMIM number, human or fly gene names, and sequence similarity, and can be accessed at http://homophila.sdsc.edu. PMID:11752278

Genetic tool development and systemic regulation in biosynthetic technology.

PubMed

Dai, Zhongxue; Zhang, Shangjie; Yang, Qiao; Zhang, Wenming; Qian, Xiujuan; Dong, Weiliang; Jiang, Min; Xin, Fengxue

2018-01-01

With the increased development in research, innovation, and policy interest in recent years, biosynthetic technology has developed rapidly, which combines engineering, electronics, computer science, mathematics, and other disciplines based on classical genetic engineering and metabolic engineering. It gives a wider perspective and a deeper level to perceive the nature of life via cell mechanism, regulatory networks, or biological evolution. Currently, synthetic biology has made great breakthrough in energy, chemical industry, and medicine industries, particularly in the programmable genetic control at multiple levels of regulation to perform designed goals. In this review, the most advanced and comprehensive developments achieved in biosynthetic technology were represented, including genetic engineering as well as synthetic genomics. In addition, the superiority together with the limitations of the current genome-editing tools were summarized.

Interbreeding among deeply divergent mitochondrial lineages in the American cockroach (Periplaneta americana)

NASA Astrophysics Data System (ADS)

von Beeren, Christoph; Stoeckle, Mark Y.; Xia, Joyce; Burke, Griffin; Kronauer, Daniel J. C.

2015-02-01

DNA barcoding promises to be a useful tool to identify pest species assuming adequate representation of genetic variants in a reference library. Here we examined mitochondrial DNA barcodes in a global urban pest, the American cockroach (Periplaneta americana). Our sampling effort generated 284 cockroach specimens, most from New York City, plus 15 additional U.S. states and six other countries, enabling the first large-scale survey of P. americana barcode variation. Periplaneta americana barcode sequences (n = 247, including 24 GenBank records) formed a monophyletic lineage separate from other Periplaneta species. We found three distinct P. americana haplogroups with relatively small differences within (<=0.6%) and larger differences among groups (2.4%-4.7%). This could be interpreted as indicative of multiple cryptic species. However, nuclear DNA sequences (n = 77 specimens) revealed extensive gene flow among mitochondrial haplogroups, confirming a single species. This unusual genetic pattern likely reflects multiple introductions from genetically divergent source populations, followed by interbreeding in the invasive range. Our findings highlight the need for comprehensive reference databases in DNA barcoding studies, especially when dealing with invasive populations that might be derived from multiple genetically distinct source populations.

Panel 3: Genetics and Precision Medicine of Otitis Media.

PubMed

Lin, Jizhen; Hafrén, Hena; Kerschner, Joseph; Li, Jian-Dong; Brown, Steve; Zheng, Qing Y; Preciado, Diego; Nakamura, Yoshihisa; Huang, Qiuhong; Zhang, Yan

2017-04-01

Objective The objective is to perform a comprehensive review of the literature up to 2015 on the genetics and precision medicine relevant to otitis media. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels were formed comprising experts in the genetics and precision medicine of otitis media. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The entire panel met at the 18th International Symposium on Recent Advances in Otitis Media in June 2015 and discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion Many genes relevant to otitis media have been identified in the last 4 years in advancing our knowledge regarding the predisposition of the middle ear mucosa to commensals and pathogens. Advances include mutant animal models and clinical studies. Many signaling pathways are involved in the predisposition of otitis media. Implications for Practice New knowledge on the genetic background relevant to otitis media forms a basis of novel potential interventions, including potential new ways to treat otitis media.

Crater Lake Apoyo Revisited - Population Genetics of an Emerging Species Flock

PubMed Central

Geiger, Matthias F.; McCrary, Jeffrey K.; Schliewen, Ulrich K.

