Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data.

PubMed

Zhou, Hua; Blangero, John; Dyer, Thomas D; Chan, Kei-Hang K; Lange, Kenneth; Sobel, Eric M

2017-04-01

Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel. © 2016 WILEY PERIODICALS, INC.

A single-gene explanation for the probability of having idiopathic talipes equinovarus

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

Rebbeck, T.R.; Buetow, K.H.; Dietz, F.R.

1993-11-01

It has been hypothesized that the pathogenesis of idiopathic talipes equinovarus (ITEV, or clubfoot) is explained by genetic regulation of development and growth. The objective of the present study was to determine whether a single Mendelian gene explains the probability of having ITEV in a sample of 143 Caucasian pedigrees from Iowa. These pedigrees were ascertained through probands with ITEV. Complex segregation analyses were undertaken using a regressive logistic model. The results of these analyses strongly rejected the hypotheses that the probability of having ITEV in these pedigrees was explained by a non-Mendelian pattern of transmission with residual sibling correlation,more » a nontransmitted (environmental) factor with residual sibling correlation, or residual sibling correlation alone. These results were consistent with the hypothesis that the probability of having ITEV was explained by the Mendelian segregation of a single gene with two alleles plus the effects of some unmeasured factor(s) shared among siblings. The segregation of alleles at this single Mendelian gene indicated that the disease allele A was incompletely dominant to the nondisease allele B. The disease allele A, associated with ITEV affection, was estimated to occur in the population of inference with a frequency of .007. After adjusting for sex-specific population incidences of ITEV, the conditional probability (penetrance) of ITEV affection given the AA, AB, and BB genotypes was computed to be 1.0, 0.039, and .0006, respectively. Individual pedigrees in this sample that most strongly supported the single Mendelian gene hypothesis were identified. These pedigrees are candidates for genetic linkage analyses or DNA association studies. 35 refs., 2 figs., 7 tabs.« less

Comparison of domestic and foreign genotypes by country and continent

USDA-ARS?s Scientific Manuscript database

Genomic evaluations for foreign animals are easily computed, and reliabilities are highest for animals well connected to the domestic reference population and managed in similar environments. Genomic and pedigree relationships, inbreeding, pedigree completeness, pedigree accuracy and genomic merit w...

Molecular pedigree reconstruction and estimation of evolutionary parameters in a wild Atlantic salmon river system with incomplete sampling: a power analysis

PubMed Central

2014-01-01

Background Pedigree reconstruction using genetic analysis provides a useful means to estimate fundamental population biology parameters relating to population demography, trait heritability and individual fitness when combined with other sources of data. However, there remain limitations to pedigree reconstruction in wild populations, particularly in systems where parent-offspring relationships cannot be directly observed, there is incomplete sampling of individuals, or molecular parentage inference relies on low quality DNA from archived material. While much can still be inferred from incomplete or sparse pedigrees, it is crucial to evaluate the quality and power of available genetic information a priori to testing specific biological hypotheses. Here, we used microsatellite markers to reconstruct a multi-generation pedigree of wild Atlantic salmon (Salmo salar L.) using archived scale samples collected with a total trapping system within a river over a 10 year period. Using a simulation-based approach, we determined the optimal microsatellite marker number for accurate parentage assignment, and evaluated the power of the resulting partial pedigree to investigate important evolutionary and quantitative genetic characteristics of salmon in the system. Results We show that at least 20 microsatellites (ave. 12 alleles/locus) are required to maximise parentage assignment and to improve the power to estimate reproductive success and heritability in this study system. We also show that 1.5 fold differences can be detected between groups simulated to have differing reproductive success, and that it is possible to detect moderate heritability values for continuous traits (h2 ~ 0.40) with more than 80% power when using 28 moderately to highly polymorphic markers. Conclusion The methodologies and work flow described provide a robust approach for evaluating archived samples for pedigree-based research, even where only a proportion of the total population is sampled. The results demonstrate the feasibility of pedigree-based studies to address challenging ecological and evolutionary questions in free-living populations, where genealogies can be traced only using molecular tools, and that significant increases in pedigree assignment power can be achieved by using higher numbers of markers. PMID:24684698

Pedigree reconstruction with genome-wide markers in potato

USDA-ARS?s Scientific Manuscript database

Reliable pedigree information facilitates a scientific approach to breeding, but errors can be introduced in many stages of a breeding program. Our objective was to use single nucleotide polymorphisms (SNPs) to check the pedigree records of elite North American potato germplasm. A population of 635 ...

Estimation of genetic diversity in Gute sheep: pedigree and microsatellite analyses of an ancient Swedish breed.

PubMed

Rochus, Christina M; Johansson, Anna M

2017-01-01

Breeds with small population size are in danger of an increased inbreeding rate and loss of genetic diversity, which puts them at risk for extinction. In Sweden there are a number of local breeds, native breeds which have adapted to specific areas in Sweden, for which efforts are being made to keep them pure and healthy over time. One example of such a breed is the Swedish Gute sheep. The objective of this study was to estimate inbreeding and genetic diversity of Swedish Gute sheep. Three datasets were analysed: pedigree information of the whole population, pedigree information for 100 animals of the population, and microsatellite genotypes for 94 of the 100 animals. The average inbreeding coefficient for lambs born during a six year time period (2007-2012) did not increase during that time period. The inbreeding calculated from the entire pedigree (0.038) and for a sample of the population (0.018) was very low. Sheep were more heterozygous at the microsatellite markers than expected (average multilocus heterozygosity and Ritland inbreeding estimates 1.01845 and -0.03931) and five of seven microsatellite markers were not in Hardy Weinberg equilibrium due to heterozygosity excess. The total effective population size estimated from the pedigree information was 155.4 and the average harmonic mean effective population size estimated from microsatellites was 88.3. Pedigree and microsatellite genotype estimations of inbreeding were consistent with a breeding program with the purpose of reducing inbreeding. Our results showed that current breeding programs of the Swedish Gute sheep are consistent with efforts of keeping this breed viable and these breeding programs are an example for other small local breeds in conserving breeds for the future.

A comparison of pedigree- and DNA-based measures for identifying inbreeding depression in the critically endangered Attwater's Prairie-chicken.

PubMed

Hammerly, Susan C; Morrow, Michael E; Johnson, Jeff A

2013-11-01

The primary goal of captive breeding programmes for endangered species is to prevent extinction, a component of which includes the preservation of genetic diversity and avoidance of inbreeding. This is typically accomplished by minimizing mean kinship in the population, thereby maintaining equal representation of the genetic founders used to initiate the captive population. If errors in the pedigree do exist, such an approach becomes less effective for minimizing inbreeding depression. In this study, both pedigree- and DNA-based methods were used to assess whether inbreeding depression existed in the captive population of the critically endangered Attwater's Prairie-chicken (Tympanuchus cupido attwateri), a subspecies of prairie grouse that has experienced a significant decline in abundance and concurrent reduction in neutral genetic diversity. When examining the captive population for signs of inbreeding, variation in pedigree-based inbreeding coefficients (f(pedigree)) was less than that obtained from DNA-based methods (f(DNA)). Mortality of chicks and adults in captivity were also positively correlated with parental relatedness (r(DNA)) and f(DNA), respectively, while no correlation was observed with pedigree-based measures when controlling for additional variables such as age, breeding facility, gender and captive/release status. Further, individual homozygosity by loci (HL) and parental rDNA values were positively correlated with adult mortality in captivity and the occurrence of a lethal congenital defect in chicks, respectively, suggesting that inbreeding may be a contributing factor increasing the frequency of this condition among Attwater's Prairie-chickens. This study highlights the importance of using DNA-based methods to better inform management decisions when pedigrees are incomplete or errors may exist due to uncertainty in pairings. © 2013 John Wiley & Sons Ltd.

Genealogical information and the structure of rural Latin-American populations: reality and fantasy.

PubMed

Castilla, E E; Adams, J

1996-01-01

Genetic data organized in the form of genealogies can provide much information regarding the history and genetic structure of human populations. A large proportion of the population of Latin America is organized in small rural semi-isolated communities, with little immigration, and until the last 50-100 years, little emigration. These communities have a strong sense of their genealogical history, and this "genealogical conscience' is a frequent leitmotif in modern Latin-American literature. In this communication, we compare the characteristics of fictitious genealogies described in two masterpieces of Latin-American literature, García Márquez' Cien Años de Soledad (A Hundred Years of Solitude), and Verissimo's O Tempo e o Vento (Time and the Wind), with one existing well-studied population in Argentina, Aicuña. All three populations exhibit a number of common characteristics, such as histories of long periods of civil war, and large pedigrees with complex paths of inheritance resulting in complex patterns of inbreeding. Genetic themes common to all three are: (1) the use of genealogical records to substantiate the property of the land or the political power of a kinship; (2) the genealogical registry of biological descendants, independent of their legal or marital status in the clan; (3) the existence of pedigrees of the aristocratic branches in the same kindreds, which illustrate the legal principle of primogeniture; (4) the value of last names as indicators of kinships and the extent of genetic isolation, and (5) the awareness of the deleterious consequences of consanguinity.

Identification of kin structure among Guam rail founders: a comparison of pedigrees and DNA profiles

USGS Publications Warehouse

Haig, Susan M.; Ballou, J.D.; Casna, N.J.

1994-01-01

Kin structure among founders can have a significant effect on subsequent population structure. Here we use the correlation between DNA profile similarity and relatedness calculated from pedigrees to test hypotheses regarding kin structure among founders to the captive Guam rail (Rallus owstoni) population. Five different pedigrees were generated under the following hypotheses: (i) founders are unrelated; (ii) founders are unrelated except for same-nest chicks; (iii) founders from the same major site are siblings; (iv) founders from the same local site are siblings; and (v) founders are related as defined by a UPGMA cluster analysis of DNA similarity data. Relatedness values from pedigrees 1, 2 and 5 had the highest correlation with DNA similarity but the correlation between relatedness and similarity were not significantly different among pedigrees. Pedigree 5 resulted in the highest correlation overall when using only relatedness values that changed as a result of different founder hypotheses. Thus, founders were assigned relatedness based on pedigree 5 because it had the highest correlations with DNA similarity, was the most conservative approach, and incorporated all field data. The analyses indicated that estimating relatedness using DNA profiles remains problematic, therefore we compared mean kinship, a measure of genetic importance, with mean DNA profile similarity to determine if genetic importance among individuals could be determined via use of DNA profiles alone. The significant correlation suggests this method may provide more information about population structure than was previously thought. Thus, DNA profiles can provide a reasonable explanation for founder relatedness and mean DNA profile similarity may be helpful in determining relative genetic importance of individuals when detailed pedigrees are absent.

The Relation Between Reproductive Value and Genetic Contribution

PubMed Central

Barton, Nicholas H.; Etheridge, Alison M.

2011-01-01

What determines the genetic contribution that an individual makes to future generations? With biparental reproduction, each individual leaves a “pedigree” of descendants, determined by the biparental relationships in the population. The pedigree of an individual constrains the lines of descent of each of its genes. An individual’s reproductive value is the expected number of copies of each of its genes that is passed on to distant generations conditional on its pedigree. For the simplest model of biparental reproduction (analogous to the Wright–Fisher model), an individual’s reproductive value is determined within ∼10 generations, independent of population size. Partial selfing and subdivision do not greatly slow this convergence. Our central result is that the probability that a gene will survive is proportional to the reproductive value of the individual that carries it and that, conditional on survival, after a few tens of generations, the distribution of the number of surviving copies is the same for all individuals, whatever their reproductive value. These results can be generalized to the joint distribution of surviving blocks of the ancestral genome. Selection on unlinked loci in the genetic background may greatly increase the variance in reproductive value, but the above results nevertheless still hold. The almost linear relationship between survival probability and reproductive value also holds for weakly favored alleles. Thus, the influence of the complex pedigree of descendants on an individual’s genetic contribution to the population can be summarized through a single number: its reproductive value. PMID:21624999

Relevance of genetic relationship in GWAS and genomic prediction.

PubMed

Pereira, Helcio Duarte; Soriano Viana, José Marcelo; Andrade, Andréa Carla Bastos; Fonseca E Silva, Fabyano; Paes, Geísa Pinheiro

2018-02-01

The objective of this study was to analyze the relevance of relationship information on the identification of low heritability quantitative trait loci (QTLs) from a genome-wide association study (GWAS) and on the genomic prediction of complex traits in human, animal and cross-pollinating populations. The simulation-based data sets included 50 samples of 1000 individuals of seven populations derived from a common population with linkage disequilibrium. The populations had non-inbred and inbred progeny structure (50 to 200) with varying number of members (5 to 20). The individuals were genotyped for 10,000 single nucleotide polymorphisms (SNPs) and phenotyped for a quantitative trait controlled by 10 QTLs and 90 minor genes showing dominance. The SNP density was 0.1 cM and the narrow sense heritability was 25%. The QTL heritabilities ranged from 1.1 to 2.9%. We applied mixed model approaches for both GWAS and genomic prediction using pedigree-based and genomic relationship matrices. For GWAS, the observed false discovery rate was kept below the significance level of 5%, the power of detection for the low heritability QTLs ranged from 14 to 50%, and the average bias between significant SNPs and a QTL ranged from less than 0.01 to 0.23 cM. The QTL detection power was consistently higher using genomic relationship matrix. Regardless of population and training set size, genomic prediction provided higher prediction accuracy of complex trait when compared to pedigree-based prediction. The accuracy of genomic prediction when there is relatedness between individuals in the training set and the reference population is much higher than the value for unrelated individuals.

Genetic identification of a common collagen disease in Puerto Ricans via identity-by-descent mapping in a health system

PubMed Central

Belbin, Gillian Morven; Odgis, Jacqueline; Sorokin, Elena P; Yee, Muh-Ching; Kohli, Sumita; Glicksberg, Benjamin S; Gignoux, Christopher R; Wojcik, Genevieve L; Van Vleck, Tielman; Jeff, Janina M; Linderman, Michael; Schurmann, Claudia; Ruderfer, Douglas; Cai, Xiaoqiang; Merkelson, Amanda; Justice, Anne E; Young, Kristin L; Graff, Misa; North, Kari E; Peters, Ulrike; James, Regina; Hindorff, Lucia; Kornreich, Ruth; Edelmann, Lisa; Gottesman, Omri; Stahl, Eli EA; Cho, Judy H; Loos, Ruth JF; Bottinger, Erwin P; Nadkarni, Girish N; Abul-Husn, Noura S

2017-01-01

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease. PMID:28895531

Features of mtDNA mutation patterns in European pedigrees and sporadic cases with leber hereditary optic neuropathy

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

Obermaier-Kusser, B.; Schubring, S.; Paprotta, A.

1994-11-01

Leber hereditary optic neuropathy (LHON) is maternally transmitted and is characterized by bilateral loss of central vision in young adults as a result of optic nerve degeneration. Fifteen transition mutations located in different genes for the mitochondrially encoded subunits of respiratory chain complexes have been associated thus far with the disease. Genetic studies have led to the classification of the pathogenic significance of these different mutations. However, more research is required to determine the causality of the mutations and the penetrance of the disease. The present study compares studies of populations of different ethnic origins, namely European LHON pedigrees andmore » sporadic cases, in order to elucidate the pathogenic mechanisms involved. 21 refs., 2 figs., 1 tab.« less

Historical pedigree reconstruction from extant populations using PArtitioning of RElatives (PREPARE).

PubMed

Shem-Tov, Doron; Halperin, Eran

2014-06-01

Recent technological improvements in the field of genetic data extraction give rise to the possibility of reconstructing the historical pedigrees of entire populations from the genotypes of individuals living today. Current methods are still not practical for real data scenarios as they have limited accuracy and assume unrealistic assumptions of monogamy and synchronized generations. In order to address these issues, we develop a new method for pedigree reconstruction, [Formula: see text], which is based on formulations of the pedigree reconstruction problem as variants of graph coloring. The new formulation allows us to consider features that were overlooked by previous methods, resulting in a reconstruction of up to 5 generations back in time, with an order of magnitude improvement of false-negatives rates over the state of the art, while keeping a lower level of false positive rates. We demonstrate the accuracy of [Formula: see text] compared to previous approaches using simulation studies over a range of population sizes, including inbred and outbred populations, monogamous and polygamous mating patterns, as well as synchronous and asynchronous mating.

A general unified framework to assess the sampling variance of heritability estimates using pedigree or marker-based relationships.

PubMed

Visscher, Peter M; Goddard, Michael E

2015-01-01

Heritability is a population parameter of importance in evolution, plant and animal breeding, and human medical genetics. It can be estimated using pedigree designs and, more recently, using relationships estimated from markers. We derive the sampling variance of the estimate of heritability for a wide range of experimental designs, assuming that estimation is by maximum likelihood and that the resemblance between relatives is solely due to additive genetic variation. We show that well-known results for balanced designs are special cases of a more general unified framework. For pedigree designs, the sampling variance is inversely proportional to the variance of relationship in the pedigree and it is proportional to 1/N, whereas for population samples it is approximately proportional to 1/N(2), where N is the sample size. Variation in relatedness is a key parameter in the quantification of the sampling variance of heritability. Consequently, the sampling variance is high for populations with large recent effective population size (e.g., humans) because this causes low variation in relationship. However, even using human population samples, low sampling variance is possible with high N. Copyright © 2015 by the Genetics Society of America.

A phasing and imputation method for pedigreed populations that results in a single-stage genomic evaluation

PubMed Central

2012-01-01

Background Efficient, robust, and accurate genotype imputation algorithms make large-scale application of genomic selection cost effective. An algorithm that imputes alleles or allele probabilities for all animals in the pedigree and for all genotyped single nucleotide polymorphisms (SNP) provides a framework to combine all pedigree, genomic, and phenotypic information into a single-stage genomic evaluation. Methods An algorithm was developed for imputation of genotypes in pedigreed populations that allows imputation for completely ungenotyped animals and for low-density genotyped animals, accommodates a wide variety of pedigree structures for genotyped animals, imputes unmapped SNP, and works for large datasets. The method involves simple phasing rules, long-range phasing and haplotype library imputation and segregation analysis. Results Imputation accuracy was high and computational cost was feasible for datasets with pedigrees of up to 25 000 animals. The resulting single-stage genomic evaluation increased the accuracy of estimated genomic breeding values compared to a scenario in which phenotypes on relatives that were not genotyped were ignored. Conclusions The developed imputation algorithm and software and the resulting single-stage genomic evaluation method provide powerful new ways to exploit imputation and to obtain more accurate genetic evaluations. PMID:22462519

First genealogy for a wild marine fish population reveals multigenerational philopatry.

PubMed

Salles, Océane C; Pujol, Benoit; Maynard, Jeffrey A; Almany, Glenn R; Berumen, Michael L; Jones, Geoffrey P; Saenz-Agudelo, Pablo; Srinivasan, Maya; Thorrold, Simon R; Planes, Serge

2016-11-15

Natal philopatry, the return of individuals to their natal area for reproduction, has advantages and disadvantages for animal populations. Natal philopatry may generate local genetic adaptation, but it may also increase the probability of inbreeding that can compromise persistence. Although natal philopatry is well documented in anadromous fishes, marine fish may also return to their birth site to spawn. How philopatry shapes wild fish populations is, however, unclear because it requires constructing multigenerational pedigrees that are currently lacking for marine fishes. Here we present the first multigenerational pedigree for a marine fish population by repeatedly genotyping all individuals in a population of the orange clownfish (Amphiprion percula) at Kimbe Island (Papua New Guinea) during a 10-y period. Based on 2927 individuals, our pedigree analysis revealed that longitudinal philopatry was recurrent over five generations. Progeny tended to settle close to their parents, with related individuals often sharing the same colony. However, successful inbreeding was rare, and genetic diversity remained high, suggesting occasional inbreeding does not impair local population persistence. Local reproductive success was dependent on the habitat larvae settled into, rather than the habitat they came from. Our study suggests that longitudinal philopatry can influence both population replenishment and local adaptation of marine fishes. Resolving multigenerational pedigrees during a relatively short period, as we present here, provides a framework for assessing the ability of marine populations to persist and adapt to accelerating climate change.

First genealogy for a wild marine fish population reveals multigenerational philopatry

PubMed Central

Salles, Océane C.; Pujol, Benoit; Maynard, Jeffrey A.; Almany, Glenn R.; Berumen, Michael L.; Jones, Geoffrey P.; Saenz-Agudelo, Pablo; Srinivasan, Maya; Thorrold, Simon R.; Planes, Serge

2016-01-01

Natal philopatry, the return of individuals to their natal area for reproduction, has advantages and disadvantages for animal populations. Natal philopatry may generate local genetic adaptation, but it may also increase the probability of inbreeding that can compromise persistence. Although natal philopatry is well documented in anadromous fishes, marine fish may also return to their birth site to spawn. How philopatry shapes wild fish populations is, however, unclear because it requires constructing multigenerational pedigrees that are currently lacking for marine fishes. Here we present the first multigenerational pedigree for a marine fish population by repeatedly genotyping all individuals in a population of the orange clownfish (Amphiprion percula) at Kimbe Island (Papua New Guinea) during a 10-y period. Based on 2927 individuals, our pedigree analysis revealed that longitudinal philopatry was recurrent over five generations. Progeny tended to settle close to their parents, with related individuals often sharing the same colony. However, successful inbreeding was rare, and genetic diversity remained high, suggesting occasional inbreeding does not impair local population persistence. Local reproductive success was dependent on the habitat larvae settled into, rather than the habitat they came from. Our study suggests that longitudinal philopatry can influence both population replenishment and local adaptation of marine fishes. Resolving multigenerational pedigrees during a relatively short period, as we present here, provides a framework for assessing the ability of marine populations to persist and adapt to accelerating climate change. PMID:27799530

Breed-Predispositions to Cancer in Pedigree Dogs

PubMed Central

Dobson, Jane M.

2013-01-01

Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies. PMID:23738139

Predicting Quantitative Traits With Regression Models for Dense Molecular Markers and Pedigree

PubMed Central

de los Campos, Gustavo; Naya, Hugo; Gianola, Daniel; Crossa, José; Legarra, Andrés; Manfredi, Eduardo; Weigel, Kent; Cotes, José Miguel

2009-01-01

The availability of genomewide dense markers brings opportunities and challenges to breeding programs. An important question concerns the ways in which dense markers and pedigrees, together with phenotypic records, should be used to arrive at predictions of genetic values for complex traits. If a large number of markers are included in a regression model, marker-specific shrinkage of regression coefficients may be needed. For this reason, the Bayesian least absolute shrinkage and selection operator (LASSO) (BL) appears to be an interesting approach for fitting marker effects in a regression model. This article adapts the BL to arrive at a regression model where markers, pedigrees, and covariates other than markers are considered jointly. Connections between BL and other marker-based regression models are discussed, and the sensitivity of BL with respect to the choice of prior distributions assigned to key parameters is evaluated using simulation. The proposed model was fitted to two data sets from wheat and mouse populations, and evaluated using cross-validation methods. Results indicate that inclusion of markers in the regression further improved the predictive ability of models. An R program that implements the proposed model is freely available. PMID:19293140

Multifactorial disease risk calculator: Risk prediction for multifactorial disease pedigrees.