2013-01-01

The polytypic Nicaraguan Midas cichlids ( Amphilophus cf. citrinellus) have been established as a model system for studying the mechanisms of speciation and patterns of diversification in allopatry and sympatry. The species assemblage in Crater Lake Apoyo has been accepted as a textbook example for sympatric speciation. Here, we present a first comprehensive data set of population genetic (mtDNA & AFLPs) proxies of species level differentiation for a representative set of individuals of all six endemic Amphilophus species occurring in Crater Lake Apoyo. AFLP genetic differentiation was partitioned into a neutral and non-neutral component based on outlier-loci detection approaches, and patterns of species divergence were explored with Bayesian clustering methods. Substantial levels of admixture between species were detected, indicating different levels of reproductive isolation between the six species. Analysis of neutral genetic variation revealed several A . zaliosus as being introgressed by an unknown contributor, hereby rendering the sympatrically evolving L. Apoyo flock polyphyletic. This is contrasted by the mtDNA analysis delivering a clear monophyly signal with Crater Lake Apoyo private haplotypes characterising all six described species, but also demonstrating different demographic histories as inferred from pairwise mismatch distributions. PMID:24086393

Dichotomy of Genetic Abnormalities in PEComas with Therapeutic Implications

PubMed Central

Agaram, Narasimhan P; Sung, Yun-Shao; Zhang, Lei; Chen, Chun-Liang; Chen, Hsiao-Wei; Singer, Samuel; Dickson, Mark A.; Berger, Michael F.; Antonescu, Cristina R

2014-01-01

Perivascular epithelioid cell neoplasms (PEComa) are a family of rare mesenchymal tumors with hybrid myo-melanocytic differentiation. Although most PEComas harbor loss of function TSC1/TSC2 mutations, a small subset were reported to carry TFE3 gene rearrangements. As no comprehensive genomic study has addressed the molecular classification of PEComa, we sought to investigate by multiple methodologies the incidence and spectrum of genetic abnormalities and their potential genotype-phenotype correlations in a large group of 38 PEComas. The tumors were located in soft tissue (11 cases) and visceral sites (27) including uterus, kidney, liver, lung and urinary bladder. Combined RNA sequencing and Fluorescence In Situ Hybridization (FISH) analysis identified 9 (23%) TFE3 gene rearranged tumors, with 3 cases showing a SFPQ/PSF-TFE3 fusion and one case a novel DVL2-TFE3 gene fusion. The TFE3-positive lesions showed a distinctive nested/alveolar morphology and were equally distributed between soft tissue and visceral sites. Additionally, novel RAD51B gene rearrangements were identified in 3 (8%) uterine PEComas, which showed a complex fusion pattern and were fused to RRAGB/OPHN1 genes in two cases. Other non-recurrent gene fusions, HTR4-ST3GAL1 and RASSF1-PDZRN3, were identified in 2 cases. Targeted exome sequencing using the IMPACT assay was used to address if the presence of gene fusions are mutually exclusive from TSC gene abnormalities. TSC2 mutations were identified in 80% of the TFE3 fusion-negative cases tested. Co-existent TP53 mutations were identified in 63% of the TSC2 mutated PEComas. Our results showed that TFE3-rearranged PEComas lacked co-existing TSC2 mutations, indicating alternative pathways of tumorigenesis. In summary, this comprehensive genetic analysis significantly expands our understanding of molecular alterations in PEComas and brings forth the genetic heterogeneity of these tumors. PMID:25651471

Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms.

PubMed

Lubitz, Steven A; Parsons, Owen E; Anderson, Christopher D; Benjamin, Emelia J; Malik, Rainer; Weng, Lu-Chen; Dichgans, Martin; Sudlow, Cathie L; Rothwell, Peter M; Rosand, Jonathan; Ellinor, Patrick T; Markus, Hugh S; Traylor, Matthew

2017-06-01

Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ( P =6×10 - 4 ) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P <1×10 - 3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P =1.2×10 - 9 , 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses. © 2017 American Heart Association, Inc.

The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis

PubMed Central

Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H.; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Barberio, Manuela Terranova; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D.; Nestle, Frank O.

2015-01-01

Summary Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analysing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets, and uncovered insights into genetic control for regulatory T cells. This dataset also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. PMID:25772697

The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

PubMed

Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

2015-04-09

Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Estimation and interpretation of genetic effects with epistasis using the NOIA model.

PubMed

Alvarez-Castro, José M; Carlborg, Orjan; Rönnegård, Lars

2012-01-01

We introduce this communication with a brief outline of the historical landmarks in genetic modeling, especially concerning epistasis. Then, we present methods for the use of genetic modeling in QTL analyses. In particular, we summarize the essential expressions of the natural and orthogonal interactions (NOIA) model of genetic effects. Our motivation for reviewing that theory here is twofold. First, this review presents a digest of the expressions for the application of the NOIA model, which are often mixed with intermediate and additional formulae in the original articles. Second, we make the required theory handy for the reader to relate the genetic concepts to the particular mathematical expressions underlying them. We illustrate those relations by providing graphical interpretations and a diagram summarizing the key features for applying genetic modeling with epistasis in comprehensive QTL analyses. Finally, we briefly review some examples of the application of NOIA to real data and the way it improves the interpretability of the results.

MCF-10A-NeoST: A New Cell System for Studying Cell-ECM and Cell-Cell Interactions in Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zantek, Nicole Dodge; Walker-Daniels, Jennifer; Stewart, Jane

2001-08-22

There is a continuing need for genetically matched cell systems to model cellular behaviors that are frequently observed in aggressive breast cancers. We report here the isolation and initial characterization of a spontaneously arising variant of MCF-10A cells, NeoST, which provides a new model to study cell adhesion and signal transduction in breast cancer. NeoST cells recapitulate important biological and biochemical features of metastatic breast cancer, including anchorage-independent growth, invasiveness in threedimensional reconstituted membranes, loss of E-cadherin expression, and increased tyrosine kinase activity. A comprehensive analysis of tyrosine kinase expression revealed overexpression or functional activation of the Axl, FAK, andmore » EphA2 tyrosine kinases in transformed MCF-10A cells. MCF-10A and these new derivatives provide a genetically matched model to study defects in cell adhesion and signaling that are relevant to cellular behaviors that often typify aggressive breast cancer cells.« less

Whole transcriptome analysis using next-generation sequencing of model species Setaria viridis to support C4 photosynthesis research.

PubMed

Xu, Jiajia; Li, Yuanyuan; Ma, Xiuling; Ding, Jianfeng; Wang, Kai; Wang, Sisi; Tian, Ye; Zhang, Hui; Zhu, Xin-Guang

2013-09-01

Setaria viridis is an emerging model species for genetic studies of C4 photosynthesis. Many basic molecular resources need to be developed to support for this species. In this paper, we performed a comprehensive transcriptome analysis from multiple developmental stages and tissues of S. viridis using next-generation sequencing technologies. Sequencing of the transcriptome from multiple tissues across three developmental stages (seed germination, vegetative growth, and reproduction) yielded a total of 71 million single end 100 bp long reads. Reference-based assembly using Setaria italica genome as a reference generated 42,754 transcripts. De novo assembly generated 60,751 transcripts. In addition, 9,576 and 7,056 potential simple sequence repeats (SSRs) covering S. viridis genome were identified when using the reference based assembled transcripts and the de novo assembled transcripts, respectively. This identified transcripts and SSR provided by this study can be used for both reverse and forward genetic studies based on S. viridis.

Genetic drivers of papillary renal cell carcinoma - TCGA

Cancer.gov

A comprehensive genomic analysis of 161 tumors from people with papillary renal cell carcinoma (PRCC) – the second most common form of kidney cancer –provided insights into the molecular basis of this cancer and may inform its classification and treatment.

Limitations of direct-to-consumer advertising for clinical genetic testing.

PubMed

Gollust, Sarah E; Hull, Sara Chandros; Wilfond, Benjamin S

2002-10-09

Although direct-to-consumer (DTC) advertisements for pharmaceuticals have been appearing in the mass media for 20 years, DTC advertisements for genetic testing have only recently appeared. Advertisements for genetic testing can provide both consumers and physicians with information about test availability in an expanding market. However, 3 factors limit the value and appropriateness of advertisements: complex information, a complicated social context surrounding genetics, and a lack of consensus about the clinical utility of some tests. Consideration of several advertisements suggests that they overstate the value of genetic testing for consumers' clinical care. Furthermore, advertisements may provide misinformation about genetics, exaggerate consumers' risks, endorse a deterministic relationship between genes and disease, and reinforce associations between diseases and ethnic groups. Advertising motivated by factors other than evidence of the clinical value of genetic tests can manipulate consumers' behavior by exploiting their fears and worries. At this time, DTC advertisements are inappropriate, given the public's limited sophistication regarding genetics and the lack of comprehensive premarket review of tests or oversight of advertisement content. Existing Federal Trade Commission and Food and Drug Administration regulations for other types of health-related advertising should be applied to advertisements for genetic tests.