PubMed

Campbell, Desmond D; Li, Yiming; Sham, Pak C

2018-03-01

Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the simplest of cases. Multifactorial Disease Risk Calculator is a web tool facilitating this. It provides a user-friendly interface, extending a reported methodology based on a liability-threshold model. Multifactorial disease models incorporating all the following features in combination are handled: quantitative risk factors (including polygenic scores), categorical risk factors (including major genetic risk loci), stratified age of onset curves, and the partition of the population variance in disease liability into genetic, shared, and unique environment effects. It allows the application of such models to disease pedigrees. Pedigree-related outputs are (i) individual disease risk for pedigree members, (ii) n year risk for unaffected pedigree members, and (iii) the disease pedigree's joint liability distribution. Risk prediction for each pedigree member is based on using the constructed disease model to appropriately weigh evidence on disease risk available from personal attributes and family history. Evidence is used to construct the disease pedigree's joint liability distribution. From this, lifetime and n year risk can be predicted. Example disease models and pedigrees are provided at the website and are used in accompanying tutorials to illustrate the features available. The website is built on an R package which provides the functionality for pedigree validation, disease model construction, and risk prediction. Website: http://grass.cgs.hku.hk:3838/mdrc/current. © 2017 WILEY PERIODICALS, INC.

Admixture analysis in relation to pedigree studies of introgression in a minority British cattle breed: the Lincoln Red.

PubMed

Bray, T C; Hall, S J G; Bruford, M W

2014-02-01

Investigation of historic population processes using molecular data has been facilitated by the use of approximate Bayesian computation (ABC), which enables the consideration of multiple alternative demographic scenarios. The Lincoln Red cattle breed provides a relatively simple example of two well-documented admixture events. Using molecular data for this breed, we found that structure did not resolve very low (<5% levels) of introgression, possibly due to sampling limitations. We evaluated the performance of two ABC approaches (2BAD and DIYABC) against those of two earlier methodologies, ADMIX and LEADMIX, by comparing their interpretations with the conclusions drawn from herdbook analysis. The ABC methods gave credible values for the proportions of the Lincoln Red genotype that are attributable to Aberdeen Angus and Limousin, although estimates of effective population size and event timing were not realistic. We suggest ABC methods are a valuable supplement to pedigree-based studies but that the accuracy of admixture determination is likely to diminish with increasing complexity of the admixture scenario. © 2013 Blackwell Verlag GmbH.

Estimation of genealogical coancestry in plant species using a pedigree reconstruction algorithm and application to an oil palm breeding population.

PubMed

Cros, David; Sánchez, Leopoldo; Cochard, Benoit; Samper, Patrick; Denis, Marie; Bouvet, Jean-Marc; Fernández, Jesús

2014-04-01

Explicit pedigree reconstruction by simulated annealing gave reliable estimates of genealogical coancestry in plant species, especially when selfing rate was lower than 0.6, using a realistic number of markers. Genealogical coancestry information is crucial in plant breeding to estimate genetic parameters and breeding values. The approach of Fernández and Toro (Mol Ecol 15:1657-1667, 2006) to estimate genealogical coancestries from molecular data through pedigree reconstruction was limited to species with separate sexes. In this study it was extended to plants, allowing hermaphroditism and monoecy, with possible selfing. Moreover, some improvements were made to take previous knowledge on the population demographic history into account. The new method was validated using simulated and real datasets. Simulations showed that accuracy of estimates was high with 30 microsatellites, with the best results obtained for selfing rates below 0.6. In these conditions, the root mean square error (RMSE) between the true and estimated genealogical coancestry was small (<0.07), although the number of ancestors was overestimated and the selfing rate could be biased. Simulations also showed that linkage disequilibrium between markers and departure from the Hardy-Weinberg equilibrium in the founder population did not affect the efficiency of the method. Real oil palm data confirmed the simulation results, with a high correlation between the true and estimated genealogical coancestry (>0.9) and a low RMSE (<0.08) using 38 markers. The method was applied to the Deli oil palm population for which pedigree data were scarce. The estimated genealogical coancestries were highly correlated (>0.9) with the molecular coancestries using 100 markers. Reconstructed pedigrees were used to estimate effective population sizes. In conclusion, this method gave reliable genealogical coancestry estimates. The strategy was implemented in the software MOLCOANC 3.0.

The importance of information on relatives for the prediction of genomic breeding values and the implications for the makeup of reference data sets in livestock breeding schemes.

PubMed

Clark, Samuel A; Hickey, John M; Daetwyler, Hans D; van der Werf, Julius H J

2012-02-09

The theory of genomic selection is based on the prediction of the effects of genetic markers in linkage disequilibrium with quantitative trait loci. However, genomic selection also relies on relationships between individuals to accurately predict genetic value. This study aimed to examine the importance of information on relatives versus that of unrelated or more distantly related individuals on the estimation of genomic breeding values. Simulated and real data were used to examine the effects of various degrees of relationship on the accuracy of genomic selection. Genomic Best Linear Unbiased Prediction (gBLUP) was compared to two pedigree based BLUP methods, one with a shallow one generation pedigree and the other with a deep ten generation pedigree. The accuracy of estimated breeding values for different groups of selection candidates that had varying degrees of relationships to a reference data set of 1750 animals was investigated. The gBLUP method predicted breeding values more accurately than BLUP. The most accurate breeding values were estimated using gBLUP for closely related animals. Similarly, the pedigree based BLUP methods were also accurate for closely related animals, however when the pedigree based BLUP methods were used to predict unrelated animals, the accuracy was close to zero. In contrast, gBLUP breeding values, for animals that had no pedigree relationship with animals in the reference data set, allowed substantial accuracy. An animal's relationship to the reference data set is an important factor for the accuracy of genomic predictions. Animals that share a close relationship to the reference data set had the highest accuracy from genomic predictions. However a baseline accuracy that is driven by the reference data set size and the overall population effective population size enables gBLUP to estimate a breeding value for unrelated animals within a population (breed), using information previously ignored by pedigree based BLUP methods.

Inbreeding trends and pedigree analysis of Bavarian mountain hounds, Hanoverian hounds and Tyrolean hounds.

PubMed

Voges, S; Distl, O

2009-10-01

The objective of this study was to analyse genetic diversity for the three scent-hound breeds Bavarian mountain hound (BMH), Hanoverian hound (HH) and Tyrolean hound (TH) using all available pedigree information from scent-hound kennel clubs for these three breeds throughout Europe. The pedigree data of the BMH and the HH date back to 1912 and 1894, respectively. Pedigree data of the TH were available from the 1960s onwards. The reference populations included all BMH (n = 3231), HH (n = 1371) and TH (n = 1167) dogs registered between 1992 and 2004. Average generation intervals were 5.3 years for the BMH and 5.0 years for the HH and TH. Average inbreeding coefficients for the reference populations were 4.5%, 6.8% and 9.5% for the BMH, HH and TH. The effective numbers of founders, ancestors and founder genomes were lowest for the TH and highest for the BMH. The effective numbers of founder genomes were 10.9, 5.6 and 4.3 for the BMH, HH and TH. Effective population size was largest for the BMH with 72.7 effective breeding animals, followed by the HH with 50.9 and TH with 26.5. The most important ten ancestors had genetic contributions to the reference populations of 54.4%, 65.2% and 77.9% in the BMH, HH and TH. The results of our study indicate the need for careful breed management in these highly specialized hound breeds to maintain genetic diversity. European stud books should be established for these dog breeds in order to avoid inbreeding due to missing pedigree records.

Efficient path-based computations on pedigree graphs with compact encodings

PubMed Central

2012-01-01

A pedigree is a diagram of family relationships, and it is often used to determine the mode of inheritance (dominant, recessive, etc.) of genetic diseases. Along with rapidly growing knowledge of genetics and accumulation of genealogy information, pedigree data is becoming increasingly important. In large pedigree graphs, path-based methods for efficiently computing genealogical measurements, such as inbreeding and kinship coefficients of individuals, depend on efficient identification and processing of paths. In this paper, we propose a new compact path encoding scheme on large pedigrees, accompanied by an efficient algorithm for identifying paths. We demonstrate the utilization of our proposed method by applying it to the inbreeding coefficient computation. We present time and space complexity analysis, and also manifest the efficiency of our method for evaluating inbreeding coefficients as compared to previous methods by experimental results using pedigree graphs with real and synthetic data. Both theoretical and experimental results demonstrate that our method is more scalable and efficient than previous methods in terms of time and space requirements. PMID:22536898

Contrasting results from molecular and pedigree-based population diversity measures in captive zebra highlight challenges facing genetic management of zoo populations.

PubMed

Ito, Hideyuki; Ogden, Rob; Langenhorst, Tanya; Inoue-Murayama, Miho

2017-01-01

Zoo conservation breeding programs manage the retention of population genetic diversity through analysis of pedigree records. The range of demographic and genetic indices determined through pedigree analysis programs allows the conservation of diversity to be monitored relative to the particular founder population for a species. Such approaches are based on a number of well-documented founder assumptions, however without knowledge of actual molecular genetic diversity there is a risk that pedigree-based measures will be misinterpreted and population genetic diversity misunderstood. We examined the genetic diversity of the captive populations of Grevy's zebra, Hartmann's mountain zebra and plains zebra in Japan and the United Kingdom through analysis of mitochondrial DNA sequences. Very low nucleotide variability was observed in Grevy's zebra. The results were evaluated with respect to current and historic diversity in the wild, and indicate that low genetic diversity in the captive population is likely a result of low founder diversity, which in turn suggests relatively low wild genetic diversity prior to recent population declines. Comparison of molecular genetic diversity measures with analogous diversity indices generated from the studbook data for Grevy's zebra and Hartmann's mountain zebra show contrasting patterns, with Grevy's zebra displaying markedly less molecular diversity than mountain zebra, despite studbook analysis indicating that the Grevy's zebra population has substantially more founders, greater effective population size, lower mean kinship, and has suffered less loss of gene diversity. These findings emphasize the need to validate theoretical estimates of genetic diversity in captive breeding programs with empirical molecular genetic data. Zoo Biol. 36:87-94, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Inherited occipital hypoplasia/syringomyelia in the cavalier King Charles spaniel: experiences in setting up a worldwide DNA collection.

PubMed

Rusbridge, Clare; Knowler, Penny; Rouleau, Guy A; Minassian, Berge A; Rothuizen, Jan

2005-01-01

Inherited diseases commonly emerge within pedigree dog populations, often due to use of repeatedly bred carrier sire(s) within a small gene pool. Accurate family records are usually available making linkage analysis possible. However, there are many factors that are intrinsically difficult about collecting DNA and collating pedigree information from a large canine population. The keys to a successful DNA collection program include (1) the need to establish and maintain support from the pedigree breed clubs and pet owners; (2) committed individual(s) who can devote the considerable amount of time and energy to coordinating sample collection and communicating with breeders and clubs; and (3) providing means by which genotypic and phenotypic information can be easily collected and stored. In this article we described the clinical characteristics of inherited occipital hypoplasia/syringomyelia (Chiari type I malformation) in the cavalier King Charles spaniel and our experiences in establishing a pedigree and DNA database to study the disease.

Bayesian pedigree inference with small numbers of single nucleotide polymorphisms via a factor-graph representation.

PubMed

Anderson, Eric C; Ng, Thomas C

2016-02-01

We develop a computational framework for addressing pedigree inference problems using small numbers (80-400) of single nucleotide polymorphisms (SNPs). Our approach relaxes the assumptions, which are commonly made, that sampling is complete with respect to the pedigree and that there is no genotyping error. It relies on representing the inferred pedigree as a factor graph and invoking the Sum-Product algorithm to compute and store quantities that allow the joint probability of the data to be rapidly computed under a large class of rearrangements of the pedigree structure. This allows efficient MCMC sampling over the space of pedigrees, and, hence, Bayesian inference of pedigree structure. In this paper we restrict ourselves to inference of pedigrees without loops using SNPs assumed to be unlinked. We present the methodology in general for multigenerational inference, and we illustrate the method by applying it to the inference of full sibling groups in a large sample (n=1157) of Chinook salmon typed at 95 SNPs. The results show that our method provides a better point estimate and estimate of uncertainty than the currently best-available maximum-likelihood sibling reconstruction method. Extensions of this work to more complex scenarios are briefly discussed. Published by Elsevier Inc.

Population Structure and Genomic Breed Composition in an Angus-Brahman Crossbred Cattle Population.

PubMed

Gobena, Mesfin; Elzo, Mauricio A; Mateescu, Raluca G

2018-01-01

Crossbreeding is a common strategy used in tropical and subtropical regions to enhance beef production, and having accurate knowledge of breed composition is essential for the success of a crossbreeding program. Although pedigree records have been traditionally used to obtain the breed composition of crossbred cattle, the accuracy of pedigree-based breed composition can be reduced by inaccurate and/or incomplete records and Mendelian sampling. Breed composition estimation from genomic data has multiple advantages including higher accuracy without being affected by missing, incomplete, or inaccurate records and the ability to be used as independent authentication of breed in breed-labeled beef products. The present study was conducted with 676 Angus-Brahman crossbred cattle with genotype and pedigree information to evaluate the feasibility and accuracy of using genomic data to determine breed composition. We used genomic data in parametric and non-parametric methods to detect population structure due to differences in breed composition while accounting for the confounding effect of close familial relationships. By applying principal component analysis (PCA) and the maximum likelihood method of ADMIXTURE to genomic data, it was possible to successfully characterize population structure resulting from heterogeneous breed ancestry, while accounting for close familial relationships. PCA results offered additional insight into the different hierarchies of genetic variation structuring. The first principal component was strongly correlated with Angus-Brahman proportions, and the second represented variation within animals that have a relatively more extended Brangus lineage-indicating the presence of a distinct pattern of genetic variation in these cattle. Although there was strong agreement between breed proportions estimated from pedigree and genetic information, there were significant discrepancies between these two methods for certain animals. This was most likely due to inaccuracies in the pedigree-based estimation of breed composition, which supported the case for using genomic information to complement and/or replace pedigree information when estimating breed composition. Comparison with a supervised analysis where purebreds are used as the training set suggest that accurate predictions can be achieved even in the absence of purebred population information.

Pedigree- and SNP-Associated Genetics and Recent Environment are the Major Contributors to Anthropometric and Cardiometabolic Trait Variation.

PubMed

Xia, Charley; Amador, Carmen; Huffman, Jennifer; Trochet, Holly; Campbell, Archie; Porteous, David; Hastie, Nicholas D; Hayward, Caroline; Vitart, Veronique; Navarro, Pau; Haley, Chris S

2016-02-01

Genome-wide association studies have successfully identified thousands of loci for a range of human complex traits and diseases. The proportion of phenotypic variance explained by significant associations is, however, limited. Given the same dense SNP panels, mixed model analyses capture a greater proportion of phenotypic variance than single SNP analyses but the total is generally still less than the genetic variance estimated from pedigree studies. Combining information from pedigree relationships and SNPs, we examined 16 complex anthropometric and cardiometabolic traits in a Scottish family-based cohort comprising up to 20,000 individuals genotyped for ~520,000 common autosomal SNPs. The inclusion of related individuals provides the opportunity to also estimate the genetic variance associated with pedigree as well as the effects of common family environment. Trait variation was partitioned into SNP-associated and pedigree-associated genetic variation, shared nuclear family environment, shared couple (partner) environment and shared full-sibling environment. Results demonstrate that trait heritabilities vary widely but, on average across traits, SNP-associated and pedigree-associated genetic effects each explain around half the genetic variance. For most traits the recently-shared environment of couples is also significant, accounting for ~11% of the phenotypic variance on average. On the other hand, the environment shared largely in the past by members of a nuclear family or by full-siblings, has a more limited impact. Our findings point to appropriate models to use in future studies as pedigree-associated genetic effects and couple environmental effects have seldom been taken into account in genotype-based analyses. Appropriate description of the trait variation could help understand causes of intra-individual variation and in the detection of contributing loci and environmental factors.

Sex linked versus autosomal inbreeding coefficient in close consanguineous marriages in the Basque country and Castile (Spain): genetic implications.

PubMed

Calderón, R; Morales, B; Peña, J A; Delgado, J

1995-10-01

Pedigree structures of 161 uncle/niece-aunt/nephew and 4420 first cousin consanguineous marriages registered during the 19th and 20th centuries in two large and very different Spanish regions have been analysed and their genetic consequences evaluated. The frequencies of the different pedigree subtypes within each degree of relationship were quite similar in both populations despite significant heterogeneity in inbreeding patterns. The mean X-linked inbreeding coefficient (Fx) for each type of cousin mating was calculated and compared to that expected for autosomal genes (F). The effect of genealogical structure on the Fx/F ratio was compared to different cultural populations worldwide. Preferentiality and avoidance of close consanguinity along with specific types of pedigrees are discussed on the basis of premarital migration and sociocultural rules still deeply rooted in certain human groups. By admitting that the observed Fx coefficient is usually higher than F in most human populations some remarks have been made in terms of population genetic risk.

Integrating Nonadditive Genomic Relationship Matrices into the Study of Genetic Architecture of Complex Traits.

PubMed

Nazarian, Alireza; Gezan, Salvador A

2016-03-01

The study of genetic architecture of complex traits has been dramatically influenced by implementing genome-wide analytical approaches during recent years. Of particular interest are genomic prediction strategies which make use of genomic information for predicting phenotypic responses instead of detecting trait-associated loci. In this work, we present the results of a simulation study to improve our understanding of the statistical properties of estimation of genetic variance components of complex traits, and of additive, dominance, and genetic effects through best linear unbiased prediction methodology. Simulated dense marker information was used to construct genomic additive and dominance matrices, and multiple alternative pedigree- and marker-based models were compared to determine if including a dominance term into the analysis may improve the genetic analysis of complex traits. Our results showed that a model containing a pedigree- or marker-based additive relationship matrix along with a pedigree-based dominance matrix provided the best partitioning of genetic variance into its components, especially when some degree of true dominance effects was expected to exist. Also, we noted that the use of a marker-based additive relationship matrix along with a pedigree-based dominance matrix had the best performance in terms of accuracy of correlations between true and estimated additive, dominance, and genetic effects. © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Whole-genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic-trait mapping.

PubMed

Dreger, Dayna L; Rimbault, Maud; Davis, Brian W; Bhatnagar, Adrienne; Parker, Heidi G; Ostrander, Elaine A

2016-12-01

In the decade following publication of the draft genome sequence of the domestic dog, extraordinary advances with application to several fields have been credited to the canine genetic system. Taking advantage of closed breeding populations and the subsequent selection for aesthetic and behavioral characteristics, researchers have leveraged the dog as an effective natural model for the study of complex traits, such as disease susceptibility, behavior and morphology, generating unique contributions to human health and biology. When designing genetic studies using purebred dogs, it is essential to consider the unique demography of each population, including estimation of effective population size and timing of population bottlenecks. The analytical design approach for genome-wide association studies (GWAS) and analysis of whole-genome sequence (WGS) experiments are inextricable from demographic data. We have performed a comprehensive study of genomic homozygosity, using high-depth WGS data for 90 individuals, and Illumina HD SNP data from 800 individuals representing 80 breeds. These data were coupled with extensive pedigree data analyses for 11 breeds that, together, allowed us to compute breed structure, demography, and molecular measures of genome diversity. Our comparative analyses characterize the extent, formation and implication of breed-specific diversity as it relates to population structure. These data demonstrate the relationship between breed-specific genome dynamics and population architecture, and provide important considerations influencing the technological and cohort design of association and other genomic studies. © 2016. Published by The Company of Biologists Ltd.

Whole-genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic-trait mapping

PubMed Central

Dreger, Dayna L.; Rimbault, Maud; Davis, Brian W.; Bhatnagar, Adrienne; Parker, Heidi G.

2016-01-01

ABSTRACT In the decade following publication of the draft genome sequence of the domestic dog, extraordinary advances with application to several fields have been credited to the canine genetic system. Taking advantage of closed breeding populations and the subsequent selection for aesthetic and behavioral characteristics, researchers have leveraged the dog as an effective natural model for the study of complex traits, such as disease susceptibility, behavior and morphology, generating unique contributions to human health and biology. When designing genetic studies using purebred dogs, it is essential to consider the unique demography of each population, including estimation of effective population size and timing of population bottlenecks. The analytical design approach for genome-wide association studies (GWAS) and analysis of whole-genome sequence (WGS) experiments are inextricable from demographic data. We have performed a comprehensive study of genomic homozygosity, using high-depth WGS data for 90 individuals, and Illumina HD SNP data from 800 individuals representing 80 breeds. These data were coupled with extensive pedigree data analyses for 11 breeds that, together, allowed us to compute breed structure, demography, and molecular measures of genome diversity. Our comparative analyses characterize the extent, formation and implication of breed-specific diversity as it relates to population structure. These data demonstrate the relationship between breed-specific genome dynamics and population architecture, and provide important considerations influencing the technological and cohort design of association and other genomic studies. PMID:27874836

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas.

PubMed

Sun, Xiangqing; Elston, Robert; Falk, Gary W; Grady, William M; Faulx, Ashley; Mittal, Sumeet K; Canto, Marcia I; Shaheen, Nicholas J; Wang, Jean S; Iyer, Prasad G; Abrams, Julian A; Willis, Joseph E; Guda, Kishore; Markowitz, Sanford; Barnholtz-Sloan, Jill S; Chandar, Apoorva; Brock, Wendy; Chak, Amitabh

2016-07-01

Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model-based and model-free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model-based linkage analysis. Model-based and model-free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome-wide associations were also tested in these families. Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female-affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.

Population structure and inbreeding from pedigree analysis of purebred dogs.

PubMed

Calboli, Federico C F; Sampson, Jeff; Fretwell, Neale; Balding, David J

2008-05-01

Dogs are of increasing interest as models for human diseases, and many canine population-association studies are beginning to emerge. The choice of breeds for such studies should be informed by a knowledge of factors such as inbreeding, genetic diversity, and population structure, which are likely to depend on breed-specific selective breeding patterns. To address the lack of such studies we have exploited one of the world's most extensive resources for canine population-genetics studies: the United Kingdom (UK) Kennel Club registration database. We chose 10 representative breeds and analyzed their pedigrees since electronic records were established around 1970, corresponding to about eight generations before present. We find extremely inbred dogs in each breed except the greyhound and estimate an inbreeding effective population size between 40 and 80 for all but 2 breeds. For all but 3 breeds, >90% of unique genetic variants are lost over six generations, indicating a dramatic effect of breeding patterns on genetic diversity. We introduce a novel index Psi for measuring population structure directly from the pedigree and use it to identify subpopulations in several breeds. As well as informing the design of canine population genetics studies, our results have implications for breeding practices to enhance canine welfare.

Compelling Evidence for a Prostate Cancer Gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics

PubMed Central

Camp, Nicola J.; Cannon-Albright, Lisa A.; Farnham, James M.; Baffoe-Bonnie, Agnes B.; George, Asha; Powell, Isaac; Bailey-Wilson, Joan E.; Carpten, John D.; Giles, Graham G.; Hopper, John L.; Severi, Gianluca; English, Dallas R.; Foulkes, William D.; Maehle, Lovise; Moller, Pal; Eeles, Ros; Easton, Douglas; Badzioch, Michael D.; Whittemore, Alice S.; Oakley-Girvan, Ingrid; Hsieh, Chih-Lin; Dimitrov, Latchezar; Xu, Jianfeng; Stanford, Janet L.; Johanneson, Bo; Deutsch, Kerry; McIntosh, Laura; Ostrander, Elaine A.; Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Hebbring, Scott; Schaid, Daniel J.; Lange, Ethan M.; Cooney, Kathleen A.; Tammela, Teuvo L.J.; Schleutker, Johanna; Paiss, Thomas; Maier, Christiane; Grönberg, Henrik; Wiklund, Fredrik; Emanuelsson, Monica; Isaacs, William B.

2009-01-01

Previously, an analysis of 14 extended, high-risk Utah pedigrees localized the chromosome 22q linkage region to 3.2 Mb at 22q12.3-13.1 (flanked on each side by three recombinants), which contained 31 annotated genes. In this large, multi-centered, collaborative study, we performed statistical recombinant mapping in fifty-four pedigrees selected to be informative for recombinant mapping from nine member groups of the International Consortium for Prostate Cancer Genetics (ICPCG). These 54 pedigrees included the 14 extended pedigrees from Utah and 40 pedigrees from eight other ICPCG member groups. The additional 40 pedigrees were selected from a total pool of 1,213 such that each pedigree was required to both contain at least four prostate cancer (PRCA) cases and exhibit evidence for linkage to the chromosome 22q region. The recombinant events in these 40 independent pedigrees confirmed the previously proposed region. Further, when all 54 pedigrees were considered, the three-recombinant consensus region was narrowed by more than a megabase to 2.2 Mb at chromosome 22q12.3 flanked by D22S281 and D22S683. This narrower region eliminated 20 annotated genes from that previously proposed, leaving only eleven genes. This region at 22q12.3 is the most consistently identified and smallest linkage region for PRCA. This collaborative study by the ICPCG illustrates the value of consortium efforts and the continued utility of linkage analysis using informative pedigrees to localize genes for complex diseases. PMID:17478474

PedHunter 2.0 and its usage to characterize the founder structure of the Old Order Amish of Lancaster County

PubMed Central

2010-01-01

Background Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically. Methods We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees. Results With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants. Discussion/Conclusions The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies. PMID:20433770

Population structure and genetic differentiation of livestock guard dog breeds from the Western Balkans.

PubMed

Ceh, E; Dovc, P

2014-08-01

Livestock guard dog (LGD) breeds from the Western Balkans are a good example of how complex genetic diversity pattern observed in dog breeds has been shaped by transition in dog breeding practices. Despite their common geographical origin and relatively recent formal recognition as separate breeds, the Karst Shepherd, Sarplaninac and Tornjak show distinct population dynamics, assessed by pedigree, microsatellite and mtDNA data. We genotyped 493 dogs belonging to five dog breeds using a set of 18 microsatellite markers and sequenced mtDNA from 94 dogs from these breeds. Different demographic histories of the Karst Shepherd and Tornjak breeds are reflected in the pedigree data with the former breed having more unbalanced contributions of major ancestors and a realized effective population size of less than 20 animals. The highest allelic richness was found in Sarplaninac (5.94), followed by Tornjak (5.72), whereas Karst Shepherd dogs exhibited the lowest allelic richness (3.33). Similarly, the highest mtDNA haplotype diversity was found in Sarplaninac, followed by Tornjak and Karst Shepherd, where only one haplotype was found. Based on FST differentiation values and high percentages of animals correctly assigned, all breeds can be considered genetically distinct. However, using microsatellite data, common ancestry between the Karst Shepherd and Sarplaninac could not be reconstructed, despite pedigree and mtDNA evidence of their historical admixture. Using neighbour-joining, STRUCTURE or DAPC methods, Sarplaninac and Caucasian Shepherd breeds could not be separated and additionally showed close proximity in the NeighborNet tree. STRUCTURE analysis of the Tornjak breed demonstrated substructuring, which needs further investigation. Altogether, results of this study show that the official separation of these dog breeds strongly affected the resolution of genetic differentiation and thus suggest that the relationships between breeds are not only determined by breed relatedness, but in small populations even more importantly by stochastic effects. © 2014 Blackwell Verlag GmbH.

PyPedal, an open source software package for pedigree analysis

USDA-ARS?s Scientific Manuscript database

The open source software package PyPedal (http://pypedal.sourceforge.net/) was first released in 2002, and provided users with a set of simple tools for manipulating pedigrees. Its flexibility has been demonstrated by its used in a number of settings for large and small populations. After substantia...

Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma.

PubMed

Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

2014-10-21

Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12,000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase 2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), inflammation (free fatty acid receptor 2 (FFAR2)) and inflammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor 1 (OLR1), toll-like receptor 3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with specific co-occurring conditions.

Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma

PubMed Central

Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

2014-01-01

Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12 000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase 2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), inflammation (free fatty acid receptor 2 (FFAR2)) and inflammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor 1 (OLR1), toll-like receptor 3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with specific co-occurring conditions. PMID:25335167

High mitochondrial mutation rates estimated from deep-rooting Costa Rican pedigrees

PubMed Central

Madrigal, Lorena; Melendez-Obando, Mauricio; Villegas-Palma, Ramon; Barrantes, Ramiro; Raventos, Henrieta; Pereira, Reynaldo; Luiselli, Donata; Pettener, Davide; Barbujani, Guido

2012-01-01

Estimates of mutation rates for the noncoding hypervariable Region I (HVR-I) of mitochondrial DNA (mtDNA) vary widely, depending on whether they are inferred from phylogenies (assuming that molecular evolution is clock-like) or directly from pedigrees. All pedigree-based studies so far were conducted on populations of European origin. In this paper we analyzed 19 deep-rooting pedigrees in a population of mixed origin in Costa Rica. We calculated two estimates of the HVR-I mutation rate, one considering all apparent mutations, and one disregarding changes at sites known to be mutational hot spots and eliminating genealogy branches which might be suspected to include errors, or unrecognized adoptions along the female lines. At the end of this procedure, we still observed a mutation rate equal to 1.24 × 10−6, per site per year, i.e., at least three-fold as high as estimates derived from phylogenies. Our results confirm that mutation rates observed in pedigrees are much higher than estimated assuming a neutral model of long-term HVRI evolution. We argue that, until the cause of these discrepancies will be fully understood, both lower estimates (i.e., those derived from phylogenetic comparisons) and higher, direct estimates such as those obtained in this study, should be considered when modeling evolutionary and demographic processes. PMID:22460349

Pedigrees or markers: Which are better in estimating relatedness and inbreeding coefficient?

PubMed

Wang, Jinliang

2016-02-01

Individual inbreeding coefficient (F) and pairwise relatedness (r) are fundamental parameters in population genetics and have important applications in diverse fields such as human medicine, forensics, plant and animal breeding, conservation and evolutionary biology. Traditionally, both parameters are calculated from pedigrees, but are now increasingly estimated from genetic marker data. Conceptually, a pedigree gives the expected F and r values, FP and rP, with the expectations being taken (hypothetically) over an infinite number of individuals with the same pedigree. In contrast, markers give the realised (actual) F and r values at the particular marker loci of the particular individuals, FM and rM. Both pedigree (FP, rP) and marker (FM, rM) estimates can be used as inferences of genomic inbreeding coefficients FG and genomic relatedness rG, which are the underlying quantities relevant to most applications (such as estimating inbreeding depression and heritability) of F and r. In the pre-genomic era, it was widely accepted that pedigrees are much better than markers in delineating FG and rG, and markers should better be used to validate, amend and construct pedigrees rather than to replace them. Is this still true in the genomic era when genome-wide dense SNPs are available? In this simulation study, I showed that genomic markers can yield much better estimates of FG and rG than pedigrees when they are numerous (say, 10(4) SNPs) under realistic situations (e.g. genome and population sizes). Pedigree estimates are especially poor for species with a small genome, where FG and rG are determined to a large extent by Mendelian segregations and may thus deviate substantially from their expectations (FP and rP). Simulations also confirmed that FM, when estimated from many SNPs, can be much more powerful than FP for detecting inbreeding depression in viability. However, I argue that pedigrees cannot be replaced completely by genomic SNPs, because the former allows for the calculation of more complicated IBD coefficients (involving more than 2 individuals, more than one locus, and more than 2 genes at a locus) for which the latter may have reduced capacity or limited power, and because the former has social and other significance for remote relationships which have little genetic significance and cannot be inferred reliably from markers. Copyright © 2015 Elsevier Inc. All rights reserved.

Predictive Model and Software for Inbreeding-Purging Analysis of Pedigreed Populations

PubMed Central

García-Dorado, Aurora; Wang, Jinliang; López-Cortegano, Eugenio

2016-01-01

The inbreeding depression of fitness traits can be a major threat to the survival of populations experiencing inbreeding. However, its accurate prediction requires taking into account the genetic purging induced by inbreeding, which can be achieved using a “purged inbreeding coefficient”. We have developed a method to compute purged inbreeding at the individual level in pedigreed populations with overlapping generations. Furthermore, we derive the inbreeding depression slope for individual logarithmic fitness, which is larger than that for the logarithm of the population fitness average. In addition, we provide a new software, PURGd, based on these theoretical results that allows analyzing pedigree data to detect purging, and to estimate the purging coefficient, which is the parameter necessary to predict the joint consequences of inbreeding and purging. The software also calculates the purged inbreeding coefficient for each individual, as well as standard and ancestral inbreeding. Analysis of simulation data show that this software produces reasonably accurate estimates for the inbreeding depression rate and for the purging coefficient that are useful for predictive purposes. PMID:27605515

A Genome Scan Conducted in a Multigenerational Pedigree with Convergent Strabismus Supports a Complex Genetic Determinism

PubMed Central

Georges, Anouk; Cambisano, Nadine; Ahariz, Naïma; Karim, Latifa; Georges, Michel

2013-01-01

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree. PMID:24376720

A genome scan conducted in a multigenerational pedigree with convergent strabismus supports a complex genetic determinism.

PubMed

Georges, Anouk; Cambisano, Nadine; Ahariz, Naïma; Karim, Latifa; Georges, Michel

2013-01-01

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree.

Single-Step BLUP with Varying Genotyping Effort in Open-Pollinated Picea glauca.

PubMed

Ratcliffe, Blaise; El-Dien, Omnia Gamal; Cappa, Eduardo P; Porth, Ilga; Klápště, Jaroslav; Chen, Charles; El-Kassaby, Yousry A

2017-03-10

Maximization of genetic gain in forest tree breeding programs is contingent on the accuracy of the predicted breeding values and precision of the estimated genetic parameters. We investigated the effect of the combined use of contemporary pedigree information and genomic relatedness estimates on the accuracy of predicted breeding values and precision of estimated genetic parameters, as well as rankings of selection candidates, using single-step genomic evaluation (HBLUP). In this study, two traits with diverse heritabilities [tree height (HT) and wood density (WD)] were assessed at various levels of family genotyping efforts (0, 25, 50, 75, and 100%) from a population of white spruce ( Picea glauca ) consisting of 1694 trees from 214 open-pollinated families, representing 43 provenances in Québec, Canada. The results revealed that HBLUP bivariate analysis is effective in reducing the known bias in heritability estimates of open-pollinated populations, as it exposes hidden relatedness, potential pedigree errors, and inbreeding. The addition of genomic information in the analysis considerably improved the accuracy in breeding value estimates by accounting for both Mendelian sampling and historical coancestry that were not captured by the contemporary pedigree alone. Increasing family genotyping efforts were associated with continuous improvement in model fit, precision of genetic parameters, and breeding value accuracy. Yet, improvements were observed even at minimal genotyping effort, indicating that even modest genotyping effort is effective in improving genetic evaluation. The combined utilization of both pedigree and genomic information may be a cost-effective approach to increase the accuracy of breeding values in forest tree breeding programs where shallow pedigrees and large testing populations are the norm. Copyright © 2017 Ratcliffe et al.

Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

PubMed

Kauwe, John S K; Ridge, Perry G; Foster, Norman L; Cannon-Albright, Lisa A

2013-01-01

Alzheimer's disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date. We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths. The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths. These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

Population Genetic Structure of the Cayo Santiago Colony of Rhesus Macaques (Macaca mulatta).

PubMed

Kanthaswamy, Sreetharan; Oldt, Robert F; Ng, Jillian; Ruiz-Lambides, Angelina V; Maldonado, Elizabeth; Martínez, Melween I; Sariol, Carlos A

2017-07-01

The rhesus macaque population at Cayo Santiago increases annually and is in urgent need of control. In-depth assessments of the colony's population genetic and pedigree structures provide a starting point for improving the colony's long-term management program. We evaluated the degree of genetic variation and coefficients of inbreeding and kinship of the Cayo Santiago colony by using pedigree and short tandem repeat (STR) data from 4738 rhesus macaques, which represent 7 extant social groups and a group of migrant males. Information on each animal's parentage, sex, birth date, and date of death or removal from the island were used to generate estimates of mean kinship, kinship value, gene value, genome uniqueness (GU), founder equivalents (fe), and founder genome equivalents (fg). Pedigree and STR analyses revealed that the social groups have not differentiated genetically from each other due to male-mediated gene flow (that is, FST estimates were in the negative range) and exhibit sufficient genetic variation, with mean estimates of allele numbers and observed and expected heterozygosity of 6.57, 0.72, and 0.70, respectively. Estimates of GU, fe, and fg show that a high effective number of founders has affected the colony's current genetic structure in a positive manner. As demographic changes occur, genetic and pedigree matrices need to be monitored consistently to ensure the health and wellbeing of the Cayo Santiago colony.

Principles in genetic risk assessment.

PubMed

Baptista, Pedro Viana

2005-03-01

Risk assessment constitutes an essential component of genetic counseling and testing, and the genetic risk should be estimated as accurately as possible for individual and family decision making. All relevant information retrieved from population studies and pedigree and genetic testing enhances the accuracy of the assessment of an individual's genetic risk. This review will focus on the following general aspects implicated in risk assessment: the increasing genetic information regarding disease; complex traits versus Mendelian disorders; and the influence of the environment and disease susceptibility. The influence of these factors on risk assessment will be discussed.

Principles in genetic risk assessment

PubMed Central

Baptista, Pedro Viana

2005-01-01

Risk assessment constitutes an essential component of genetic counseling and testing, and the genetic risk should be estimated as accurately as possible for individual and family decision making. All relevant information retrieved from population studies and pedigree and genetic testing enhances the accuracy of the assessment of an individual's genetic risk. This review will focus on the following general aspects implicated in risk assessment: the increasing genetic information regarding disease; complex traits versus Mendelian disorders; and the influence of the environment and disease susceptibility. The influence of these factors on risk assessment will be discussed. PMID:18360538

Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

PubMed Central

Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

2014-01-01

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder. PMID:24522887

Low incidence of inbreeding in a long-lived primate population isolated for 75 years.

PubMed

Widdig, Anja; Muniz, Laura; Minkner, Mirjam; Barth, Yvonne; Bley, Stefanie; Ruiz-Lambides, Angelina; Junge, Olaf; Mundry, Roger; Kulik, Lars

2017-01-01

When close relatives mate, offspring are expected to suffer fitness consequences due to inbreeding depression. Inbreeding has previously been quantified in two ways: using a sufficiently large panel of markers or deep and complete pedigrees over several generations. However, the application of both approaches is still limited by the challenge of compiling such data for species with long generation times, such as primates. Here, we assess inbreeding in rhesus macaques living on Cayo Santiago (Puerto Rico), a population genetically isolated since 1938, but descendant of a large set of presumably unrelated founders. Using comprehensive genetic data, we calculated inbreeding coefficients ( F ) for 2669 individuals with complete three generation pedigrees and 609 individuals with complete four generation pedigrees. We found that 0.79 and 7.39% of individuals had an F  > 0 when using data from three and four generation pedigrees, respectively. No evidence of an increase in inbreeding over the study period (up to 23 years) was found. Furthermore, the observed mean relatedness of breeding pairs differed significantly from the distribution of parental relatedness expected as simulated based on previous reproductive data, suggesting that kin generally avoid breeding with each other. Finally, inbreeding was not a predictor of early mortality measured as survival until weaning and sexual maturation, respectively. Our results remain consistent with three estimators of inbreeding (standardized heterozygosity, internal relatedness, and homozygosity by loci) using up to 42 highly polymorphic microsatellites for the same set of individuals. Together, our results demonstrate that close inbreeding may not be prevalent even in populations isolated over long periods when mechanisms of inbreeding avoidance can operate. When close relatives mate, offspring may suffer from such inbreeding, e.g., via lower survival and/or fertility. Using (i) a large panel of genetic markers and (ii) complete three or four generation pedigrees, respectively, we show that incidences of inbreeding in a long-lived primate population are rare, even after genetic isolation for 75 years. Moreover, our simulations suggest that kin in our population generally avoid breeding with each other. Finally, the few inbred individuals detected in our large sample did not suffer from lower survival. Given that many animal species face dramatic habitat loss combined with critical population declines, our study provides important implications for conservation biology in general and for population management in particular.

Genetic diversity analysis of two commercial breeds of pigs using genomic and pedigree data.

PubMed

Zanella, Ricardo; Peixoto, Jane O; Cardoso, Fernando F; Cardoso, Leandro L; Biegelmeyer, Patrícia; Cantão, Maurício E; Otaviano, Antonio; Freitas, Marcelo S; Caetano, Alexandre R; Ledur, Mônica C

2016-03-30

Genetic improvement in livestock populations can be achieved without significantly affecting genetic diversity if mating systems and selection decisions take genetic relationships among individuals into consideration. The objective of this study was to examine the genetic diversity of two commercial breeds of pigs. Genotypes from 1168 Landrace (LA) and 1094 Large White (LW) animals from a commercial breeding program in Brazil were obtained using the Illumina PorcineSNP60 Beadchip. Inbreeding estimates based on pedigree (F x) and genomic information using runs of homozygosity (F ROH) and the single nucleotide polymorphisms (SNP) by SNP inbreeding coefficient (F SNP) were obtained. Linkage disequilibrium (LD), correlation of linkage phase (r) and effective population size (N e ) were also estimated. Estimates of inbreeding obtained with pedigree information were lower than those obtained with genomic data in both breeds. We observed that the extent of LD was slightly larger at shorter distances between SNPs in the LW population than in the LA population, which indicates that the LW population was derived from a smaller N e . Estimates of N e based on genomic data were equal to 53 and 40 for the current populations of LA and LW, respectively. The correlation of linkage phase between the two breeds was equal to 0.77 at distances up to 50 kb, which suggests that genome-wide association and selection should be performed within breed. Although selection intensities have been stronger in the LA breed than in the LW breed, levels of genomic and pedigree inbreeding were lower for the LA than for the LW breed. The use of genomic data to evaluate population diversity in livestock animals can provide new and more precise insights about the effects of intense selection for production traits. Resulting information and knowledge can be used to effectively increase response to selection by appropriately managing the rate of inbreeding, minimizing negative effects of inbreeding depression and therefore maintaining desirable levels of genetic diversity.

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees

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

Freimer, N.B.; Reus, V.I.; Vinogradov, S.

1996-05-31

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging formmore » recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals. 26 refs., 2 figs., 5 tabs.« less

Inbreeding depression in a critically endangered carnivore.

PubMed

Norén, Karin; Godoy, Erika; Dalén, Love; Meijer, Tomas; Angerbjörn, Anders

2016-07-01

Harmful effects arising from matings between relatives (inbreeding) is a long-standing observation that is well founded in theory. Empirical evidence for inbreeding depression in natural populations is however rare because of the challenges of assembling pedigrees supplemented with fitness traits. We examined the occurrence of inbreeding and subsequent inbreeding depression using a unique data set containing a genetically verified pedigree with individual fitness traits for a critically endangered arctic fox (Vulpes lagopus) population. The study covered nine years and was comprised of 33 litters with a total of 205 individuals. We recorded that the present population was founded by only five individuals. Over the study period, the population exhibited a tenfold increase in average inbreeding coefficient with a final level corresponding to half-sib matings. Inbreeding mainly occurred between cousins, but we also observed two cases of full-sib matings. The pedigree data demonstrated clear evidence of inbreeding depression on traditional fitness traits where inbred individuals displayed reduced survival and reproduction. Fitness traits were however differently affected by the fluctuating resource abundande. Inbred individuals born at low-quality years displayed reduced first-year survival, while inbred individuals born at high-quality years were less likely to reproduce. The documentation of inbreeding depression in fundamental fitness traits suggests that inbreeding depression can limit population recovery. Introducing new genetic material to promote a genetic rescue effect may thus be necessary for population long-term persistence. © 2016 John Wiley & Sons Ltd.

Protecting the privacy of family members in survey and pedigree research.

PubMed

Botkin, J

2001-01-10

The recent controversy at Virginia Commonwealth University involving research ethics raises important and complex issues in survey and pedigree research. The primary questions are whether family members of survey respondents themselves become subjects of the project and if they are subjects whether informed consent must be obtained for investigators to retain private information on these individuals. This article provides an analysis of the ethical issues and regulatory standards involved in this debate for consideration by investigators and institutional review boards. The analysis suggests that strong protections for the rights and welfare of subjects and their family members can be incorporated into survey and pedigree research protocols without hindering projects with extensive consent requirements.