Nutrigenomics and ethics interface: direct-to-consumer services and commercial aspects.

PubMed

Ries, Nola M; Castle, David

2008-12-01

A growing variety and number of genetic tests are advertised and sold directly to consumers (DTC) via the Internet, including nutrigenomic tests and associated products and services. Consumers have more access to genetic information about themselves, but access does not entail certainty about the implications of test results. Potential personal and public health harms and benefits are associated with DTC access to genetic testing services. Early policy responses to direct-to-consumer (DTC) genetic testing often involved calls for bans, and some jurisdictions prohibited DTC genetic tests. Recent policy responses by oversight bodies acknowledge expansion in the range of DTC tests available and suggest that a "one-size-fits-all" regulatory approach is not appropriate for all genetic tests. This review discusses ethical and regulatory aspects of DTC genetic testing, focusing particularly on nutrigenomic tests. We identify policy options for regulating DTC genetic tests, including full or partial prohibitions, enforcement of existing truth-in-advertising laws, and more comprehensive information disclosure about genetic tests. We advocate the latter option as an important means to improve transparency about current evidence on the strengths and limits of gene-disease associations and allow consumers to make informed purchasing decisions in the DTC marketplace.

Assessment of Genetic Diversity and Population Genetic Structure of Corylus mandshurica in China Using SSR Markers.

PubMed

Zong, Jian-Wei; Zhao, Tian-Tian; Ma, Qing-Hua; Liang, Li-Song; Wang, Gui-Xi

2015-01-01

Corylus mandshurica, also known as pilose hazelnut, is an economically and ecologically important species in China. In this study, ten polymorphic simple sequence repeat (SSR) markers were applied to evaluate the genetic diversity and population structure of 348 C. mandshurica individuals among 12 populations in China. The SSR markers expressed a relatively high level of genetic diversity (Na = 15.3, Ne = 5.6604, I = 1.8853, Ho = 0.6668, and He = 0.7777). According to the coefficient of genetic differentiation (Fst = 0.1215), genetic variation within the populations (87.85%) were remarkably higher than among populations (12.15%). The average gene flow (Nm = 1.8080) significantly impacts the genetic structure of C. mandshurica populations. The relatively high gene flow (Nm = 1.8080) among wild C. mandshurica may be caused by wind-pollinated flowers, highly nutritious seeds and self-incompatible mating system. The UPGMA (unweighted pair group method of arithmetic averages) dendrogram was divided into two main clusters. Moreover, the results of STRUCTURE analysis suggested that C. mandshurica populations fell into two main clusters. Comparison of the UPGMA dendrogram and the Bayesian STRUCTURE analysis showed general agreement between the population subdivisions and the genetic relationships among populations of C. mandshurica. Group I accessions were located in Northeast China, while Group II accessions were in North China. It is worth noting that a number of genetically similar populations were located in the same geographic region. The results further showed that there was obvious genetic differentiation among populations from Northeast China to North China. Results from the Mantel test showed a weak but still significant positive correlation between Nei's genetic distance and geographic distance (km) among populations (r = 0.419, P = 0.005), suggesting that genetic differentiation in the 12 C. mandshurica populations might be related to geographic distance. These data provide comprehensive information for the development of conservation strategies of these valuable hazelnut resources.

Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases.

PubMed

George, Rani; Kovak, Karen; Cox, Summer L

2015-06-01

Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

Improving biobank consent comprehension: a national randomized survey to assess the effect of a simplified form and review/retest intervention.

PubMed

Beskow, Laura M; Lin, Li; Dombeck, Carrie B; Gao, Emily; Weinfurt, Kevin P

2017-05-01

To determine the individual and combined effects of a simplified form and a review/retest intervention on biobanking consent comprehension. We conducted a national online survey in which participants were randomized within four educational strata to review a simplified or traditional consent form. Participants then completed a comprehension quiz; for each item answered incorrectly, they reviewed the corresponding consent form section and answered another quiz item on that topic. Consistent with our first hypothesis, comprehension among those who received the simplified form was not inferior to that among those who received the traditional form. Contrary to expectations, receipt of the simplified form did not result in significantly better comprehension compared with the traditional form among those in the lowest educational group. The review/retest procedure significantly improved quiz scores in every combination of consent form and education level. Although improved, comprehension remained a challenge in the lowest-education group. Higher quiz scores were significantly associated with willingness to participate. Ensuring consent comprehension remains a challenge, but simplified forms have virtues independent of their impact on understanding. A review/retest intervention may have a significant effect, but assessing comprehension raises complex questions about setting thresholds for understanding and consequences of not meeting them.Genet Med advance online publication 13 October 2016.

Genetics of Species Differences in the Wild Annual Sunflowers, Helianthus annuus and H. petiolaris

PubMed Central

Lexer, Christian; Rosenthal, David M.; Raymond, Olivier; Donovan, Lisa A.; Rieseberg, Loren H.

2005-01-01

Much of our knowledge of speciation genetics stems from quantitative trait locus (QTL) studies. However, interpretations of the size and distribution of QTL underlying species differences are complicated by differences in the way QTL magnitudes are estimated. Also, many studies fail to exploit information about QTL directions or to compare inter- and intraspecific QTL variation. Here, we comprehensively analyze an extensive QTL data set for an interspecific backcross between two wild annual sunflowers, Helianthus annuus and H. petiolaris, interpret different estimates of QTL magnitudes, identify trait groups that have diverged through selection, and compare inter- and intraspecific QTL magnitudes. Our results indicate that even minor QTL (in terms of backcross variance) may be surprisingly large compared to levels of standing variation in the parental species or phenotypic differences between them. Morphological traits, particularly flower morphology, were more strongly or consistently selected than life history or physiological traits. Also, intraspecific QTL were generally smaller than interspecific ones, consistent with the prediction that larger QTL are more likely to spread to fixation across a subdivided population. Our results inform the genetics of species differences in Helianthus and suggest an approach for the simultaneous mapping of inter- and intraspecific QTL. PMID:15545657

Plasmodium falciparum Genetic Diversity in Bangladesh Does Not Suggest a Hypoendemic Population Structure

PubMed Central

Alam, Mohammad Shafiul; Elahi, Rubayet; Mohon, Abu Naser; Al-Amin, Hasan Mohammad; Kibria, Mohammad Golam; Khan, Wasif A.; Khanum, Hamida; Haque, Rashidul

2016-01-01

Despite the recommendation for the use of merozoite surface protein 1 (msp1), merozoite surface protein 2 (msp2), and glutamate-rich protein (glurp) genes as markers in drug efficacy studies by World Health Organization and their limited use in Bangladesh, the circulating Plasmodium falciparum population genetic structure has not yet been assessed in Bangladesh. This study presents a comprehensive report on the circulating P. falciparum population structure based on msp1, msp2, and glurp polymorphic gene markers in Bangladesh. Among the 130 pretreatment (day 0) P. falciparum samples from seven malaria-endemic districts, 14 distinct genotypes were observed for msp1, 20 for msp2, and 13 for glurp. Polyclonal infection was reported in 94.6% (N = 123) of the samples. Multiplicity of infection (MOI) for msp1 was the highest (1.5) among the MOIs of the markers. The heterozygosity for msp1, msp2, and glurp was 0.89, 0.93, and 0.83, respectively. Data according to different malaria-endemic areas are also presented and discussed. Bangladesh is considered as a malaria-hypoendemic country. However, the prevalence of polyclonal infection and the genetic diversity of P. falciparum do not represent hypoendemicity. PMID:27139455

Functional analysis of regulatory single-nucleotide polymorphisms.

PubMed

Pampín, Sandra; Rodríguez-Rey, José C

2007-04-01

The identification of regulatory polymorphisms has become a key problem in human genetics. In the past few years there has been a conceptual change in the way in which regulatory single-nucleotide polymorphisms are studied. We revise the new approaches and discuss how gene expression studies can contribute to a better knowledge of the genetics of common diseases. New techniques for the association of single-nucleotide polymorphisms with changes in gene expression have been recently developed. This, together with a more comprehensive use of the old in-vitro methods, has produced a great amount of genetic information. When added to current databases, it will help to design better tools for the detection of regulatory single-nucleotide polymorphisms. The identification of functional regulatory single-nucleotide polymorphisms cannot be done by the simple inspection of DNA sequence. In-vivo techniques, based on primer-extension, and the more recently developed 'haploChIP' allow the association of gene variants to changes in gene expression. Gene expression analysis by conventional in-vitro techniques is the only way to identify the functional consequences of regulatory single-nucleotide polymorphisms. The amount of information produced in the last few years will help to refine the tools for the future analysis of regulatory gene variants.