Runs of homozygosity and population history in cattle

PubMed Central

2012-01-01

Background Runs of homozygosity (ROH) are contiguous lengths of homozygous genotypes that are present in an individual due to parents transmitting identical haplotypes to their offspring. The extent and frequency of ROHs may inform on the ancestry of an individual and its population. Here we use high density (n = 777,962) bi-allelic SNPs in a range of cattle breed samples to correlate ROH with the pedigree-based inbreeding coefficients and to validate subsequent analyses using 54,001 SNP genotypes. This study provides a first testing of the inference drawn from ROH through comparison with estimates of inbreeding from calculations based on the detailed pedigree data available for several breeds. Results All animals genotyped on the HD panel displayed at least one ROH that was between 1–5 Mb in length with certain regions of the genome more likely to be involved in a ROH than others. Strong correlations (r = 0.75, p < 0.0001) existed between the pedigree-based inbreeding coefficient and a statistic based on sum of ROH of length > 0.5 KB and suggests that in the absence of an animal’s pedigree data, the extent of a genome under ROH may be used to infer aspects of recent population history even from relatively few samples. Conclusions Our findings suggest that ROH are frequent across all breeds but differing patterns of ROH length and burden illustrate variations in breed origins and recent management. PMID:22888858

A comparison of different algorithms for phasing haplotypes using Holstein cattle genotypes and pedigree data.

PubMed

Miar, Younes; Sargolzaei, Mehdi; Schenkel, Flavio S

2017-04-01

Phasing genotypes to haplotypes is becoming increasingly important due to its applications in the study of diseases, population and evolutionary genetics, imputation, and so on. Several studies have focused on the development of computational methods that infer haplotype phase from population genotype data. The aim of this study was to compare phasing algorithms implemented in Beagle, Findhap, FImpute, Impute2, and ShapeIt2 software using 50k and 777k (HD) genotyping data. Six scenarios were considered: no-parents, sire-progeny pairs, sire-dam-progeny trios, each with and without pedigree information in Holstein cattle. Algorithms were compared with respect to their phasing accuracy and computational efficiency. In the studied population, Beagle and FImpute were more accurate than other phasing algorithms. Across scenarios, phasing accuracies for Beagle and FImpute were 99.49-99.90% and 99.44-99.99% for 50k, respectively, and 99.90-99.99% and 99.87-99.99% for HD, respectively. Generally, FImpute resulted in higher accuracy when genotypic information of at least one parent was available. In the absence of parental genotypes and pedigree information, Beagle and Impute2 (with double the default number of states) were slightly more accurate than FImpute. Findhap gave high phasing accuracy when parents' genotypes and pedigree information were available. In terms of computing time, Findhap was the fastest algorithm followed by FImpute. FImpute was 30 to 131, 87 to 786, and 353 to 1,400 times faster across scenarios than Beagle, ShapeIt2, and Impute2, respectively. In summary, FImpute and Beagle were the most accurate phasing algorithms. Moreover, the low computational requirement of FImpute makes it an attractive algorithm for phasing genotypes of large livestock populations. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island

PubMed Central

Macgregor, Stuart; Bellis, Claire; Lea, Rod A; Cox, Hannah; Dyer, Tom; Blangero, John; Visscher, Peter M; Griffiths, Lyn R

2010-01-01

The population of Norfolk Island, located off the eastern coast of Australia, possesses an unusual and fascinating history. Most present-day islanders are related to a small number of the ‘Bounty' mutineer founders. These founders consisted of Caucasian males and Polynesian females and led to an admixed present-day population. By examining a single large pedigree of 5742 individuals, spanning >200 years, we analyzed the influence of admixture and founder effect on various cardiovascular disease (CVD)-related traits. On account of the relative isolation of the population, on average one-third of the genomes of present-day islanders (single large pedigree individuals) is derived from 17 initial founders. The proportion of Polynesian ancestry in the present-day individuals was found to significantly influence total triglycerides, body mass index, systolic blood pressure and diastolic blood pressure. For various cholesterol traits, the influence of ancestry was less marked but overall the direction of effect for all CVD-related traits was consistent with Polynesian ancestry conferring greater CVD risk. Marker-derived homozygosity was computed and agreed with measures of inbreeding derived from pedigree information. Founder effect (inbreeding and marker-derived homozygosity) significantly influenced height. In conclusion, both founder effect and extreme admixture have substantially influenced the genetic architecture of a variety of CVD-related traits in this population. PMID:19584896

Genetic parameters for milk fatty acids, milk yield and quality traits of a Holstein cattle population reared under tropical conditions.

PubMed

Petrini, J; Iung, L H S; Rodriguez, M A P; Salvian, M; Pértille, F; Rovadoscki, G A; Cassoli, L D; Coutinho, L L; Machado, P F; Wiggans, G R; Mourão, G B

2016-10-01

Information about genetic parameters is essential for selection decisions and genetic evaluation. These estimates are population specific; however, there are few studies with dairy cattle populations reared under tropical and sub-tropical conditions. Thus, the aim was to obtain estimates of heritability and genetic correlations for milk yield and quality traits using pedigree and genomic information from a Holstein population maintained in a tropical environment. Phenotypic records (n = 36 457) of 4203 cows as well as the genotypes for 57 368 single nucleotide polymorphisms from 755 of these cows were used. Covariance components were estimated using the restricted maximum likelihood method under a mixed animal model, considering a pedigree-based relationship matrix or a combined pedigree-genomic matrix. High heritabilities (around 0.30) were estimated for lactose and protein content in milk whereas moderate values (between 0.19 and 0.26) were obtained for percentages of fat, saturated fatty acids and palmitic acid in milk. Genetic correlations ranging from -0.38 to -0.13 were determined between milk yield and composition traits. The smaller estimates compared to other similar studies can be due to poor environmental conditions, which may reduce genetic variability. These results highlight the importance in using genetic parameters estimated in the population under evaluation for selection decisions. © 2016 Blackwell Verlag GmbH.

A family-based probabilistic method for capturing de novo mutations from high-throughput short-read sequencing data.

PubMed

Cartwright, Reed A; Hussin, Julie; Keebler, Jonathan E M; Stone, Eric A; Awadalla, Philip

2012-01-06

Recent advances in high-throughput DNA sequencing technologies and associated statistical analyses have enabled in-depth analysis of whole-genome sequences. As this technology is applied to a growing number of individual human genomes, entire families are now being sequenced. Information contained within the pedigree of a sequenced family can be leveraged when inferring the donors' genotypes. The presence of a de novo mutation within the pedigree is indicated by a violation of Mendelian inheritance laws. Here, we present a method for probabilistically inferring genotypes across a pedigree using high-throughput sequencing data and producing the posterior probability of de novo mutation at each genomic site examined. This framework can be used to disentangle the effects of germline and somatic mutational processes and to simultaneously estimate the effect of sequencing error and the initial genetic variation in the population from which the founders of the pedigree arise. This approach is examined in detail through simulations and areas for method improvement are noted. By applying this method to data from members of a well-defined nuclear family with accurate pedigree information, the stage is set to make the most direct estimates of the human mutation rate to date.

Genomic Variation of Inbreeding and Ancestry in the Remaining Two Isle Royale Wolves.

PubMed

Hedrick, Philip W; Kardos, Marty; Peterson, Rolf O; Vucetich, John A

2017-03-01

Inbreeding, relatedness, and ancestry have traditionally been estimated with pedigree information, however, molecular genomic data can provide more detailed examination of these properties. For example, pedigree information provides estimation of the expected value of these measures but molecular genomic data can estimate the realized values of these measures in individuals. Here, we generate the theoretical distribution of inbreeding, relatedness, and ancestry for the individuals in the pedigree of the Isle Royale wolves, the first examination of such variation in a wild population with a known pedigree. We use the 38 autosomes of the dog genome and their estimated map lengths in our genomic analysis. Although it is known that the remaining wolves are highly inbred, closely related, and descend from only 3 ancestors, our analyses suggest that there is significant variation in the realized inbreeding and relatedness around pedigree expectations. For example, the expected inbreeding in a hypothetical offspring from the 2 remaining wolves is 0.438 but the realized 95% genomic confidence interval is from 0.311 to 0.565. For individual chromosomes, a substantial proportion of the whole chromosomes are completely identical by descent. This examination provides a background to use when analyzing molecular genomic data for individual levels of inbreeding, relatedness, and ancestry. The level of variation in these measures is a function of the time to the common ancestor(s), the number of chromosomes, and the rate of recombination. In the Isle Royale wolf population, the few generations to a common ancestor results in the high variance in genomic inbreeding. © The American Genetic Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Optimal marker-assisted selection to increase the effective size of small populations.

PubMed

Wang, J

2001-02-01

An approach to the optimal utilization of marker and pedigree information in minimizing the rates of inbreeding and genetic drift at the average locus of the genome (not just the marked loci) in a small diploid population is proposed, and its efficiency is investigated by stochastic simulations. The approach is based on estimating the expected pedigree of each chromosome by using marker and individual pedigree information and minimizing the average coancestry of selected chromosomes by quadratic integer programming. It is shown that the approach is much more effective and much less computer demanding in implementation than previous ones. For pigs with 10 offspring per mother genotyped for two markers (each with four alleles at equal initial frequency) per chromosome of 100 cM, the approach can increase the average effective size for the whole genome by approximately 40 and 55% if mating ratios (the number of females mated with a male) are 3 and 12, respectively, compared with the corresponding values obtained by optimizing between-family selection using pedigree information only. The efficiency of the marker-assisted selection method increases with increasing amount of marker information (number of markers per chromosome, heterozygosity per marker) and family size, but decreases with increasing genome size. For less prolific species, the approach is still effective if the mating ratio is large so that a high marker-assisted selection pressure on the rarer sex can be maintained.

Estimating inbreeding rates in natural populations: addressing the problem of incomplete pedigrees

Treesearch

Mark P. Miller; Susan M. Haig; Jonathan D. Ballou; Ashley Steel

2017-01-01

Understanding and estimating inbreeding is essential for managing threatened and endangered wildlife populations. However, determination of inbreeding rates in natural populations is confounded by incomplete parentage information. We present an approach for quantifying inbreeding rates for populations with incomplete parentage information. The approach exploits...

Using Object Oriented Bayesian Networks to Model Linkage, Linkage Disequilibrium and Mutations between STR Markers

PubMed Central

Kling, Daniel; Egeland, Thore; Mostad, Petter

2012-01-01

In a number of applications there is a need to determine the most likely pedigree for a group of persons based on genetic markers. Adequate models are needed to reach this goal. The markers used to perform the statistical calculations can be linked and there may also be linkage disequilibrium (LD) in the population. The purpose of this paper is to present a graphical Bayesian Network framework to deal with such data. Potential LD is normally ignored and it is important to verify that the resulting calculations are not biased. Even if linkage does not influence results for regular paternity cases, it may have substantial impact on likelihood ratios involving other, more extended pedigrees. Models for LD influence likelihoods for all pedigrees to some degree and an initial estimate of the impact of ignoring LD and/or linkage is desirable, going beyond mere rules of thumb based on marker distance. Furthermore, we show how one can readily include a mutation model in the Bayesian Network; extending other programs or formulas to include such models may require considerable amounts of work and will in many case not be practical. As an example, we consider the two STR markers vWa and D12S391. We estimate probabilities for population haplotypes to account for LD using a method based on data from trios, while an estimate for the degree of linkage is taken from the literature. The results show that accounting for haplotype frequencies is unnecessary in most cases for this specific pair of markers. When doing calculations on regular paternity cases, the markers can be considered statistically independent. In more complex cases of disputed relatedness, for instance cases involving siblings or so-called deficient cases, or when small differences in the LR matter, independence should not be assumed. (The networks are freely available at http://arken.umb.no/~dakl/BayesianNetworks.) PMID:22984448

Diversity Arrays Technology (DArT) Marker Platforms for Diversity Analysis and Linkage Mapping in a Complex Crop, the Octoploid Cultivated Strawberry (Fragaria × ananassa)

PubMed Central

Sánchez-Sevilla, José F.; Horvath, Aniko; Botella, Miguel A.; Gaston, Amèlia; Folta, Kevin; Kilian, Andrzej; Denoyes, Beatrice; Amaya, Iraida

2015-01-01

Cultivated strawberry (Fragaria × ananassa) is a genetically complex allo-octoploid crop with 28 pairs of chromosomes (2n = 8x = 56) for which a genome sequence is not yet available. The diploid Fragaria vesca is considered the donor species of one of the octoploid sub-genomes and its available genome sequence can be used as a reference for genomic studies. A wide number of strawberry cultivars are stored in ex situ germplasm collections world-wide but a number of previous studies have addressed the genetic diversity present within a limited number of these collections. Here, we report the development and application of two platforms based on the implementation of Diversity Array Technology (DArT) markers for high-throughput genotyping in strawberry. The first DArT microarray was used to evaluate the genetic diversity of 62 strawberry cultivars that represent a wide range of variation based on phenotype, geographical and temporal origin and pedigrees. A total of 603 DArT markers were used to evaluate the diversity and structure of the population and their cluster analyses revealed that these markers were highly efficient in classifying the accessions in groups based on historical, geographical and pedigree-based cues. The second DArTseq platform took benefit of the complexity reduction method optimized for strawberry and the development of next generation sequencing technologies. The strawberry DArTseq was used to generate a total of 9,386 SNP markers in the previously developed ‘232’ × ‘1392’ mapping population, of which, 4,242 high quality markers were further selected to saturate this map after several filtering steps. The high-throughput platforms here developed for genotyping strawberry will facilitate genome-wide characterizations of large accessions sets and complement other available options. PMID:26675207

Genetic basis of systemic lupus erythematosus: a review of the unique genetic contributions in African Americans.

PubMed

Harley, John B; Kelly, Jennifer A

2002-08-01

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving critical genetic and environmental risk factors. SLE is a relatively common disease among African American women, affecting as many as one in 250. A collection of more than 250 African American and European American pedigrees multiplex for SLE have been collected in Oklahoma over the past decade for the purpose of identifying the genetic risk factors involved in the pathogenesis of SLE. A genome scan has been performed, and interestingly, the linkage results usually dominate in families from one or the other of these ethnicities. For example, the linkage effect at 1q21-22 near FcgammaRIIA is much stronger in the African American pedigrees than in the European American pedigrees. On the other hand, a gene near the top of chromosome4 (at 4p l6-15) contributes to SLE in the European American pedigrees, but not in the African American pedigrees. The racially-specific results lead to the tentative conclusion of genetic differences associated with SLE in African Americans and European Americans. The identification of the genes responsible for the observed linkage effects will provide fundamental knowledge concerning SLE and may even provide new targets for therapy and strategies to defeat this enigmatic and difficult disease.

GenoMatrix: A Software Package for Pedigree-Based and Genomic Prediction Analyses on Complex Traits.

PubMed

Nazarian, Alireza; Gezan, Salvador Alejandro

2016-07-01

Genomic and pedigree-based best linear unbiased prediction methodologies (G-BLUP and P-BLUP) have proven themselves efficient for partitioning the phenotypic variance of complex traits into its components, estimating the individuals' genetic merits, and predicting unobserved (or yet-to-be observed) phenotypes in many species and fields of study. The GenoMatrix software, presented here, is a user-friendly package to facilitate the process of using genome-wide marker data and parentage information for G-BLUP and P-BLUP analyses on complex traits. It provides users with a collection of applications which help them on a set of tasks from performing quality control on data to constructing and manipulating the genomic and pedigree-based relationship matrices and obtaining their inverses. Such matrices will be then used in downstream analyses by other statistical packages. The package also enables users to obtain predicted values for unobserved individuals based on the genetic values of observed related individuals. GenoMatrix is available to the research community as a Windows 64bit executable and can be downloaded free of charge at: http://compbio.ufl.edu/software/genomatrix/. © The American Genetic Association. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pedigree analysis in the Austrian Noriker draught horse: genetic diversity and the impact of breeding for coat colour on population structure.

PubMed

Druml, T; Baumung, R; Sölkner, J

2009-10-01

The pedigree of the current Austrian Noriker draught horse population comprising 2808 horses was traced back to the animals considered as founders of this breed. In total, the number of founders was 1991, the maximum pedigree length was 31 generations, with an average of 12.3 complete generations. Population structure in this autochthonous Austrian draught horse breed is defined by seven breeding regions (Carinthia, Lower Austria, Salzburg, Styria, Tyrol, Upper Austria and Vorarlberg) or through six coat colour groups (Bay, Black, Chestnut, Roan, Leopard, Tobiano). Average inbreeding coefficients within the breeding regions ranged from 4.5% to 5.5%; for the colour groups, the coefficients varied from 3.5% to 5.9%. Other measures of genetic variability like the effective number of founders, ancestors and founder genomes revealed a slightly different genetic background of the subpopulations. Average co-ancestries between and within breeding areas showed that the Salzburg population may be considered as the nucleus or original stock whereas all other subpopulations showed high relationship to horses from Salzburg. The target of draught horse breeding in the 21st century does not meet the breeding concept of maximizing genetic gains any more. Stabilizing selection takes place. In this study, we show that demographic factors as well as structure given by different coat colours helped to maintain genetic diversity in this endangered horse breed.

Rates of inbreeding and genetic adaptation for populations managed as herds in zoos with a rotational mating system or with optimized contribution of parents.

PubMed

Mucha, S; Komen, H

2016-08-01

This study compares two genetic management scenarios for species kept in herds, such as deer. The simulations were designed so that their results can be extended to a wide range of zoo populations. In the first scenario, the simulated populations of size 3 × 20, 6 × 40 or 20 × 60 (herds × animals in herd) were managed with a rotational mating (RM) scheme in which 10%, 20% or 50% of males were selected for breeding and moved between herds in a circular fashion. The second scenario was based on optimal contribution theory (OC). OC requires an accurate pedigree to calculate kinship; males were selected and assigned numbers of offspring to minimize kinship in the next generation. RM was efficient in restriction of inbreeding and produced results comparable with OC. However, RM can result in genetic adaptation of the population to the zoo environment, in particular when 20% or less males are selected for rotation and selection of animals is not random. Lowest rates of inbreeding were obtained by combining OC with rotation of males as in the RM scheme. RM is easy to implement in practice and does not require pedigree data. When full pedigree is available, OC management is preferable. © 2015 Blackwell Verlag GmbH.

Exploration of genetic architecture through sib-ship reconstruction in advanced breeding population of Eucalyptus nitens.

PubMed

Klápště, Jaroslav; Suontama, Mari; Telfer, Emily; Graham, Natalie; Low, Charlie; Stovold, Toby; McKinley, Russel; Dungey, Heidi

2017-01-01

Accurate inference of relatedness between individuals in breeding population contributes to the precision of genetic parameter estimates, effectiveness of inbreeding management and the amount of genetic progress delivered from breeding programs. Pedigree reconstruction has been proven to be an efficient tool to correct pedigree errors and recover hidden relatedness in open pollinated progeny tests but the method can be limited by the lack of parental genotypes and the high proportion of alien pollen from outside the breeding population. Our study investigates the efficiency of sib-ship reconstruction in an advanced breeding population of Eucalyptus nitens with only partially tracked pedigree. The sib-ship reconstruction allowed the identification of selfs (4% of the sample) and the exploration of their potential effect on inbreeding depression in the traits studied. We detected signs of inbreeding depression in diameter at breast height and growth strain while no indications were observed in wood density, wood stiffness and tangential air-dry shrinkage. After the application of a corrected sib-ship relationship matrix, additive genetic variance and heritability were observed to increase where signs of inbreeding depression were initially detected. Conversely, the same genetic parameters for traits that appeared to be free of inbreeding depression decreased in size. It therefore appeared that greater genetic variance may be due, at least in part, to contributions from inbreeding in these studied populations rather than a removal of inbreeding as is traditionally thought.

Indirect genetic estimates of breeding population size in the polyploid green sturgeon (Acipenser medirostris).

PubMed

Israel, J A; May, B

2010-03-01

The utility of genetic measures for kinship reconstruction in polysomic species is not well evaluated. We developed a framework to test hypotheses about estimating breeding population size indirectly from collections of outmigrating green sturgeon juveniles. We evaluated a polysomic dataset, in allelic frequency and phenotypic formats, from green sturgeon to describe the relationship among known progeny from experimental families. The distributions of relatedness values for kin classes were used for reconstructing green sturgeon pedigrees from juveniles of unknown relationship. We compared three rarefaction functions that described the relationship between the number of kin groups and number of samples in a pedigree to estimate the annual abundance of spawners contributing to the threatened green sturgeon Southern Distinct Population Segment in the upper Sacramento River. Results suggested the estimated abundance of breeding green sturgeon remained roughly constant in the upper Sacramento River over a 5-year period, ranging from 10 to 28 individuals depending on the year and rarefaction method. These results demonstrate an empirical understanding for the distribution of relatedness values among individuals is a benefit for assessing pedigree reconstruction methods and identifying misclassification rates. Monitoring of rare species using these indirect methods is feasible and can provide insight into breeding and ontogenetic behaviour. While this framework was developed for specific application to studying fish populations in a riverscape, the framework could be advanced to improve genetic estimation of breeding population size and to identify important breeding habitats of rare species when combined with finer-scaled sampling of offspring.

Quantitative analysis of population-scale family trees with millions of relatives.

PubMed

Kaplanis, Joanna; Gordon, Assaf; Shor, Tal; Weissbrod, Omer; Geiger, Dan; Wahl, Mary; Gershovits, Michael; Markus, Barak; Sheikh, Mona; Gymrek, Melissa; Bhatia, Gaurav; MacArthur, Daniel G; Price, Alkes L; Erlich, Yaniv

2018-04-13

Family trees have vast applications in fields as diverse as genetics, anthropology, and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. We collected 86 million profiles from publicly available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of human longevity and to provide insights into the geographical dispersion of families. We also report a simple digital procedure to overlay other data sets with our resource. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Genetic versus census estimators of the opportunity for sexual selection in the wild.

PubMed

Dunn, Stacey J; Waits, Lisette P; Byers, John A

2012-04-01

Abstract The existence of a direct link between intensity of sexual selection and mating-system type is widely accepted. However, the quantification of sexual selection has proven problematic. Several measures of sexual selection have been proposed, including the operational sex ratio (OSR), the breeding sex ratio (BSR), and the opportunity for sexual selection (I(mates)). For a wild population of pronghorn (Antilocapra americana), we calculated OSR and BSR. We estimated I(mates) from census data on the spatial and temporal distribution of receptive females in rut and from a multigenerational genetic pedigree. OSR and BSR indicated weak sexual selection on males, but census and pedigree I(mates) suggested stronger sexual selection on males than on females. OSR and BSR correlated with census but not pedigree estimates of I(mates), and census I(mates) did not correlate with pedigree estimates. This suggests that the behavioral mating system, as deduced from the spatial and temporal distribution of females, does not predict the genetic mating system of pronghorn. The differences we observed between estimators were primarily due to female mate sampling and choice and to the sex ratio. For most species, behavioral data are not perfectly accurate and therefore will be an insufficient alternative to using multigenerational pedigrees to quantify sexual selection.