Colorectal Cancer in Iran: Molecular Epidemiology and Screening Strategies

PubMed Central

Dolatkhah, Roya; Somi, Mohammad Hossein; Bonyadi, Mortaza Jabbarpour; Asvadi Kermani, Iraj; Farassati, Faris; Dastgiri, Saeed

2015-01-01

Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs. PMID:25685149

A systematic review of genetic diversity of human rotavirus circulating in South Korea.

PubMed

Than, Van Thai; Jeong, Sunyoung; Kim, Wonyong

2014-12-01

Rotavirus infections continue to be the leading cause of severe diarrhea in young Korean children. Rotavirus data acquired from uninterrupted surveillance studies between 1989 and 2009 in South Korea were analyzed to better understand the genetic diversity and evolution. The relationship between rotaviruses and the currently licensed rotavirus vaccine viruses was also examined. The most prevalent rotavirus strains, with genotype G1P[8], followed by G3P[8], G4P[6], and G2P[4], accounted for approximately 76.7% of the total identified strains, and more recently, rotavirus G9P[8] has significance increased to be the fifth most common genotype. Phylogenetic analyses underscored the heterogeneity between viral populations within each genotype, with different lineages and sub-lineages. Although the currently licensed rotavirus vaccines are effective, safe, and economical, additional data from rotavirus monitoring is necessary to evaluate the efficacy of these vaccines for their sustained use in South Korea. The present study provides comprehensive and up-to-date information regarding the epidemiology, genetic diversity, and evolution of the circulating rotaviruses in South Korea. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well-established knowledge to new frontiers.

PubMed

Unolt, Marta; Versacci, Paolo; Anaclerio, Silvia; Lambiase, Caterina; Calcagni, Giulio; Trezzi, Matteo; Carotti, Adriano; Crowley, Terrence Blaine; Zackai, Elaine H; Goldmuntz, Elizabeth; Gaynor, James William; Digilio, Maria Cristina; McDonald-McGinn, Donna M; Marino, Bruno

2018-04-16

Congenital heart diseases (CHDs) and cardiovascular abnormalities are one of the pillars of clinical diagnosis of 22q11.2 deletion syndrome (22q11.2DS) and still represent the main cause of mortality in the affected children. In the past 30 years, much progress has been made in describing the anatomical patterns of CHD, in improving their diagnosis, medical treatment, and surgical procedures for these conditions, as well as in understanding the underlying genetic and developmental mechanisms. However, further studies are still needed to better determine the true prevalence of CHDs in 22q11.2DS, including data from prenatal studies and on the adult population, to further clarify the genetic mechanisms behind the high variability of phenotypic expression of 22q11.2DS, and to fully understand the mechanism responsible for the increased postoperative morbidity and for the premature death of these patients. Moreover, the increased life expectancy of persons with 22q11.2DS allowed the expansion of the adult population that poses new challenges for clinicians such as acquired cardiovascular problems and complexity related to multisystemic comorbidity. In this review, we provide a comprehensive review of the existing literature about 22q11.2DS in order to summarize the knowledge gained in the past years of clinical experience and research, as well as to identify the remaining gaps in comprehension of this syndrome and the possible future research directions. © 2018 Wiley Periodicals, Inc.

Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families.

PubMed

Martin-Merida, Inmaculada; Aguilera-Garcia, Domingo; Jose, Patricia Fernandez-San; Blanco-Kelly, Fiona; Zurita, Olga; Almoguera, Berta; Garcia-Sandoval, Blanca; Avila-Fernandez, Almudena; Arteche, Ana; Minguez, Pablo; Carballo, Miguel; Corton, Marta; Ayuso, Carmen