An ABC estimate of pedigree error rate: application in dog, sheep and cattle breeds.

PubMed

Leroy, G; Danchin-Burge, C; Palhiere, I; Baumung, R; Fritz, S; Mériaux, J C; Gautier, M

2012-06-01

On the basis of correlations between pairwise individual genealogical kinship coefficients and allele sharing distances computed from genotyping data, we propose an approximate Bayesian computation (ABC) approach to assess pedigree file reliability through gene-dropping simulations. We explore the features of the method using simulated data sets and show precision increases with the number of markers. An application is further made with five dog breeds, four sheep breeds and one cattle breed raised in France and displaying various characteristics and population sizes, using microsatellite or SNP markers. Depending on the breeds, pedigree error estimations range between 1% and 9% in dog breeds, 1% and 10% in sheep breeds and 4% in cattle breeds. © 2011 The Authors, Animal Genetics © 2011 Stichting International Foundation for Animal Genetics.

A Narrow and Highly Significant Linkage Signal for Severe Bipolar Disorder in the Chromosome 5q33 Region in Latin American Pedigrees

PubMed Central

Jasinska, A.J.; Service, S.; Jawaheer, D.; DeYoung, J.; Levinson, M.; Zhang, Z.; Kremeyer, B.; Muller, H.; Aldana, I.; Garcia, J.; Restrepo, G.; Lopez, C.; Palacio, C.; Duque, C.; Parra, M.; Vega, J.; Ortiz, D.; Bedoya, G.; Mathews, C.; Davanzo, P.; Fournier, E.; Bejarano, J.; Ramirez, M.; Ortiz, C. Araya; Araya, X.; Molina, J.; Sabatti, C.; Reus, V.; Ospina, J.; Macaya, G.; Ruiz-Linares, A.; Freimer, N.B.

2016-01-01

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees. PMID:19319892

Founder representation and effective population size in old versus young breeds-genetic diversity of Finnish and Nordic Spitz.

PubMed

Kumpulainen, M; Anderson, H; Svevar, T; Kangasvuo, I; Donner, J; Pohjoismäki, J

2017-10-01

Finnish Spitz is 130-year-old breed and has been highly popular in Finland throughout its history. Nordic Spitz is very similar to Finnish Spitz by origin and use, but is a relatively recent breed with much smaller population size. To see how breed age and breeding history have influenced the current population, we performed comprehensive population genetic analysis using pedigree data of 28,119 Finnish and 9,009 Nordic Spitzes combined with genomewide single nucleotide polymorphism (SNP) data from 135 Finnish and 110 Nordic Spitzes. We found that the Finnish Spitz has undergone repeated male bottlenecks resulting in dramatic loss of genetic diversity, reflected by 20 effective founders (f a ) and mean heterozygosity (Hz) of 0.313. The realized effective population size in the breed based on pedigree analysis (N¯ec) is 168, whereas the genetic effective population size (N eg ) computed the decay of linkage disequilibrium (r 2 ) is only 57 individuals. Nordic Spitz, although once been near extinction, has not been exposed to similar repeated bottlenecks than Finnish Spitz and had f a of 27 individuals. However, due to the smaller total population size, the breed has also smaller effective population size than Finnish Spitz (N¯ec = 98 and N eg  = 49). Interestingly, the r 2 data show that the effective population size has contracted dramatically since the establishment of the breed, emphasizing the role of breed standards as constrains for the breeding population. Despite the small population size, Nordic Spitz still maintains SNP heterozygosity levels similar to mixed breed dogs (mean Hz = 0.409). Our study demonstrates that although pedigree analyses cannot provide estimates of the present diversity within a breed, the effective population sizes inferred from them correlate with the genotyping results. The genetic relationships of the northern Spitz breeds and the benefits of the open breed registry are discussed. © 2017 Blackwell Verlag GmbH.

Severe inbreeding depression in a wild wolf (Canis lupus) population.

PubMed

Liberg, Olof; Andrén, Henrik; Pedersen, Hans-Christian; Sand, Håkan; Sejberg, Douglas; Wabakken, Petter; Kesson, Mikael; Bensch, Staffan

2005-03-22

The difficulty of obtaining pedigrees for wild populations has hampered the possibility of demonstrating inbreeding depression in nature. In a small, naturally restored, wild population of grey wolves in Scandinavia, founded in 1983, we constructed a pedigree for 24 of the 28 breeding pairs established in the period 1983-2002. Ancestry for the breeding animals was determined through a combination of field data (snow tracking and radio telemetry) and DNA microsatellite analysis. The population was founded by only three individuals. The inbreeding coefficient F varied between 0.00 and 0.41 for wolves born during the study period. The number of surviving pups per litter during their first winter after birth was strongly correlated with inbreeding coefficients of pups (R2=0.39, p<0.001). This inbreeding depression was recalculated to match standard estimates of lethal equivalents (2B), corresponding to 6.04 (2.58-9.48, 95% CI) litter-size-reducing equivalents in this wolf population.

Pedigree reconstruction from SNP data: parentage assignment, sibship clustering and beyond.

PubMed

Huisman, Jisca

2017-09-01

Data on hundreds or thousands of single nucleotide polymorphisms (SNPs) provide detailed information about the relationships between individuals, but currently few tools can turn this information into a multigenerational pedigree. I present the r package sequoia, which assigns parents, clusters half-siblings sharing an unsampled parent and assigns grandparents to half-sibships. Assignments are made after consideration of the likelihoods of all possible first-, second- and third-degree relationships between the focal individuals, as well as the traditional alternative of being unrelated. This careful exploration of the local likelihood surface is implemented in a fast, heuristic hill-climbing algorithm. Distinction between the various categories of second-degree relatives is possible when likelihoods are calculated conditional on at least one parent of each focal individual. Performance was tested on simulated data sets with realistic genotyping error rate and missingness, based on three different large pedigrees (N = 1000-2000). This included a complex pedigree with overlapping generations, occasional close inbreeding and some unknown birth years. Parentage assignment was highly accurate down to about 100 independent SNPs (error rate <0.1%) and fast (<1 min) as most pairs can be excluded from being parent-offspring based on opposite homozygosity. For full pedigree reconstruction, 40% of parents were assumed nongenotyped. Reconstruction resulted in low error rates (<0.3%), high assignment rates (>99%) in limited computation time (typically <1 h) when at least 200 independent SNPs were used. In three empirical data sets, relatedness estimated from the inferred pedigree was strongly correlated to genomic relatedness. © 2017 The Authors. Molecular Ecology Resources Published by John Wiley & Sons Ltd.

PREST-plus identifies pedigree errors and cryptic relatedness in the GAW18 sample using genome-wide SNP data.

PubMed

Sun, Lei; Dimitromanolakis, Apostolos

2014-01-01

Pedigree errors and cryptic relatedness often appear in families or population samples collected for genetic studies. If not identified, these issues can lead to either increased false negatives or false positives in both linkage and association analyses. To identify pedigree errors and cryptic relatedness among individuals from the 20 San Antonio Family Studies (SAFS) families and cryptic relatedness among the 157 putatively unrelated individuals, we apply PREST-plus to the genome-wide single-nucleotide polymorphism (SNP) data and analyze estimated identity-by-descent (IBD) distributions for all pairs of genotyped individuals. Based on the given pedigrees alone, PREST-plus identifies the following putative pairs: 1091 full-sib, 162 half-sib, 360 grandparent-grandchild, 2269 avuncular, 2717 first cousin, 402 half-avuncular, 559 half-first cousin, 2 half-sib+first cousin, 957 parent-offspring and 440,546 unrelated. Using the genotype data, PREST-plus detects 7 mis-specified relative pairs, with their IBD estimates clearly deviating from the null expectations, and it identifies 4 cryptic related pairs involving 7 individuals from 6 families.

HLA-linked rheumatoid arthritis

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

Hasstedt, S.J.; Clegg, D.O.; Ingles, L.

Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. Inmore » addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. 79 refs., 9 tabs.« less

Efficient Genome-Wide Sequencing and Low-Coverage Pedigree Analysis from Noninvasively Collected Samples

PubMed Central

Snyder-Mackler, Noah; Majoros, William H.; Yuan, Michael L.; Shaver, Amanda O.; Gordon, Jacob B.; Kopp, Gisela H.; Schlebusch, Stephen A.; Wall, Jeffrey D.; Alberts, Susan C.; Mukherjee, Sayan; Zhou, Xiang; Tung, Jenny

2016-01-01

Research on the genetics of natural populations was revolutionized in the 1990s by methods for genotyping noninvasively collected samples. However, these methods have remained largely unchanged for the past 20 years and lag far behind the genomics era. To close this gap, here we report an optimized laboratory protocol for genome-wide capture of endogenous DNA from noninvasively collected samples, coupled with a novel computational approach to reconstruct pedigree links from the resulting low-coverage data. We validated both methods using fecal samples from 62 wild baboons, including 48 from an independently constructed extended pedigree. We enriched fecal-derived DNA samples up to 40-fold for endogenous baboon DNA and reconstructed near-perfect pedigree relationships even with extremely low-coverage sequencing. We anticipate that these methods will be broadly applicable to the many research systems for which only noninvasive samples are available. The lab protocol and software (“WHODAD”) are freely available at www.tung-lab.org/protocols-and-software.html and www.xzlab.org/software.html, respectively. PMID:27098910

Accuracy of Predicted Genomic Breeding Values in Purebred and Crossbred Pigs.

PubMed

Hidalgo, André M; Bastiaansen, John W M; Lopes, Marcos S; Harlizius, Barbara; Groenen, Martien A M; de Koning, Dirk-Jan

2015-05-26

Genomic selection has been widely implemented in dairy cattle breeding when the aim is to improve performance of purebred animals. In pigs, however, the final product is a crossbred animal. This may affect the efficiency of methods that are currently implemented for dairy cattle. Therefore, the objective of this study was to determine the accuracy of predicted breeding values in crossbred pigs using purebred genomic and phenotypic data. A second objective was to compare the predictive ability of SNPs when training is done in either single or multiple populations for four traits: age at first insemination (AFI); total number of piglets born (TNB); litter birth weight (LBW); and litter variation (LVR). We performed marker-based and pedigree-based predictions. Within-population predictions for the four traits ranged from 0.21 to 0.72. Multi-population prediction yielded accuracies ranging from 0.18 to 0.67. Predictions across purebred populations as well as predicting genetic merit of crossbreds from their purebred parental lines for AFI performed poorly (not significantly different from zero). In contrast, accuracies of across-population predictions and accuracies of purebred to crossbred predictions for LBW and LVR ranged from 0.08 to 0.31 and 0.11 to 0.31, respectively. Accuracy for TNB was zero for across-population prediction, whereas for purebred to crossbred prediction it ranged from 0.08 to 0.22. In general, marker-based outperformed pedigree-based prediction across populations and traits. However, in some cases pedigree-based prediction performed similarly or outperformed marker-based prediction. There was predictive ability when purebred populations were used to predict crossbred genetic merit using an additive model in the populations studied. AFI was the only exception, indicating that predictive ability depends largely on the genetic correlation between PB and CB performance, which was 0.31 for AFI. Multi-population prediction was no better than within-population prediction for the purebred validation set. Accuracy of prediction was very trait-dependent. Copyright © 2015 Hidalgo et al.

PedVizApi: a Java API for the interactive, visual analysis of extended pedigrees.

PubMed

Fuchsberger, Christian; Falchi, Mario; Forer, Lukas; Pramstaller, Peter P

2008-01-15

PedVizApi is a Java API (application program interface) for the visual analysis of large and complex pedigrees. It provides all the necessary functionality for the interactive exploration of extended genealogies. While available packages are mostly focused on a static representation or cannot be added to an existing application, PedVizApi is a highly flexible open source library for the efficient construction of visual-based applications for the analysis of family data. An extensive demo application and a R interface is provided. http://www.pedvizapi.org

Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits

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

Schork, N.J.; Boehnke, M.; Terwilliger, J.D.

1993-11-01

Nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, the authors explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. The authors compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. Themore » authors also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, the authors also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that the authors consider, the authors find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, the authors also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. The authors discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models. 37 refs., 1 fig., 4 tabs.« less

Impacts of early viability selection on management of inbreeding and genetic diversity in conservation.

PubMed

Grueber, Catherine E; Hogg, Carolyn J; Ivy, Jamie A; Belov, Katherine

2015-04-01

Maintaining genetic diversity is a crucial goal of intensive management of threatened species, particularly for those populations that act as sources for translocation or re-introduction programmes. Most captive genetic management is based on pedigrees and a neutral theory of inheritance, an assumption that may be violated by selective forces operating in captivity. Here, we explore the conservation consequences of early viability selection: differential offspring survival that occurs prior to management or research observations, such as embryo deaths in utero. If early viability selection produces genotypic deviations from Mendelian predictions, it may undermine management strategies intended to minimize inbreeding and maintain genetic diversity. We use empirical examples to demonstrate that straightforward approaches, such as comparing litter sizes of inbred vs. noninbred breeding pairs, can be used to test whether early viability selection likely impacts estimates of inbreeding depression. We also show that comparing multilocus genotype data to pedigree predictions can reveal whether early viability selection drives systematic biases in genetic diversity, patterns that would not be detected using pedigree-based statistics alone. More sophisticated analysis combining genomewide molecular data with pedigree information will enable conservation scientists to test whether early viability selection drives deviations from neutrality across wide stretches of the genome, revealing whether this form of selection biases the pedigree-based statistics and inference upon which intensive management is based. © 2015 John Wiley & Sons Ltd.

Applications of machine learning and data mining methods to detect associations of rare and common variants with complex traits.

PubMed

Lu, Ake Tzu-Hui; Austin, Erin; Bonner, Ashley; Huang, Hsin-Hsiung; Cantor, Rita M

2014-09-01

Machine learning methods (MLMs), designed to develop models using high-dimensional predictors, have been used to analyze genome-wide genetic and genomic data to predict risks for complex traits. We summarize the results from six contributions to our Genetic Analysis Workshop 18 working group; these investigators applied MLMs and data mining to analyses of rare and common genetic variants measured in pedigrees. To develop risk profiles, group members analyzed blood pressure traits along with single-nucleotide polymorphisms and rare variant genotypes derived from sequence and imputation analyses in large Mexican American pedigrees. Supervised MLMs included penalized regression with varying penalties, support vector machines, and permanental classification. Unsupervised MLMs included sparse principal components analysis and sparse graphical models. Entropy-based components analyses were also used to mine these data. None of the investigators fully capitalized on the genetic information provided by the complete pedigrees. Their approaches either corrected for the nonindependence of the individuals within the pedigrees or analyzed only those who were independent. Some methods allowed for covariate adjustment, whereas others did not. We evaluated these methods using a variety of metrics. Four contributors conducted primary analyses on the real data, and the other two research groups used the simulated data with and without knowledge of the underlying simulation model. One group used the answers to the simulated data to assess power and type I errors. Although the MLMs applied were substantially different, each research group concluded that MLMs have advantages over standard statistical approaches with these high-dimensional data. © 2014 WILEY PERIODICALS, INC.

Half of 23 Belgian dog breeds has a compromised genetic diversity, as revealed by genealogical and molecular data analysis.

PubMed

Wijnrocx, K; François, L; Stinckens, A; Janssens, S; Buys, N

2016-10-01

The genetic diversity in 23 dog breeds raised in Belgium was investigated using both genealogical analysis and microsatellite markers. Some of these breeds are native breeds, with only small populations maintained. Pedigree and molecular data, obtained from the Belgian kennel club, were used to calculate the inbreeding coefficients, realised effective population size as well as probabilities of gene origin and average observed heterozygosity. Inbreeding coefficients ranged from 0.8 to 44.7% and realised effective population size varied between 3.2 and 829.1, according to the used method and breed. Mean observed heterozygosity ranged from 0.47 to 0.73. Both pedigree and molecular methods reveal low genetic diversity and presence of bottlenecks, especially in native Belgian breeds with small population sizes. Furthermore, principal component analysis on the set of investigated diversity parameters revealed no groups of breeds that could be identified in which similar breeding strategies could be applied to maintain genetic diversity. © 2016 Blackwell Verlag GmbH.

[Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia].

PubMed

Zeng, Li-ping; Hu, Zheng-mao; Mu, Li-li; Mei, Gui-sen; Lu, Xiu-ling; Zheng, Yong-jun; Li, Pei-jian; Zhang, Ying-xue; Pan, Qian; Long, Zhi-gao; Dai, He-ping; Zhang, Zhuo-hua; Xia, Jia-hui; Zhao, Jing-ping; Xia, Kun

2011-06-01

To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR; American Psychiatric Association, 2000). All subjects signed informed consent. In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α = 0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P= 0.0367) at D1S484. The single point NPL score was 1.95(P= 0.0145) and the multi-point NPL score was 2.39 (P= 0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P= 0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive inheritance mode the maximum single-point HLOD score was 1.26 (α = 0.40) and the multi-point HLOD was 1.12 (α = 0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P= 0.0402) and the multi-point NPL score was 1.92 (P= 0.0206) at D6S289. Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.

Irish study of high-density Schizophrenia families: Field methods and power to detect linkage

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

Kendler, K.S.; Straub, R.E.; MacLean, C.J.

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/ormore » hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. 75 refs., 6 tabs.« less

Validity and power of association testing in family-based sampling designs: evidence for and against the common wisdom.

PubMed

Knight, Stacey; Camp, Nicola J

2011-04-01

Current common wisdom posits that association analyses using family-based designs have inflated type 1 error rates (if relationships are ignored) and independent controls are more powerful than familial controls. We explore these suppositions. We show theoretically that family-based designs can have deflated type-error rates. Through simulation, we examine the validity and power of family designs for several scenarios: cases from randomly or selectively ascertained pedigrees; and familial or independent controls. Family structures considered are as follows: sibships, nuclear families, moderate-sized and extended pedigrees. Three methods were considered with the χ(2) test for trend: variance correction (VC), weighted (weights assigned to account for genetic similarity), and naïve (ignoring relatedness) as well as the Modified Quasi-likelihood Score (MQLS) test. Selectively ascertained pedigrees had similar levels of disease enrichment; random ascertainment had no such restriction. Data for 1,000 cases and 1,000 controls were created under the null and alternate models. The VC and MQLS methods were always valid. The naïve method was anti-conservative if independent controls were used and valid or conservative in designs with familial controls. The weighted association method was generally valid for independent controls, and was conservative for familial controls. With regard to power, independent controls were more powerful for small-to-moderate selectively ascertained pedigrees, but familial and independent controls were equivalent in the extended pedigrees and familial controls were consistently more powerful for all randomly ascertained pedigrees. These results suggest a more complex situation than previously assumed, which has important implications for study design and analysis. © 2011 Wiley-Liss, Inc.

Analysis of founders and performance test effects on an autochthonous horse population through pedigree analysis: structure, genetic variability and inbreeding.

PubMed

Giontella, A; Pieramati, C; Silvestrelli, M; Sarti, F M

2018-05-29

The Maremmano is an autochthonous Italian horse breed, which probably descended from the native horses of the Etruscans (VI century B.C.); the Studbook was acknowledged in 1980, and it includes 12 368 horses born from that year up to 2015. The aim of this study was to evaluate the effect of the selection program on the genetic variability of the Maremmano population; the analysis was performed using both the 'Endog v 4.8' program available at http://webs.ucm.es/info/prodanim/html/JP_Web.htm and in-house software on official pedigree data. Four Reference Populations were considered, and the most important one was the population of the 12 368 Maremmano horses officially registered in the National Studbook. The pedigree completeness of this population was very good because it was more than 90% at the third parental generation and more than 70% at the fifth generation; the pedigree traced back to a maximum of 10.50 generations with an average of 3.30 complete generations and 5.70 equivalent complete generations. The average generation interval was 10.65±4.72 years, with stallions used for longer periods than mares. The intervals ranged from 10.15±4.45 (mother-daughter) to 10.99±4.93 (father-daughter). The effective number of founders (f e) was 74 and the effective number of ancestors (f a) was 30 so that the ratio f e/f a was 2.47. The founder genome equivalents (f g) was 13.72 with a ratio f g/f e equal to 0.18. The mean of the genetic conservation index was 5.55±3.37, and it ranged from 0.81 to 21.32. The average inbreeding coefficient was 2.94%, with an increase of 0.1%/year, and the average relatedness coefficient was 5.52%. The effective population size (N e) computed by an individual increase in inbreeding was 68.1±13.00; the N e on equivalent generations was 42.00, and this value slightly increased to 42.20 when computed by Log regression on equivalent generations. The analysis confirmed the presence of seven traditional male lines. The percentage of Thoroughbred blood in the foals born in 2015 was 20.30% and has increased 0.21%/year since 1980; in particular, it increased more than twice (0.51%/year) until 1993 and afterwards slightly fluctuated. The pedigree analysis confirmed the completeness of genealogical information and the traditional importance that breeders gave to the male lines; although the genetic diversity of Maremmano seemed to be not endangered by the selection program, some effects on the population structure were found and a more scientific approach to genetic conservation should be incorporated in the selection plans.

Effect of incomplete pedigrees on estimates of inbreeding and inbreeding depression for days to first service and summit milk yield in Holsteins and Jerseys.

PubMed

Cassell, B G; Adamec, V; Pearson, R E

2003-09-01

A method to measure completeness of pedigree information is applied to populations of Holstein (registered and grade) and Jersey (largely registered) cows. Inbreeding coefficients where missing ancestors make no contribution were compared to a method using average relationships for missing ancestors. Estimated inbreeding depression was from an animal model that simultaneously adjusted for breeding values. Inbreeding and its standard deviation increased with more information, from 0.04 +/- 0.84 to 1.65 +/- 2.05 and 2.06 +/- 2.22 for grade Holsteins with <31%, 31 to 70%, and 71 to 100% complete five-generation pedigrees. Inbreeding from the method of average relationships for missing ancestors was 2.75 +/- 1.06, 3.10 +/- 2.21, and 2.89 +/- 2.37 for the same groups. Pedigrees of registered Holsteins and Jerseys were over 97% and over 89% complete, respectively. Inbreeding depression in days to first service and summit milk yield was estimated from both methods. Inbreeding depression for days to first service was not consistently significant for grade Holsteins and ranged from -0.37 d/1% increase in inbreeding (grade Holstein pedigrees <31% complete) to 0.15 d for grade Holstein pedigrees >70% complete. Estimates were similar for both methods. Inbreeding depression for registered Holsteins and Jerseys were positive (undesirable) but not significant for days to first service. Inbreeding depressed summit milk yield significantly in all groups by both methods. Summit milk yield declined by -0.12 to -0.06 kg/d per 1% increase in inbreeding in Holsteins and by -0.08 kg/1% increase in inbreeding in Jerseys. Pedigrees of grade animals are frequently incomplete and can yield misleading estimates of inbreeding depression. This problem is not overcome by inserting average relationships for missing ancestors in calculation of inbreeding coefficients.

Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree.

PubMed

Rodriguez-Acevedo, Astrid J; Maher, Bridget H; Lea, Rodney A; Benton, Miles; Griffiths, Lyn R

2013-10-01

Oestrogen receptor 1 ( ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor ( PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man "Bounty Mutineer" and Tahitian founders. A significant number of molecular markers in the ESR1 (143) and PGR (43) genes were evaluated in a sample of 285 related individuals (135 males; 150 females). A pedigree-based analysis in the GenABEL package was used to analyse the results. A total of 10 markers in the ESR1 gene showed association with migraine ( P  < 0.05) in the Norfolk Island population. No association was detected with PGR . Three haplotypes in ESR1 were found to be associated with migraine ( P  = 0.004, 0.03, 0.005). Future genetic studies in larger populations and expression analysis are required to clarify the role of ESR1 in migraine susceptibility.

Genetic genealogy comes of age: perspectives on the use of deep-rooted pedigrees in human population genetics.

PubMed

Larmuseau, M H D; Van Geystelen, A; van Oven, M; Decorte, R

2013-04-01

In this article, we promote the implementation of extensive genealogical data in population genetic studies. Genealogical records can provide valuable information on the origin of DNA donors in a population genetic study, going beyond the commonly collected data such as residence, birthplace, language, and self-reported ethnicity. Recent studies demonstrated that extended genealogical data added to surname analysis can be crucial to detect signals of (past) population stratification and to interpret the population structure in a more objective manner. Moreover, when in-depth pedigree data are combined with haploid markers, it is even possible to disentangle signals of temporal differentiation within a population genetic structure during the last centuries. Obtaining genealogical data for all DNA donors in a population genetic study is a labor-intensive task but the vastly growing (genetic) genealogical databases, due to the broad interest of the public, are making this job more time-efficient if there is a guarantee for sufficient data quality. At the end, we discuss the advantages and pitfalls of using genealogy within sampling campaigns and we provide guidelines for future population genetic studies. Copyright © 2013 Wiley Periodicals, Inc.

Further evidence for a locus for autosomal dominant juvenile glaucoma on chromosome 1q and evidence for genetic heterogeneity

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

Wiggs, J.; Paglinauan, C.; Stawski, S.

1994-09-01

Glaucoma is a term used to describe a group of disorders which have in common a characteristic degeneration of the optic nerve associated with typical visual field defects and usually associated with elevated intraocular pressure. Two percent of white Americans and 6-10% of black Americans are affected by the disease. Compelling data indicate that susceptibility to many types of glaucoma is inherited. Hereditary juvenile glaucoma is one form of glaucoma that develops in children and is inherited as an autosomal dominant trait with high penetrance. Using a single large Caucasian pedigree affected with autosomal dominant juvenile glaucoma, Sheffield discovered positivemore » linkage to a group of markers that map to a 30 cM region on the long arm of chromosome 1 (1q21-q31). We have subsequently identified three unrelated Caucasian pedigrees affected with autosomal dominant juvenile glaucoma that also demonstrate linkage to this region on chromosome 1, with the highest combined lod score of 5.12 at theta = .05 for marker D1S218. The identification of critical recombinant individuals in our three pedigrees has allowed us to further localize the disease gene to a 12 cM region between markers D1S242 and D1S431. In addition, we have identified several pedigrees which do not demonstrate linkage to chromosome 1q, including a black family affected with autosomal dominant juvenile glaucoma that is indistinguishable clinically from the disorder affecting the caucasian pedigrees and three pedigrees affected with pigmentary dispersion syndrome, a form of glaucoma that also affects the juvenile population and is also inherited as an autosomal dominant trait. These findings provide evidence for genetic heterogeneity in juvenile glaucoma.« less

Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.

PubMed Central

Takano, H; Cancel, G; Ikeuchi, T; Lorenzetti, D; Mawad, R; Stevanin, G; Didierjean, O; Dürr, A; Oyake, M; Shimohata, T; Sasaki, R; Koide, R; Igarashi, S; Hayashi, S; Takiyama, Y; Nishizawa, M; Tanaka, H; Zoghbi, H; Brice, A; Tsuji, S

1998-01-01

To test the hypothesis that the frequencies of normal alleles (ANs) with a relatively large number of CAG repeats (large ANs) are related to the prevalences of the dominant spinocerebellar ataxias (SCAs)-SCA types 1, 2, 3 (Machado-Joseph disease), 6, and dentatorubral-pallidoluysian atrophy (DRPLA)-we investigated the relative prevalences of these diseases in 202 Japanese and 177 Caucasian families and distributions of the number of CAG repeats of ANs at these disease loci in normal individuals in each population. The relative prevalences of SCA1 and SCA2 were significantly higher in Caucasian pedigrees (15% and 14%, respectively) than in Japanese pedigrees (3% and 5%, respectively), corresponding to the observation that the frequencies of large ANs of SCA1 (alleles >30 repeats) and of SCA2 (alleles >22 repeats) were significantly higher in Caucasians than in Japanese. The relative prevalences of MJD/SCA3, SCA6, and DRPLA were significantly higher in Japanese pedigrees (43%, 11%, and 20%, respectively) than in Caucasian pedigrees (30%, 5%, and 0%, respectively), corresponding to the observation that the frequencies of large ANs of MJD/SCA3 (>27 repeats), SCA6 (>13 repeats), and DRPLA (>17 repeats) were significantly higher in Japanese than in Caucasians. The close correlations of the relative prevalences of the dominant SCAs with the distributions of large ANs strongly support the assumption that large ANs contribute to generation of expanded alleles (AEs) and the relative prevalences of the dominant SCAs. PMID:9758625

Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects

PubMed Central

Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A.

2016-01-01

The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates’ offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of “half-sibling” in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure. PMID:26801647

Efficiency of the Use of Pedigree and Molecular Marker Information in Conservation Programs

PubMed Central

Fernández, Jesús; Villanueva, Beatriz; Pong-Wong, Ricardo; Toro, Miguel Ángel

2005-01-01

The value of molecular markers and pedigree records, separately or in combination, to assist in the management of conserved populations has been tested. The general strategy for managing the population was to optimize contributions of parents to the next generation for minimizing the global weighted coancestry. Strategies differed in the type of information used to compute global coancestries, the number and type of evaluated individuals, and the system of mating. Genealogical information proved to be very useful (at least for 10 generations of management) to arrange individuals' contributions via the minimization of global coancestry. In fact, the level of expected heterozygosity after 10 generations yielded by this strategy was 88–100% of the maximum possible improvement obtained if the genotype for all loci was known. Marker information was of very limited value if used alone. The amount and degree of polymorphism of markers to be used to compute molecular coancestry had to be high to mimic the performance of the strategy relying on pedigree, especially in the short term (for example, >10 markers per chromosome with 10 alleles each were needed if only the parents' genotype was available). When both sources of information are combined to calculate the coancestry conditional on markers, clear increases in effective population size (Ne) were found, but observed diversity levels (either gene or allelic diversity) in the early generations were quite similar to the ones obtained with pedigree alone. The advantage of including molecular information is greater when information is available on a greater number of individuals (offspring and parents vs. parents only). However, for realistic situations (i.e., large genomes) the benefits of using information on offspring are small. The same conclusions were reached when comparing the use of the different types of information (genealogical or/and molecular) to perform minimum coancestry matings. PMID:15879510

Optimizing Training Population Size and Genotyping Strategy for Genomic Prediction Using Association Study Results and Pedigree Information. A Case of Study in Advanced Wheat Breeding Lines.

PubMed

Cericola, Fabio; Jahoor, Ahmed; Orabi, Jihad; Andersen, Jeppe R; Janss, Luc L; Jensen, Just

2017-01-01

Wheat breeding programs generate a large amount of variation which cannot be completely explored because of limited phenotyping throughput. Genomic prediction (GP) has been proposed as a new tool which provides breeding values estimations without the need of phenotyping all the material produced but only a subset of it named training population (TP). However, genotyping of all the accessions under analysis is needed and, therefore, optimizing TP dimension and genotyping strategy is pivotal to implement GP in commercial breeding schemes. Here, we explored the optimum TP size and we integrated pedigree records and genome wide association studies (GWAS) results to optimize the genotyping strategy. A total of 988 advanced wheat breeding lines were genotyped with the Illumina 15K SNPs wheat chip and phenotyped across several years and locations for yield, lodging, and starch content. Cross-validation using the largest possible TP size and all the SNPs available after editing (~11k), yielded predictive abilities (rGP) ranging between 0.5-0.6. In order to explore the Training population size, rGP were computed using progressively smaller TP. These exercises showed that TP of around 700 lines were enough to yield the highest observed rGP. Moreover, rGP were calculated by randomly reducing the SNPs number. This showed that around 1K markers were enough to reach the highest observed rGP. GWAS was used to identify markers associated with the traits analyzed. A GWAS-based selection of SNPs resulted in increased rGP when compared with random selection and few hundreds SNPs were sufficient to obtain the highest observed rGP. For each of these scenarios, advantages of adding the pedigree information were shown. Our results indicate that moderate TP sizes were enough to yield high rGP and that pedigree information and GWAS results can be used to greatly optimize the genotyping strategy.

GENLIB: an R package for the analysis of genealogical data.

PubMed

Gauvin, Héloïse; Lefebvre, Jean-François; Moreau, Claudia; Lavoie, Eve-Marie; Labuda, Damian; Vézina, Hélène; Roy-Gagnon, Marie-Hélène

2015-05-15

Founder populations have an important role in the study of genetic diseases. Access to detailed genealogical records is often one of their advantages. These genealogical data provide unique information for researchers in evolutionary and population genetics, demography and genetic epidemiology. However, analyzing large genealogical datasets requires specialized methods and software. The GENLIB software was developed to study the large genealogies of the French Canadian population of Quebec, Canada. These genealogies are accessible through the BALSAC database, which contains over 3 million records covering the whole province of Quebec over four centuries. Using this resource, extended pedigrees of up to 17 generations can be constructed from a sample of present-day individuals. We have extended and implemented GENLIB as a package in the R environment for statistical computing and graphics, thus allowing optimal flexibility for users. The GENLIB package includes basic functions to manage genealogical data allowing, for example, extraction of a part of a genealogy or selection of specific individuals. There are also many functions providing information to describe the size and complexity of genealogies as well as functions to compute standard measures such as kinship, inbreeding and genetic contribution. GENLIB also includes functions for gene-dropping simulations. The goal of this paper is to present the full functionalities of GENLIB. We used a sample of 140 individuals from the province of Quebec (Canada) to demonstrate GENLIB's functions. Ascending genealogies for these individuals were reconstructed using BALSAC, yielding a large pedigree of 41,523 individuals. Using GENLIB's functions, we provide a detailed description of these genealogical data in terms of completeness, genetic contribution of founders, relatedness, inbreeding and the overall complexity of the genealogical tree. We also present gene-dropping simulations based on the whole genealogy to investigate identical-by-descent sharing of alleles and chromosomal segments of different lengths and estimate probabilities of identical-by-descent sharing. The R package GENLIB provides a user friendly and flexible environment to analyze extensive genealogical data, allowing an efficient and easy integration of different types of data, analytical methods and additional developments and making this tool ideal for genealogical analysis.

Compatibility of pedigree-based and marker-based relationship matrices for single-step genetic evaluation.

PubMed

Christensen, Ole F

2012-12-03

Single-step methods provide a coherent and conceptually simple approach to incorporate genomic information into genetic evaluations. An issue with single-step methods is compatibility between the marker-based relationship matrix for genotyped animals and the pedigree-based relationship matrix. Therefore, it is necessary to adjust the marker-based relationship matrix to the pedigree-based relationship matrix. Moreover, with data from routine evaluations, this adjustment should in principle be based on both observed marker genotypes and observed phenotypes, but until now this has been overlooked. In this paper, I propose a new method to address this issue by 1) adjusting the pedigree-based relationship matrix to be compatible with the marker-based relationship matrix instead of the reverse and 2) extending the single-step genetic evaluation using a joint likelihood of observed phenotypes and observed marker genotypes. The performance of this method is then evaluated using two simulated datasets. The method derived here is a single-step method in which the marker-based relationship matrix is constructed assuming all allele frequencies equal to 0.5 and the pedigree-based relationship matrix is constructed using the unusual assumption that animals in the base population are related and inbred with a relationship coefficient γ and an inbreeding coefficient γ / 2. Taken together, this γ parameter and a parameter that scales the marker-based relationship matrix can handle the issue of compatibility between marker-based and pedigree-based relationship matrices. The full log-likelihood function used for parameter inference contains two terms. The first term is the REML-log-likelihood for the phenotypes conditional on the observed marker genotypes, whereas the second term is the log-likelihood for the observed marker genotypes. Analyses of the two simulated datasets with this new method showed that 1) the parameters involved in adjusting marker-based and pedigree-based relationship matrices can depend on both observed phenotypes and observed marker genotypes and 2) a strong association between these two parameters exists. Finally, this method performed at least as well as a method based on adjusting the marker-based relationship matrix. Using the full log-likelihood and adjusting the pedigree-based relationship matrix to be compatible with the marker-based relationship matrix provides a new and interesting approach to handle the issue of compatibility between the two matrices in single-step genetic evaluation.

Surveying the Maize community for their diversity and pedigree visualization needs to prioritize tool development and curation

PubMed Central

Braun, Bremen L.; Schott, David A.; Portwood, II, John L.; Schaeffer, Mary L.; Harper, Lisa C.; Gardiner, Jack M.; Cannon, Ethalinda K.; Andorf, Carson M.

2017-01-01

Abstract The Maize Genetics and Genomics Database (MaizeGDB) team prepared a survey to identify breeders’ needs for visualizing pedigrees, diversity data and haplotypes in order to prioritize tool development and curation efforts at MaizeGDB. The survey was distributed to the maize research community on behalf of the Maize Genetics Executive Committee in Summer 2015. The survey garnered 48 responses from maize researchers, of which more than half were self-identified as breeders. The survey showed that the maize researchers considered their top priorities for visualization as: (i) displaying single nucleotide polymorphisms in a given region for a given list of lines, (ii) showing haplotypes for a given list of lines and (iii) presenting pedigree relationships visually. The survey also asked which populations would be most useful to display. The following two populations were on top of the list: (i) 3000 publicly available maize inbred lines used in Romay et al. (Comprehensive genotyping of the USA national maize inbred seed bank. Genome Biol, 2013;14:R55) and (ii) maize lines with expired Plant Variety Protection Act (ex-PVP) certificates. Driven by this strong stakeholder input, MaizeGDB staff are currently working in four areas to improve its interface and web-based tools: (i) presenting immediate progenies of currently available stocks at the MaizeGDB Stock pages, (ii) displaying the most recent ex-PVP lines described in the Germplasm Resources Information Network (GRIN) on the MaizeGDB Stock pages, (iii) developing network views of pedigree relationships and (iv) visualizing genotypes from SNP-based diversity datasets. These survey results can help other biological databases to direct their efforts according to user preferences as they serve similar types of data sets for their communities. Database URL: https://www.maizegdb.org PMID:28605768

A likelihood ratio-based method to predict exact pedigrees for complex families from next-generation sequencing data.

PubMed

Heinrich, Verena; Kamphans, Tom; Mundlos, Stefan; Robinson, Peter N; Krawitz, Peter M

2017-01-01

Next generation sequencing technology considerably changed the way we screen for pathogenic mutations in rare Mendelian disorders. However, the identification of the disease-causing mutation amongst thousands of variants of partly unknown relevance is still challenging and efficient techniques that reduce the genomic search space play a decisive role. Often segregation- or linkage analysis are used to prioritize candidates, however, these approaches require correct information about the degree of relationship among the sequenced samples. For quality assurance an automated control of pedigree structures and sample assignment is therefore highly desirable in order to detect label mix-ups that might otherwise corrupt downstream analysis. We developed an algorithm based on likelihood ratios that discriminates between different classes of relationship for an arbitrary number of genotyped samples. By identifying the most likely class we are able to reconstruct entire pedigrees iteratively, even for highly consanguineous families. We tested our approach on exome data of different sequencing studies and achieved high precision for all pedigree predictions. By analyzing the precision for varying degrees of relatedness or inbreeding we could show that a prediction is robust down to magnitudes of a few hundred loci. A java standalone application that computes the relationships between multiple samples as well as a Rscript that visualizes the pedigree information is available for download as well as a web service at www.gene-talk.de CONTACT: heinrich@molgen.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

A likelihood ratio-based method to predict exact pedigrees for complex families from next-generation sequencing data

PubMed Central

Kamphans, Tom; Mundlos, Stefan; Robinson, Peter N.; Krawitz, Peter M.

2017-01-01

Motivation: Next generation sequencing technology considerably changed the way we screen for pathogenic mutations in rare Mendelian disorders. However, the identification of the disease-causing mutation amongst thousands of variants of partly unknown relevance is still challenging and efficient techniques that reduce the genomic search space play a decisive role. Often segregation- or linkage analysis are used to prioritize candidates, however, these approaches require correct information about the degree of relationship among the sequenced samples. For quality assurance an automated control of pedigree structures and sample assignment is therefore highly desirable in order to detect label mix-ups that might otherwise corrupt downstream analysis. Results: We developed an algorithm based on likelihood ratios that discriminates between different classes of relationship for an arbitrary number of genotyped samples. By identifying the most likely class we are able to reconstruct entire pedigrees iteratively, even for highly consanguineous families. We tested our approach on exome data of different sequencing studies and achieved high precision for all pedigree predictions. By analyzing the precision for varying degrees of relatedness or inbreeding we could show that a prediction is robust down to magnitudes of a few hundred loci. Availability and Implementation: A java standalone application that computes the relationships between multiple samples as well as a Rscript that visualizes the pedigree information is available for download as well as a web service at www.gene-talk.de. Contact: heinrich@molgen.mpg.de Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27565584

Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck.

PubMed

Wilson, Ian J; Carling, Phillipa J; Alston, Charlotte L; Floros, Vasileios I; Pyle, Angela; Hudson, Gavin; Sallevelt, Suzanne C E H; Lamperti, Costanza; Carelli, Valerio; Bindoff, Laurence A; Samuels, David C; Wonnapinij, Passorn; Zeviani, Massimo; Taylor, Robert W; Smeets, Hubert J M; Horvath, Rita; Chinnery, Patrick F

2016-03-01

With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ∼1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations. © The Author 2016. Published by Oxford University Press.

[Clinical features of a Chinese pedigree with Waardenburg syndrome type 2].

PubMed

Yang, Shu-zhi; Yuan, Hui-jun; Bai, Lin-na; Cao, Ju-yang; Xu, Ye; Shen, Wei-dong; Ji, Fei; Yang, Wei-yan

2005-10-12

To investigate detailed clinical features of a Chinese pedigree with Waardenburg syndrome type 2. Members of this pedigree were interviewed to identify personal or family medical histories of hearing loss, the use of aminoglycosides, and other clinical abnormalities by filling questionnaire. The audiological and other clinical evaluations of the proband and other members of this family were conducted, including pure-tone audiometry, immittance and auditory brain-stem response and ophthalmological, dermatologic, hair, temporal bone CT examinations. This family is categorized as Waardenburg syndrome type 2 according to its clinical features. It's an autosomal dominant disorder with incomplete penetrance. The clinical features varied greatly among family members and characterized by sensorineural hearing loss, heterochromia irides, freckle on the face and premature gray hair. Hearing loss can be unilateral or bilateral, congenital or late onset in this family. This Chinese family has some unique clinical features comparing with the international diagnostic criteria for Waardenburg syndrome. This study may provide some evidences to amend the diagnostic criteria for Waardenburg syndrome in Chinese population.

[Using exon combined target region capture sequencing chip to detect the disease-causing genes of retinitis pigmentosa].

PubMed

Rong, Weining; Chen, Xuejuan; Li, Huiping; Liu, Yani; Sheng, Xunlun

2014-06-01

To detect the disease-causing genes of 10 retinitis pigmentosa pedigrees by using exon combined target region capture sequencing chip. Pedigree investigation study. From October 2010 to December 2013, 10 RP pedigrees were recruited for this study in Ningxia Eye Hospital. All the patients and family members received complete ophthalmic examinations. DNA was abstracted from patients, family members and controls. Using exon combined target region capture sequencing chip to screen the candidate disease-causing mutations. Polymerase chain reaction (PCR) and direct sequencing were used to confirm the disease-causing mutations. Seventy patients and 23 normal family members were recruited from 10 pedigrees. Among 10 RP pedigrees, 1 was autosomal dominant pedigrees and 9 were autosomal recessive pedigrees. 7 mutations related to 5 genes of 5 pedigrees were detected. A frameshift mutation on BBS7 gene was detected in No.2 pedigree, the patients of this pedigree combined with central obesity, polydactyly and mental handicap. No.2 pedigree was diagnosed as Bardet-Biedl syndrome finally. A missense mutation was detected in No.7 and No.10 pedigrees respectively. Because the patients suffered deafness meanwhile, the final diagnosis was Usher syndrome. A missense mutation on C3 gene related to age-related macular degeneration was also detected in No. 7 pedigrees. A nonsense mutation and a missense mutation on CRB1 gene were detected in No. 1 pedigree and a splicesite mutation on PROM1 gene was detected in No. 5 pedigree. Retinitis pigmentosa is a kind of genetic eye disease with diversity clinical phenotypes. Rapid and effective genetic diagnosis technology combined with clinical characteristics analysis is helpful to improve the level of clinical diagnosis of RP.

Similar effects of QTL Haplotypes for Bacterial Cold Water Disease resistance across two generations in a commercial rainbow trout breeding population

USDA-ARS?s Scientific Manuscript database

Previously we have demonstrated that genomic selection (GS) for bacterial cold water disease (BCWD) resistance can double the accuracy of traditional pedigree-based selection in a commercial rainbow trout breeding population. The objective of this study was to evaluate the effectiveness of marker ...

Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder.