2018-05-01

To provide a comprehensive overview of the molecular basis of autosomal dominant retinitis pigmentosa (adRP) in Spanish families. Thus, we established the molecular characterization rate, gene prevalence, and mutational spectrum in the largest European cohort reported to date. A total of 258 unrelated Spanish families with a clinical diagnosis of RP and suspected autosomal dominant inheritance were included. Clinical diagnosis was based on complete ophthalmologic examination and family history. Retrospective and prospective analysis of Spanish adRP families was carried out using a combined strategy consisting of classic genetic techniques and next-generation sequencing (NGS) for single-nucleotide variants and copy number variation (CNV) screening. Overall, 60% of our families were genetically solved. Interestingly, 3.1% of the cohort carried pathogenic CNVs. Disease-causing variants were found in an autosomal dominant gene in 55% of the families; however, X-linked and autosomal recessive forms were also identified in 3% and 2%, respectively. Four genes (RHO, PRPF31, RP1, and PRPH2) explained up to 62% of the solved families. Missense changes were most frequently found in adRP-associated genes; however, CNVs represented a relevant disease cause in PRPF31- and CRX-associated forms. Implementation of NGS technologies in the adRP study clearly increased the diagnostic yield compared with classic approaches. Our study outcome expands the spectrum of disease-causing variants, provides accurate data on mutation gene prevalence, and highlights the implication of CNVs as important contributors to adRP etiology.

A Genetic Linkage Map for Cattle

PubMed Central

Bishop, M. D.; Kappes, S. M.; Keele, J. W.; Stone, R. T.; Sunden, SLF.; Hawkins, G. A.; Toldo, S. S.; Fries, R.; Grosz, M. D.; Yoo, J.; Beattie, C. W.

1994-01-01

We report the most extensive physically anchored linkage map for cattle produced to date. Three-hundred thirteen genetic markers ordered in 30 linkage groups, anchored to 24 autosomal chromosomes (n = 29), the X and Y chromosomes, four unanchored syntenic groups and two unassigned linkage groups spanning 2464 cM of the bovine genome are summarized. The map also assigns 19 type I loci to specific chromosomes and/or syntenic groups and four cosmid clones containing informative microsatellites to chromosomes 13, 25 and 29 anchoring syntenic groups U11, U7 and U8, respectively. This map provides the skeletal framework prerequisite to development of a comprehensive genetic map for cattle and analysis of economic trait loci (ETL). PMID:7908653

A genetic epidemiology approach to cyber-security.

PubMed

Gil, Santiago; Kott, Alexander; Barabási, Albert-László

2014-07-16

While much attention has been paid to the vulnerability of computer networks to node and link failure, there is limited systematic understanding of the factors that determine the likelihood that a node (computer) is compromised. We therefore collect threat log data in a university network to study the patterns of threat activity for individual hosts. We relate this information to the properties of each host as observed through network-wide scans, establishing associations between the network services a host is running and the kinds of threats to which it is susceptible. We propose a methodology to associate services to threats inspired by the tools used in genetics to identify statistical associations between mutations and diseases. The proposed approach allows us to determine probabilities of infection directly from observation, offering an automated high-throughput strategy to develop comprehensive metrics for cyber-security.

A genetic epidemiology approach to cyber-security

PubMed Central

Gil, Santiago; Kott, Alexander; Barabási, Albert-László

2014-01-01

While much attention has been paid to the vulnerability of computer networks to node and link failure, there is limited systematic understanding of the factors that determine the likelihood that a node (computer) is compromised. We therefore collect threat log data in a university network to study the patterns of threat activity for individual hosts. We relate this information to the properties of each host as observed through network-wide scans, establishing associations between the network services a host is running and the kinds of threats to which it is susceptible. We propose a methodology to associate services to threats inspired by the tools used in genetics to identify statistical associations between mutations and diseases. The proposed approach allows us to determine probabilities of infection directly from observation, offering an automated high-throughput strategy to develop comprehensive metrics for cyber-security. PMID:25028059

Genetic dissection of the α-globin super-enhancer in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hay, Deborah; Hughes, Jim R.; Babbs, Christian

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. Furthermore, these super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation,more » without clear evidence of synergistic or higher-order effects. This study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.« less

The Genetic Precursors and the Advantageous and Disadvantageous Sequelae of Inhibited Temperament: An Evolutionary Perspective

PubMed Central

Davies, Patrick T.; Cicchetti, Dante; and, Rochelle F. Hentges; Sturge-Apple, Melissa L.