PubMed

Service, Susan; Molina, Julio; Deyoung, Joseph; Jawaheer, Damini; Aldana, Ileana; Vu, Thuy; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Fournier, Eduardo; Ramirez, Magui; Mathews, Carol A; Davanzo, Pablo; Macaya, Gabriel; Sandkuijl, Lodewijk; Sabatti, Chiara; Reus, Victor; Freimer, Nelson

2006-06-05

We have ascertained in the Central Valley of Costa Rica a new kindred (CR201) segregating for severe bipolar disorder (BP-I). The family was identified by tracing genealogical connections among eight persons initially independently ascertained for a genome wide association study of BP-I. For the genome screen in CR201, we trimmed the family down to 168 persons (82 of whom are genotyped), containing 25 individuals with a best-estimate diagnosis of BP-I. A total of 4,690 SNP markers were genotyped. Analysis of the data was hampered by the size and complexity of the pedigree, which prohibited using exact multipoint methods on the entire kindred. Two-point parametric linkage analysis, using a conservative model of transmission, produced a maximum LOD score of 2.78 on chromosome 6, and a total of 39 loci with LOD scores >1.0. Multipoint parametric and non-parametric linkage analysis was performed separately on four sections of CR201, and interesting (nominal P-value from either analysis <0.01), although not statistically significant, regions were highlighted on chromosomes 1, 2, 3, 12, 16, 19, and 22, in at least one section of the pedigree, or when considering all sections together. The difficulties of analyzing genome wide SNP data for complex disorders in large, potentially informative, kindreds are discussed.

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

Steinhaus, K.A.; Bennett, R.L.; Resta, R.G.

To determine consistency in usage of pedigree symbols by genetics professionals, we reviewed pedigrees printed in 10 human genetic and medical journals and 24 medical genetics textbooks. We found no consistent symbolization for common situations such as pregnancy, spontaneous abortion, death, or test results. Inconsistency in pedigree design can create difficulties in the interpretation of family studies and detract from the pedigree`s basic strength of simple and accurate communication of medical information. We recommend the development of standard pedigree symbols, and their incorporation into genetic publications, professional genetics training programs, pedigree software programs, and genetic board examinations. 5 refs., 11more » figs., 2 tabs.« less

The occurrence and suspected mode of inheritance of congenital subaortic stenosis and tricuspid valve dysplasia in Dogue de Bordeaux dogs.

PubMed

Ohad, D G; Avrahami, A; Waner, T; David, L

2013-08-01

The Dogue de Bordeaux (DdB) breed has gone through several genetic 'bottle necks' and has a relatively small effective population size. Importing new stock into Israel has been limited, further narrowing the already restricted local gene-pool and increasing the chances of inherited defects. In 56 DdB dogs examined between 2003 and 2010, the authors sought to study the proportion congenital subaortic stenosis (SAS) and tricuspid valve dysplasia (TVD). The aim was also to identify a probable mode of inheritance (MOI) using segregation and pedigree analyses of genealogical data available from 13/21 DdB dogs diagnosed with these conditions between 2004 and 2007. Among all breeds in the country, TVD was highest in the DdB breed, which also displayed the second highest proportion of SAS. Echocardiographic measurements and selected physical examination findings from 26 normal DdB dogs, 18 DdB dogs with SAS, and 12 DdB dogs with TVD are reported. Based on pedigree and segregation analyses, the most probable MOI appeared to be autosomal recessive. Pedigree analyses helped to identify three ancestors that might have introduced these two congenital heart defects into the local DdB population. Excluding those three dogs and their progeny from future mating could therefore reduce the prevalence of these diseases in the DdB population in Israel. The unusual local breeding circumstances may offer a unique opportunity to identify associated SAS and TVD genes in the DdB, as well as in other dog breeds. Copyright © 2013 Elsevier Ltd. All rights reserved.

Qualitative and Quantitative Pedigree Analysis: Graph Theory, Computer Software, and Case Studies.

ERIC Educational Resources Information Center

Jungck, John R.; Soderberg, Patti

1995-01-01

Presents a series of elementary mathematical tools for re-representing pedigrees, pedigree generators, pedigree-driven database management systems, and case studies for exploring genetic relationships. (MKR)

A population-based analysis of germline BAP1 mutations in melanoma.

PubMed

O'Shea, Sally J; Robles-Espinoza, Carla Daniela; McLellan, Lauren; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D Timothy; Newton-Bishop, Julia A; Adams, David J

2017-02-15

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. © The Author 2017. Published by Oxford University Press.

A population-based analysis of germline BAP1 mutations in melanoma

PubMed Central

O’Shea, Sally J.; Robles-Espinoza, Carla Daniela; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D. Timothy; Newton-Bishop, Julia A.

2017-01-01

Abstract Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. PMID:28062663

Development of genomic microsatellite multiplex PCR using dye-labeled universal primer and its validation in pedigree analysis of Pacific oyster ( Crassostrea gigas)

NASA Astrophysics Data System (ADS)

Liu, Ting; Li, Qi; Song, Junlin; Yu, Hong

2017-02-01

There is an increasing requirement for traceability of aquaculture products, both for consumer protection and for food safety. There are high error rates in the conventional traceability systems depending on physical labels. Genetic traceability technique depending on DNA-based tracking system can overcome this problem. Genealogy information is essential for genetic traceability, and microsatellite DNA marker is a good choice for pedigree analysis. As increasing genotyping throughput of microsatellites, microsatellite multiplex PCR has become a fast and cost-effective technique. As a commercially important cultured aquatic species, Pacific oyster Crassostrea gigas has the highest global production. The objective of this study was to develop microsatellite multiplex PCR panels with dye-labeled universal primer for pedigree analysis in C. gigas, and these multiplex PCRs were validated using 12 full-sib families with known pedigrees. Here we developed six informative multiplex PCRs using 18 genomic microsatellites in C. gigas. Each multiplex panel contained a single universal primer M13(-21) used as a tail on each locus-specific forward primer and a single universal primer M13(-21) labeled with fluorophores. The polymorphisms of the markers were moderate, with an average of 10.3 alleles per locus and average polymorphic information content of 0.740. The observed heterozygosity per locus ranged from 0.492 to 0.822. Cervus simulations revealed that the six panels would still be of great value when massive families were analysed. Pedigree analysis of real offspring demonstrated that 100% of the offspring were unambiguously allocated to their parents when two multiplex PCRs were used. The six sets of multiplex PCRs can be an important tool for tracing cultured individuals, population genetic analysis, and selective breeding program in C. gigas.

Genetic control of complex traits, with a focus on reproduction in pigs.

PubMed

Zak, Louisa J; Gaustad, Ann Helen; Bolarin, Alfonso; Broekhuijse, Marleen L W J; Walling, Grant A; Knol, Egbert F

2017-09-01

Reproductive traits are complex, and desirable reproductive phenotypes, such as litter size or semen quality, are true polygenetic traits determined by multiple gene regulatory pathways. Each individual gene contributes to the overall variation in these traits, so genetic improvements can be achieved using conventional selection methodology. In the past, a pedigree-based-relationship matrix was used; this is now replaced by a combination of pedigree-based- and genomic-relationship matrices. The heritability of reproductive traits is low to moderate, so large-scale data recording is required to identify specific, selectable attributes. Male reproductive traits-including ejaculate volume and sperm progressive motility-are moderately heritable, and could be used in selection programs. A few high-merit artificial-insemination boars can impact many sow populations, so additional knowledge about male reproduction-specifically pre-pubertal detection of infertility and the technologies of semen cryopreservation and sex sorting-should further improve global breeding efforts. Conversely, female pig reproduction is currently a limiting factor of genetic improvement. Litter size and farrowing interval are the main obstacles to increasing selection intensity and to reducing generation interval in a breeding program. Age at puberty and weaning-to-estrus interval can be selected for, thereby reducing the number of non-productive days. The number of piglets born alive and litter weights are also reliably influenced by genetic selection. Characterization of genotype-environment interactions will provide opportunities to match genetics to specific farm systems. Continued investment to understand physiological models for improved phenotyping and the development of technologies to facilitate pig embryo production for genetic selection are warranted to ensure optimal breeding in future generations. © 2017 Wiley Periodicals, Inc.

A method for detecting IBD regions simultaneously in multiple individuals—with applications to disease genetics

PubMed Central

Moltke, Ida; Albrechtsen, Anders; Hansen, Thomas v.O.; Nielsen, Finn C.; Nielsen, Rasmus

2011-01-01

All individuals in a finite population are related if traced back long enough and will, therefore, share regions of their genomes identical by descent (IBD). Detection of such regions has several important applications—from answering questions about human evolution to locating regions in the human genome containing disease-causing variants. However, IBD regions can be difficult to detect, especially in the common case where no pedigree information is available. In particular, all existing non-pedigree based methods can only infer IBD sharing between two individuals. Here, we present a new Markov Chain Monte Carlo method for detection of IBD regions, which does not rely on any pedigree information. It is based on a probabilistic model applicable to unphased SNP data. It can take inbreeding, allele frequencies, genotyping errors, and genomic distances into account. And most importantly, it can simultaneously infer IBD sharing among multiple individuals. Through simulations, we show that the simultaneous modeling of multiple individuals makes the method more powerful and accurate than several other non-pedigree based methods. We illustrate the potential of the method by applying it to data from individuals with breast and/or ovarian cancer, and show that a known disease-causing mutation can be mapped to a 2.2-Mb region using SNP data from only five seemingly unrelated affected individuals. This would not be possible using classical linkage mapping or association mapping. PMID:21493780

[Genealogical Analysis of the Use of Two Wheatgrass (Agropyron) Species in Common Wheat (Triticum aestivum L.) Breeding for Disease Resistance].

PubMed

Martynova, S P; Dobrotvorskaya, T V; Krupnov, V A

2016-02-01

During the last 80 years, in order to increase the genetic variability of wheat, translocations containing nine elongated wheatgrass (Agropyron elongatum) and eight intermediate wheatgrass (Agropyron intermedium) genes, which control resistance to pathogens, were transferred to this crop culture. Genealogical and statistical analysis of 1500 varieties developed using the wheatgrass gave evidence of the continuing increase in the proportion of such varieties in the total number of wheat varieties over the last half-century. Translocations from Ag. elongatum most commonly occur in the pedigrees of the varieties from the United States, less frequently they can be found in Australian and Chinese varieties, and they are extremely rare--in European and African ones. Ag. intermedium most frequently occurs in the pedigrees of the Eastern European varieties, mainly in those from Russia, as well as in the varieties from China. The observed uneven distribution of such varieties may be associated with either the effectiveness of the translocation in the development of resistance to the local populations of pathogens or with the effect of the translocation on the adaptive traits of plants. By computer tracking of pedigrees, we performed an inventory of the translocation donors from A. elongatum and A. intermedium used in the breeding programs in the United States, Russia, Australia, India, and China. The most widely occurring combinations of the gene complex Lr24/Sr24 of Ag. elongatum with other resistance genes were revealed. In Russia there were developed varieties in which the 6D chromosome was substituted by the 6Ai chromosome of Ag. intermedium, which controls disease resistance and the adaptivity of plants. The identification and introgression of new translocations indicates that the possibilities of using wheatgrass species for broadening of genetic variability of wheat are far from being exhausted.

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

McDowell, G.A.; Blitzer, M.G.; Mules, E.H.

A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the [beta]-hexosaminidase A (Hex A) [alpha]-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the [alpha]-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined formore » 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families. 29 refs., 4 figs.« less

Impact of fitting dominance and additive effects on accuracy of genomic prediction of breeding values in layers.

PubMed

Heidaritabar, M; Wolc, A; Arango, J; Zeng, J; Settar, P; Fulton, J E; O'Sullivan, N P; Bastiaansen, J W M; Fernando, R L; Garrick, D J; Dekkers, J C M

2016-10-01

Most genomic prediction studies fit only additive effects in models to estimate genomic breeding values (GEBV). However, if dominance genetic effects are an important source of variation for complex traits, accounting for them may improve the accuracy of GEBV. We investigated the effect of fitting dominance and additive effects on the accuracy of GEBV for eight egg production and quality traits in a purebred line of brown layers using pedigree or genomic information (42K single-nucleotide polymorphism (SNP) panel). Phenotypes were corrected for the effect of hatch date. Additive and dominance genetic variances were estimated using genomic-based [genomic best linear unbiased prediction (GBLUP)-REML and BayesC] and pedigree-based (PBLUP-REML) methods. Breeding values were predicted using a model that included both additive and dominance effects and a model that included only additive effects. The reference population consisted of approximately 1800 animals hatched between 2004 and 2009, while approximately 300 young animals hatched in 2010 were used for validation. Accuracy of prediction was computed as the correlation between phenotypes and estimated breeding values of the validation animals divided by the square root of the estimate of heritability in the whole population. The proportion of dominance variance to total phenotypic variance ranged from 0.03 to 0.22 with PBLUP-REML across traits, from 0 to 0.03 with GBLUP-REML and from 0.01 to 0.05 with BayesC. Accuracies of GEBV ranged from 0.28 to 0.60 across traits. Inclusion of dominance effects did not improve the accuracy of GEBV, and differences in their accuracies between genomic-based methods were small (0.01-0.05), with GBLUP-REML yielding higher prediction accuracies than BayesC for egg production, egg colour and yolk weight, while BayesC yielded higher accuracies than GBLUP-REML for the other traits. In conclusion, fitting dominance effects did not impact accuracy of genomic prediction of breeding values in this population. © 2016 Blackwell Verlag GmbH.

Intrafamilial phenotypic heterogeneity of the Poland complex: a case report.

PubMed

Parano, E; Falsaperla, R; Pavone, V; Toscano, A; Bolan, E A; Trifiletti, R R

1995-08-01

Three cases of familial unilateral gluteal hypoplasia are reported. The index case in addition to having gluteal hypoplasia also has unilateral pectoral muscle hypoplasia. Another relative has unilateral symbrachydactyly of the distal phalanges of one foot. All four affected individuals in our pedigree were female. We propose that our cases are best classified as part of the Poland complex of anomalies. Our cases emphasize that intrafamilial phenotypic heterogeneity is possible within the Poland complex.

Prediction of genetic values of quantitative traits in plant breeding using pedigree and molecular markers.

PubMed

Crossa, José; Campos, Gustavo de Los; Pérez, Paulino; Gianola, Daniel; Burgueño, Juan; Araus, José Luis; Makumbi, Dan; Singh, Ravi P; Dreisigacker, Susanne; Yan, Jianbing; Arief, Vivi; Banziger, Marianne; Braun, Hans-Joachim

2010-10-01

The availability of dense molecular markers has made possible the use of genomic selection (GS) for plant breeding. However, the evaluation of models for GS in real plant populations is very limited. This article evaluates the performance of parametric and semiparametric models for GS using wheat (Triticum aestivum L.) and maize (Zea mays) data in which different traits were measured in several environmental conditions. The findings, based on extensive cross-validations, indicate that models including marker information had higher predictive ability than pedigree-based models. In the wheat data set, and relative to a pedigree model, gains in predictive ability due to inclusion of markers ranged from 7.7 to 35.7%. Correlation between observed and predictive values in the maize data set achieved values up to 0.79. Estimates of marker effects were different across environmental conditions, indicating that genotype × environment interaction is an important component of genetic variability. These results indicate that GS in plant breeding can be an effective strategy for selecting among lines whose phenotypes have yet to be observed.

Pedigree-based estimation of covariance between dominance deviations and additive genetic effects in closed rabbit lines considering inbreeding and using a computationally simpler equivalent model.

PubMed

Fernández, E N; Legarra, A; Martínez, R; Sánchez, J P; Baselga, M

2017-06-01

Inbreeding generates covariances between additive and dominance effects (breeding values and dominance deviations). In this work, we developed and applied models for estimation of dominance and additive genetic variances and their covariance, a model that we call "full dominance," from pedigree and phenotypic data. Estimates with this model such as presented here are very scarce both in livestock and in wild genetics. First, we estimated pedigree-based condensed probabilities of identity using recursion. Second, we developed an equivalent linear model in which variance components can be estimated using closed-form algorithms such as REML or Gibbs sampling and existing software. Third, we present a new method to refer the estimated variance components to meaningful parameters in a particular population, i.e., final partially inbred generations as opposed to outbred base populations. We applied these developments to three closed rabbit lines (A, V and H) selected for number of weaned at the Polytechnic University of Valencia. Pedigree and phenotypes are complete and span 43, 39 and 14 generations, respectively. Estimates of broad-sense heritability are 0.07, 0.07 and 0.05 at the base versus 0.07, 0.07 and 0.09 in the final generations. Narrow-sense heritability estimates are 0.06, 0.06 and 0.02 at the base versus 0.04, 0.04 and 0.01 at the final generations. There is also a reduction in the genotypic variance due to the negative additive-dominance correlation. Thus, the contribution of dominance variation is fairly large and increases with inbreeding and (over)compensates for the loss in additive variation. In addition, estimates of the additive-dominance correlation are -0.37, -0.31 and 0.00, in agreement with the few published estimates and theoretical considerations. © 2017 Blackwell Verlag GmbH.

Family genome browser: visualizing genomes with pedigree information.

PubMed

Juan, Liran; Liu, Yongzhuang; Wang, Yongtian; Teng, Mingxiang; Zang, Tianyi; Wang, Yadong

2015-07-15

Families with inherited diseases are widely used in Mendelian/complex disease studies. Owing to the advances in high-throughput sequencing technologies, family genome sequencing becomes more and more prevalent. Visualizing family genomes can greatly facilitate human genetics studies and personalized medicine. However, due to the complex genetic relationships and high similarities among genomes of consanguineous family members, family genomes are difficult to be visualized in traditional genome visualization framework. How to visualize the family genome variants and their functions with integrated pedigree information remains a critical challenge. We developed the Family Genome Browser (FGB) to provide comprehensive analysis and visualization for family genomes. The FGB can visualize family genomes in both individual level and variant level effectively, through integrating genome data with pedigree information. Family genome analysis, including determination of parental origin of the variants, detection of de novo mutations, identification of potential recombination events and identical-by-decent segments, etc., can be performed flexibly. Diverse annotations for the family genome variants, such as dbSNP memberships, linkage disequilibriums, genes, variant effects, potential phenotypes, etc., are illustrated as well. Moreover, the FGB can automatically search de novo mutations and compound heterozygous variants for a selected individual, and guide investigators to find high-risk genes with flexible navigation options. These features enable users to investigate and understand family genomes intuitively and systematically. The FGB is available at http://mlg.hit.edu.cn/FGB/. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Investigating the inheritance of prolapsed nictitating membrane glands in a large canine pedigree

PubMed Central

Edelmann, Michele L.; Miyadera, Keiko; Iwabe, Simone; Komáromy, András M.

2014-01-01

Objective To investigate the inheritance of prolapsed nictitating membrane glands (PNMG) in a large pedigree of purpose-bred mongrel dogs. Animals studied Two lines of purpose-bred mongrel dogs kept at a research facility with controlled environment were analyzed for frequent occurrences of PNMG. The first line (GS line) consisted of 201 dogs, derived from one German shorthaired pointer and seven mongrel dogs. The second line (M line) was established from one mongrel dog and three miniature longhaired dachshund (MLHD) dogs followed by closed breeding practice (n = 50). The two canine lines were connected by a female dog, which contributed genetically to both lines. Procedures Medical records of all dogs were reviewed retrospectively for signalment, parental data, and the presence of PNMG. Pedigrees were constructed to facilitate assessment of inheritance. Results The overall prevalence of PNMG in the GS line was 4.0% (8/201) over a 12-year period. The prevalence in the M line was 10.0% (5/50) over 6 years, which increased to 23.1% (3/13) when only dogs aged 2 years or older were considered. Analysis of the pedigrees ruled out simple modes of Mendelian inheritance in both canine lines. Conclusion The high prevalence of PNMG in two canine lines bred and maintained under a strictly controlled environment supported the involvement of genetic risk factors. The mode of inheritance remains to be determined, but it appears to be complex and potentially multigenic. PMID:23240682

Methods to estimate effective population size using pedigree data: Examples in dog, sheep, cattle and horse

PubMed Central

2013-01-01

Background Effective population sizes of 140 populations (including 60 dog breeds, 40 sheep breeds, 20 cattle breeds and 20 horse breeds) were computed using pedigree information and six different computation methods. Simple demographical information (number of breeding males and females), variance of progeny size, or evolution of identity by descent probabilities based on coancestry or inbreeding were used as well as identity by descent rate between two successive generations or individual identity by descent rate. Results Depending on breed and method, effective population sizes ranged from 15 to 133 056, computation method and interaction between computation method and species showing a significant effect on effective population size (P < 0.0001). On average, methods based on number of breeding males and females and variance of progeny size produced larger values (4425 and 356, respectively), than those based on identity by descent probabilities (average values between 93 and 203). Since breeding practices and genetic substructure within dog breeds increased inbreeding, methods taking into account the evolution of inbreeding produced lower effective population sizes than those taking into account evolution of coancestry. The correlation level between the simplest method (number of breeding males and females, requiring no genealogical information) and the most sophisticated one ranged from 0.44 to 0.60 according to species. Conclusions When choosing a method to compute effective population size, particular attention should be paid to the species and the specific genetic structure of the population studied. PMID:23281913

Registration of Warhorse wheat

USDA-ARS?s Scientific Manuscript database

'Warhorse' (Reg. No. CV-1096, PI 670157) hard red winter (HRW) wheat (Triticum aestivum L.) was developed and released by the Montana Agricultural Experiment Station in September 2013. Warhorse is of unknown pedigree, derived from a composite of three topcrosses made to the same F1 population in 200...

A comparative genetic analysis of the Irish greyhound population using multilocus DNA fingerprinting, canine single locus minisatellites and canine microsatellites.

PubMed

Sutton, M D; Holmes, N G; Brennan, F B; Binns, M M; Kelly, E P; Duke, E J

1998-06-01

Pairwise analysis of HinfI/33.6 DNA fingerprints from a total of one hundred and fifty-three Irish greyhounds of known pedigree were used to determine band-share estimates of unrelated, first-degree and second-degree relationships. Forty-eight unrelated Irish greyhounds were used to determine allele frequencies for three single-locus minisatellites, and following a preliminary screen, eight of the most polymorphic tetra-nucleotide microsatellites from a panel of 15. The results indicated that both band-share estimates by DNA fingerprinting and microsatellite allele frequencies are highly effective in resolving parentage in this greyhound population, while single-locus minisatellites showed limited polymorphism and could not be used alone for routine parentage testing in this breed. The present study also demonstrated that, to obtain optimal resolution of parentage, sample sets of known pedigree status are required to determine the band-share distribution and/or microsatellite allele frequencies.

Unraveling additive from nonadditive effects using genomic relationship matrices.