2014-01-01

Guided by evolutionary game theory (Korte, Koolhaas, Wingfield, & McEwen, 2005), this study aimed to identify the genetic precursors and the psychosocial sequelae of inhibited temperament in a sociodemographically disadvantaged and racially diverse sample of 201 two-year-old children who experienced elevated levels of domestic violence. Using a multi-method, prospective design across three annual measurement occasions, SEM analyses indicated that trained observer ratings of inhibited temperament at age two were uniquely predicted by polymorphisms in dopamine and serotonin transporter genes. Children's inhibited temperament, in turn, indirectly predicted decreases in their externalizing problems at age four through its association with greater behavioral flexibility at three years of age. Results highlight the value of integrating evolutionary and developmental conceptualizations in more comprehensively charting the developmental cascades of inhibited temperament. PMID:23527493

Genetic dissection of the α-globin super-enhancer in vivo

DOE PAGES

Hay, Deborah; Hughes, Jim R.; Babbs, Christian; ...

2016-07-04

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. Furthermore, these super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation,more » without clear evidence of synergistic or higher-order effects. This study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.« less

GoldenBraid 2.0: A Comprehensive DNA Assembly Framework for Plant Synthetic Biology1[C][W][OA

PubMed Central

Sarrion-Perdigones, Alejandro; Vazquez-Vilar, Marta; Palací, Jorge; Castelijns, Bas; Forment, Javier; Ziarsolo, Peio; Blanca, José; Granell, Antonio; Orzaez, Diego

2013-01-01

Plant synthetic biology aims to apply engineering principles to plant genetic design. One strategic requirement of plant synthetic biology is the adoption of common standardized technologies that facilitate the construction of increasingly complex multigene structures at the DNA level while enabling the exchange of genetic building blocks among plant bioengineers. Here, we describe GoldenBraid 2.0 (GB2.0), a comprehensive technological framework that aims to foster the exchange of standard DNA parts for plant synthetic biology. GB2.0 relies on the use of type IIS restriction enzymes for DNA assembly and proposes a modular cloning schema with positional notation that resembles the grammar of natural languages. Apart from providing an optimized cloning strategy that generates fully exchangeable genetic elements for multigene engineering, the GB2.0 toolkit offers an ever-growing open collection of DNA parts, including a group of functionally tested, premade genetic modules to build frequently used modules like constitutive and inducible expression cassettes, endogenous gene silencing and protein-protein interaction tools, etc. Use of the GB2.0 framework is facilitated by a number of Web resources that include a publicly available database, tutorials, and a software package that provides in silico simulations and laboratory protocols for GB2.0 part domestication and multigene engineering. In short, GB2.0 provides a framework to exchange both information and physical DNA elements among bioengineers to help implement plant synthetic biology projects. PMID:23669743

GoldenBraid 2.0: a comprehensive DNA assembly framework for plant synthetic biology.

PubMed

Sarrion-Perdigones, Alejandro; Vazquez-Vilar, Marta; Palací, Jorge; Castelijns, Bas; Forment, Javier; Ziarsolo, Peio; Blanca, José; Granell, Antonio; Orzaez, Diego

2013-07-01

Plant synthetic biology aims to apply engineering principles to plant genetic design. One strategic requirement of plant synthetic biology is the adoption of common standardized technologies that facilitate the construction of increasingly complex multigene structures at the DNA level while enabling the exchange of genetic building blocks among plant bioengineers. Here, we describe GoldenBraid 2.0 (GB2.0), a comprehensive technological framework that aims to foster the exchange of standard DNA parts for plant synthetic biology. GB2.0 relies on the use of type IIS restriction enzymes for DNA assembly and proposes a modular cloning schema with positional notation that resembles the grammar of natural languages. Apart from providing an optimized cloning strategy that generates fully exchangeable genetic elements for multigene engineering, the GB2.0 toolkit offers an evergrowing open collection of DNA parts, including a group of functionally tested, premade genetic modules to build frequently used modules like constitutive and inducible expression cassettes, endogenous gene silencing and protein-protein interaction tools, etc. Use of the GB2.0 framework is facilitated by a number of Web resources that include a publicly available database, tutorials, and a software package that provides in silico simulations and laboratory protocols for GB2.0 part domestication and multigene engineering. In short, GB2.0 provides a framework to exchange both information and physical DNA elements among bioengineers to help implement plant synthetic biology projects.