PubMed

Muñoz, Patricio R; Resende, Marcio F R; Gezan, Salvador A; Resende, Marcos Deon Vilela; de Los Campos, Gustavo; Kirst, Matias; Huber, Dudley; Peter, Gary F

2014-12-01

The application of quantitative genetics in plant and animal breeding has largely focused on additive models, which may also capture dominance and epistatic effects. Partitioning genetic variance into its additive and nonadditive components using pedigree-based models (P-genomic best linear unbiased predictor) (P-BLUP) is difficult with most commonly available family structures. However, the availability of dense panels of molecular markers makes possible the use of additive- and dominance-realized genomic relationships for the estimation of variance components and the prediction of genetic values (G-BLUP). We evaluated height data from a multifamily population of the tree species Pinus taeda with a systematic series of models accounting for additive, dominance, and first-order epistatic interactions (additive by additive, dominance by dominance, and additive by dominance), using either pedigree- or marker-based information. We show that, compared with the pedigree, use of realized genomic relationships in marker-based models yields a substantially more precise separation of additive and nonadditive components of genetic variance. We conclude that the marker-based relationship matrices in a model including additive and nonadditive effects performed better, improving breeding value prediction. Moreover, our results suggest that, for tree height in this population, the additive and nonadditive components of genetic variance are similar in magnitude. This novel result improves our current understanding of the genetic control and architecture of a quantitative trait and should be considered when developing breeding strategies. Copyright © 2014 by the Genetics Society of America.

Recovery of Native Genetic Background in Admixed Populations Using Haplotypes, Phenotypes, and Pedigree Information – Using Cika Cattle as a Case Breed

PubMed Central

Simčič, Mojca; Smetko, Anamarija; Sölkner, Johann; Seichter, Doris; Gorjanc, Gregor; Kompan, Dragomir; Medugorac, Ivica

2015-01-01

The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had direct or indirect historical contribution to the genetic makeup of the breed of interest. PMID:25923207

Congenital vestibular disease in captive Sumatran tigers (Panthera tigris ssp. sumatrae) in Australasia.

PubMed

Wheelhouse, Jaimee L; Hulst, Frances; Beatty, Julia A; Hogg, Carolyn J; Child, Georgina; Wade, Claire M; Barrs, Vanessa R

2015-11-01

The Sumatran tiger (Panthera tigris ssp. sumatrae) is a critically endangered species in the wild. To ensure that demographic and genetic integrity are maintained in the longer term, those Sumatran tigers held in captivity are managed as a global population under a World Association of Zoos and Aquariums Global Species Management Plan (GSMP). A retrospective study, including segregation and pedigree analysis, was conducted to investigate potential cases of congenital vestibular disease (CVD) in captive Sumatran tigers in Australasian zoos using medical and husbandry records, as well as video footage obtained from 50 tigers between 1975 and 2013. Data from the GSMP Sumatran tiger studbook were made available for pedigree and segregation analysis. Fourteen cases of CVD in 13 Sumatran tiger cubs and one hybrid cub (Panthera tigris ssp. sumatrae × Panthera tigris) were identified. Vestibular signs including head tilt, circling, ataxia, strabismus and nystagmus were observed between birth and 2 months of age. These clinical signs persisted for a median of 237 days and had resolved by 2 years of age in all cases. Pedigree analysis revealed that all affected tigers were closely related and shared a single common ancestor in the last four generations. A genetic cause for the disease is suspected and, based on pedigree and segregation analysis, an autosomal dominant mode of inheritance is likely. Further investigations to determine the world-wide prevalence and underlying pathology of this disorder are warranted. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Role of Probability-Based Inference in an Intelligent Tutoring System.

ERIC Educational Resources Information Center

Mislevy, Robert J.; Gitomer, Drew H.

Probability-based inference in complex networks of interdependent variables is an active topic in statistical research, spurred by such diverse applications as forecasting, pedigree analysis, troubleshooting, and medical diagnosis. This paper concerns the role of Bayesian inference networks for updating student models in intelligent tutoring…

Evaluation of a functional variant assay for selecting beef cattle

USDA-ARS?s Scientific Manuscript database

A commercially available genotyping assay for functional variants was chosen to obtain genotypes needed for a selection experiment in populations of pedigreed cattle that have not been extensively genotyped. The assay design included probes for coding sequence variation in 88% of annotated protein c...

Traces of medieval migrations in a socially stratified population from Northern Italy. Evidence from uniparental markers and deep-rooted pedigrees

PubMed Central

Boattini, A; Sarno, S; Pedrini, P; Medoro, C; Carta, M; Tucci, S; Ferri, G; Alù, M; Luiselli, D; Pettener, D

2015-01-01

Social and cultural factors had a critical role in determining the genetic structure of Europe. Therefore, socially stratified populations may help to focus on specific episodes of European demographic history. In this study, we use uniparental markers to analyse the genetic structure of Partecipanza in San Giovanni in Persiceto (Northern Italy), a peculiar institution whose origins date back to the Middle Ages and whose members form the patrilineal descent of a group of founder families. From a maternal point of view (mtDNA), Partecipanza is genetically homogeneous with the rest of the population. However, we observed a significant differentiation for Y-chromosomes. In addition, by comparing 17 Y-STR profiles with deep-rooted paternal pedigrees, we estimated a Y-STR mutation rate equal to 3.90 * 10−3 mutations per STR per generation and an average generation duration time of 33.38 years. When we used these values for tentative dating, we estimated 1300-600 years ago for the origins of the Partecipanza. These results, together with a peculiar Y-chromosomal composition and historical evidence, suggest that Germanic populations (Lombards in particular) settled in the area during the Migration Period (400–800 AD, approximately) and may have had an important role in the foundation of this community. PMID:25204305

Traces of medieval migrations in a socially stratified population from Northern Italy. Evidence from uniparental markers and deep-rooted pedigrees.

PubMed

Boattini, A; Sarno, S; Pedrini, P; Medoro, C; Carta, M; Tucci, S; Ferri, G; Alù, M; Luiselli, D; Pettener, D

2015-02-01

Social and cultural factors had a critical role in determining the genetic structure of Europe. Therefore, socially stratified populations may help to focus on specific episodes of European demographic history. In this study, we use uniparental markers to analyse the genetic structure of Partecipanza in San Giovanni in Persiceto (Northern Italy), a peculiar institution whose origins date back to the Middle Ages and whose members form the patrilineal descent of a group of founder families. From a maternal point of view (mtDNA), Partecipanza is genetically homogeneous with the rest of the population. However, we observed a significant differentiation for Y-chromosomes. In addition, by comparing 17 Y-STR profiles with deep-rooted paternal pedigrees, we estimated a Y-STR mutation rate equal to 3.90 * 10(-3) mutations per STR per generation and an average generation duration time of 33.38 years. When we used these values for tentative dating, we estimated 1300-600 years ago for the origins of the Partecipanza. These results, together with a peculiar Y-chromosomal composition and historical evidence, suggest that Germanic populations (Lombards in particular) settled in the area during the Migration Period (400-800 AD, approximately) and may have had an important role in the foundation of this community.

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

Comparing estimates of genetic variance across different relationship models.

PubMed

Legarra, Andres

2016-02-01

Use of relationships between individuals to estimate genetic variances and heritabilities via mixed models is standard practice in human, plant and livestock genetics. Different models or information for relationships may give different estimates of genetic variances. However, comparing these estimates across different relationship models is not straightforward as the implied base populations differ between relationship models. In this work, I present a method to compare estimates of variance components across different relationship models. I suggest referring genetic variances obtained using different relationship models to the same reference population, usually a set of individuals in the population. Expected genetic variance of this population is the estimated variance component from the mixed model times a statistic, Dk, which is the average self-relationship minus the average (self- and across-) relationship. For most typical models of relationships, Dk is close to 1. However, this is not true for very deep pedigrees, for identity-by-state relationships, or for non-parametric kernels, which tend to overestimate the genetic variance and the heritability. Using mice data, I show that heritabilities from identity-by-state and kernel-based relationships are overestimated. Weighting these estimates by Dk scales them to a base comparable to genomic or pedigree relationships, avoiding wrong comparisons, for instance, "missing heritabilities". Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of linkage analysis methods for genome-wide scanning of extended pedigrees, with application to the TG/HDL-C ratio in the Framingham Heart Study

PubMed Central

Horne, Benjamin D; Malhotra, Alka; Camp, Nicola J

2003-01-01

Background High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) jointly increase coronary disease risk. We performed linkage analysis for TG/HDL-C ratio in the Framingham Heart Study data as a quantitative trait, using methods implemented in LINKAGE, GENEHUNTER (GH), MCLINK, and SOLAR. Results were compared to each other and to those from a previous evaluation using SOLAR for TG/HDL-C ratio on this sample. We also investigated linked pedigrees in each region using by-pedigree analysis. Results Fourteen regions with at least suggestive linkage evidence were identified, including some that may increase and some that may decrease coronary risk. Ten of the 14 regions were identified by more than one analysis, and several of these regions were not previously detected. The best regions identified for each method were on chromosomes 2 (LOD = 2.29, MCLINK), 5 (LOD = 2.65, GH), 7 (LOD = 2.67, SOLAR), and 22 (LOD = 3.37, LINKAGE). By-pedigree multi-point LOD values in MCLINK showed linked pedigrees for all five regions, ranging from 3 linked pedigrees (chromosome 5) to 14 linked pedigrees (chromosome 7), and suggested localizations of between 9 cM and 27 cM in size. Conclusion Reasonable concordance was found across analysis methods. No single method identified all regions, either by full sample LOD or with by-pedigree analysis. Concordance across methods appeared better at the pedigree level, with many regions showing by-pedigree support in MCLINK when no evidence was observed in the full sample. Thus, investigating by-pedigree linkage evidence may provide a useful tool for evaluating linkage regions. PMID:14975161

Comparison of linkage analysis methods for genome-wide scanning of extended pedigrees, with application to the TG/HDL-C ratio in the Framingham Heart Study.

PubMed

Horne, Benjamin D; Malhotra, Alka; Camp, Nicola J

2003-12-31

High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) jointly increase coronary disease risk. We performed linkage analysis for TG/HDL-C ratio in the Framingham Heart Study data as a quantitative trait, using methods implemented in LINKAGE, GENEHUNTER (GH), MCLINK, and SOLAR. Results were compared to each other and to those from a previous evaluation using SOLAR for TG/HDL-C ratio on this sample. We also investigated linked pedigrees in each region using by-pedigree analysis. Fourteen regions with at least suggestive linkage evidence were identified, including some that may increase and some that may decrease coronary risk. Ten of the 14 regions were identified by more than one analysis, and several of these regions were not previously detected. The best regions identified for each method were on chromosomes 2 (LOD = 2.29, MCLINK), 5 (LOD = 2.65, GH), 7 (LOD = 2.67, SOLAR), and 22 (LOD = 3.37, LINKAGE). By-pedigree multi-point LOD values in MCLINK showed linked pedigrees for all five regions, ranging from 3 linked pedigrees (chromosome 5) to 14 linked pedigrees (chromosome 7), and suggested localizations of between 9 cM and 27 cM in size. Reasonable concordance was found across analysis methods. No single method identified all regions, either by full sample LOD or with by-pedigree analysis. Concordance across methods appeared better at the pedigree level, with many regions showing by-pedigree support in MCLINK when no evidence was observed in the full sample. Thus, investigating by-pedigree linkage evidence may provide a useful tool for evaluating linkage regions.

VIPER: a visualisation tool for exploring inheritance inconsistencies in genotyped pedigrees

PubMed Central

2012-01-01

Background Pedigree genotype datasets are used for analysing genetic inheritance and to map genetic markers and traits. Such datasets consist of hundreds of related animals genotyped for thousands of genetic markers and invariably contain multiple errors in both the pedigree structure and in the associated individual genotype data. These errors manifest as apparent inheritance inconsistencies in the pedigree, and invalidate analyses of marker inheritance patterns across the dataset. Cleaning raw datasets of bad data points (incorrect pedigree relationships, unreliable marker assays, suspect samples, bad genotype results etc.) requires expert exploration of the patterns of exposed inconsistencies in the context of the inheritance pedigree. In order to assist this process we are developing VIPER (Visual Pedigree Explorer), a software tool that integrates an inheritance-checking algorithm with a novel space-efficient pedigree visualisation, so that reported inheritance inconsistencies are overlaid on an interactive, navigable representation of the pedigree structure. Methods and results This paper describes an evaluation of how VIPER displays the different scales and types of dataset that occur experimentally, with a description of how VIPER's display interface and functionality meet the challenges presented by such data. We examine a range of possible error types found in real and simulated pedigree genotype datasets, demonstrating how these errors are exposed and explored using the VIPER interface and we evaluate the utility and usability of the interface to the domain expert. Evaluation was performed as a two stage process with the assistance of domain experts (geneticists). The initial evaluation drove the iterative implementation of further features in the software prototype, as required by the users, prior to a final functional evaluation of the pedigree display for exploring the various error types, data scales and structures. Conclusions The VIPER display was shown to effectively expose the range of errors found in experimental genotyped pedigrees, allowing users to explore the underlying causes of reported inheritance inconsistencies. This interface will provide the basis for a full data cleaning tool that will allow the user to remove isolated bad data points, and reversibly test the effect of removing suspect genotypes and pedigree relationships. PMID:22607476

Localization of a Susceptibility Gene for Familial Nonmedullary Thyroid Carcinoma to Chromosome 2q21

PubMed Central

McKay, James D.; Lesueur, Fabienne; Jonard, Laurence; Pastore, Alessandro; Williamson, Jan; Hoffman, Linda; Burgess, John; Duffield, Anne; Papotti, Mauro; Stark, Markus; Sobol, Hagay; Maes, Béatrice; Murat, Arnaud; Kääriäinen, Helena; Bertholon-Grégoire, Mireille; Zini, Michele; Rossing, Mary Anne; Toubert, Marie-Elisabeth; Bonichon, Françoise; Cavarec, Marie; Bernard, Anne-Marie; Boneu, Andrée; Leprat, Frédéric; Haas, Oskar; Lasset, Christine; Schlumberger, Martin; Canzian, Federico; Goldgar, David E.; Romeo, Giovanni

2001-01-01

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (α=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (α=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21. PMID:11438887

Genetical Genomics Identifies the Genetic Architecture for Growth and Weevil Resistance in Spruce

PubMed Central

Porth, Ilga; White, Richard; Jaquish, Barry; Alfaro, René; Ritland, Carol; Ritland, Kermit

2012-01-01

In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. PMID:22973444

[Establishment of immortal lymphoblastoid cell bank of keloids pedigree].

PubMed

Song, Mei; Gao, Jian-hua; Yan, Xin; Liu, Xiao-jun; Chen, Yang

2006-11-01

To provide perpetual research materials for long term studies by establishing immortal lymphoblastoid cell bank of keloids pedigree. The immortal lymphoblastoid cell lines of keloids pedigree were established by Epstein-Barr virus transformation of peripheral blood B lymphocytes. 27 immortal lymphoblastoid cell lines of keloids pedigree were obtained successfully, all of the immortal lymphoblastoid cell lines were successfully revivificated after been frozen in liquid nitrogen. It is important to establish immortal lymphoblastoid cell bank of keloids pedigree and provide long-term DNA materials for deep study of keloids in the future.

An improved 10-SSR pyrus fingerprinting DNA test to confirm parentage [abstract

USDA-ARS?s Scientific Manuscript database

Pedigree confirmation is a critical part of breeding, managing genetic resources, and developing genetic mapping populations for out-crossing plants, such as the genus Pyrus. Individuals which are not progeny of a biparental cross can cause mapping errors or result in the costly genotyping of indivi...

Breeding black walnuts in the age of genomics

Treesearch

Mark V. Coggeshall; Jeanne Romero-Severson

2013-01-01

Molecular markers have been used in several walnut species to help reconstruct breeding program pedigrees, to characterize genetic structure in natural Juglans populations, to determine the impact of different timber harvest scenarios on residual levels of genetic diversity, and to quantify the effects of interspecific hybridization on subsequent...

Impact of Line 1 on the South African Hereford Population

USDA-ARS?s Scientific Manuscript database

The goal of this research was to document the influence of Line 1 Hereford cattle, developed by the United States Department of Agriculture (USDA) at its research facility in Miles City, Montana, on Hereford cattle in South Africa. Analytical approaches made use of both recorded pedigree and microsa...

A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population.

PubMed

Liu, Fan; Arias-Vásquez, Alejandro; Sleegers, Kristel; Aulchenko, Yurii S; Kayser, Manfred; Sanchez-Juan, Pascual; Feng, Bing-Jian; Bertoli-Avella, Aida M; van Swieten, John; Axenovich, Tatiana I; Heutink, Peter; van Broeckhoven, Christine; Oostra, Ben A; van Duijn, Cornelia M

2007-07-01

Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes.

Is my study system good enough? A case study for identifying maternal effects.

PubMed

Holand, Anna Marie; Steinsland, Ingelin

2016-06-01

In this paper, we demonstrate how simulation studies can be used to answer questions about identifiability and consequences of omitting effects from a model. The methodology is presented through a case study where identifiability of genetic and/or individual (environmental) maternal effects is explored. Our study system is a wild house sparrow ( Passer domesticus ) population with known pedigree. We fit pedigree-based (generalized) linear mixed models (animal models), with and without additive genetic and individual maternal effects, and use deviance information criterion (DIC) for choosing between these models. Pedigree and R-code for simulations are available. For this study system, the simulation studies show that only large maternal effects can be identified. The genetic maternal effect (and similar for individual maternal effect) has to be at least half of the total genetic variance to be identified. The consequences of omitting a maternal effect when it is present are explored. Our results indicate that the total (genetic and individual) variance are accounted for. When an individual (environmental) maternal effect is omitted from the model, this only influences the estimated (direct) individual (environmental) variance. When a genetic maternal effect is omitted from the model, both (direct) genetic and (direct) individual variance estimates are overestimated.

Completeness of pedigree and family cancer history for ovarian cancer patients.

PubMed

Son, Yedong; Lim, Myong Cheol; Seo, Sang Soo; Kang, Sokbom; Park, Sang Yoon

2014-10-01

To investigate the completeness of pedigree and of number of pedigree analysis to know the acceptable familial history in Korean women with ovarian cancer. Interview was conducted in 50 ovarian cancer patients for obtaining familial history three times over the 6 weeks. The completeness of pedigree is estimated in terms of familial history of disease (cancer), health status (health living, disease and death), and onset age of disease and death. The completion of pedigree was 79.3, 85.1, and 85.6% at the 1st, 2nd, and 3rd time of interview and the time for pedigree analysis was 34.3, 10.8, and 3.1 minutes, respectively. The factors limiting pedigree analysis were as follows: out of contact with their relatives (38%), no living ancestors who know the family history (34%), dispersed family member because of the Korean War (16%), unknown cause of death (12%), reluctance to ask medical history of relatives (10%), and concealing their ovarian cancer (10%). The percentage of cancers revealed in 1st (2%) and 2nd degree (8%) relatives were increasing through surveys, especially colorectal cancer related with Lynch syndrome (4%). Analysis of pedigree at least two times is acceptable in Korean woman with ovarian cancer from the first study. The completion of pedigree is increasing, while time to take family history is decreasing during three time survey.

Accommodating Chromosome Inversions in Linkage Analysis

PubMed Central

Chen, Gary K.; Slaten, Erin; Ophoff, Roel A.; Lange, Kenneth

2006-01-01

This work develops a population-genetics model for polymorphic chromosome inversions. The model precisely describes how an inversion changes the nature of and approach to linkage equilibrium. The work also describes algorithms and software for allele-frequency estimation and linkage analysis in the presence of an inversion. The linkage algorithms implemented in the software package Mendel estimate recombination parameters and calculate the posterior probability that each pedigree member carries the inversion. Application of Mendel to eight Centre d'Étude du Polymorphisme Humain pedigrees in a region containing a common inversion on 8p23 illustrates its potential for providing more-precise estimates of the location of an unmapped marker or trait gene. Our expanded cytogenetic analysis of these families further identifies inversion carriers and increases the evidence of linkage. PMID:16826515

Probabilistic expert systems for forensic inference from DNA markers in horses: applications to confirm genealogies with lack of genetic data.

PubMed

Dobosz, Marina; Bocci, Chiara; Bonuglia, Margherita; Grasso, Cinzia; Merigioli, Sara; Russo, Alessandra; De Iuliis, Paolo

2010-01-01

Microsatellites have been used for parentage testing and individual identification in forensic science because they are highly polymorphic and show abundant sequences dispersed throughout most eukaryotic nuclear genomes. At present, genetic testing based on DNA technology is used for most domesticated animals, including horses, to confirm identity, to determine parentage, and to validate registration certificates. But if genetic data of one of the putative parents are missing, verifying a genealogy could be questionable. The aim of this paper is to illustrate a new approach to analyze complex cases of disputed relationship with microsatellites markers. These cases were solved by analyzing the genotypes of the offspring and other horses' genotypes in the pedigrees of the putative dam/sire with probabilistic expert systems (PESs). PES was especially efficient in supplying reliable, error-free Bayesian probabilities in complex cases with missing pedigree data. One of these systems was developed for forensic purposes (FINEX program) and is particularly valuable in human analyses. We applied this program to parentage analysis in horses, and we will illustrate how different cases have been successfully worked out.

Sensitivity of lod scores to changes in diagnostic status.

PubMed Central

Hodge, S E; Greenberg, D A

1992-01-01

This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a single offspring in a nuclear family changes status. The nuclear-family situation, in addition to being of interest in its own right, also has general theoretical importance, since nuclear families are "transparent"; that is, one can track genetic events more precisely in nuclear families than in complex pedigrees. We demonstrate that in nuclear families log10 [(1-theta)/theta] gives an upper limit on the impact that a single offspring's change in status can have on the lod score at that recombination fraction (theta). These limits hold for a fully penetrant dominant condition and fully informative marker, in either phase-known or phase-unknown matings. Moreover, log10 [(1-theta)/theta] (where theta denotes the value of theta at which Zmax occurs) gives an upper limit on the impact of a single offspring's status change on the maximum lod score (Zmax). In extended pedigrees, in contrast to nuclear families, no comparable limit can be set on the impact of a single individual on the lod score. Complex pedigrees are subject to both stabilizing and destabilizing influences, and these are described. Finally, we describe a "sensitivity analysis," in which, after all linkage analysis is completed, every informative individual in the data set is changed, one at a time, to see the effect which each separate change has on the lod scores. The procedure includes identifying "critical individuals," i.e., those who would have the greatest impact on the lod scores, should their diagnostic status in fact change. To illustrate use of the sensitivity analysis, we apply it to the large bipolar pedigree reported by Egeland et al. and Kelsoe et al. We show that the changes in lod scores observed there, on the order of 1.1-1.2 per person, are not unusual. We recommend that investigators include a sensitivity analysis as a standard part of reporting the results of a linkage analysis. PMID:1570835

Sensitivity of lod scores to changes in diagnostic status.

PubMed

Hodge, S E; Greenberg, D A

1992-05-01

This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a single offspring in a nuclear family changes status. The nuclear-family situation, in addition to being of interest in its own right, also has general theoretical importance, since nuclear families are "transparent"; that is, one can track genetic events more precisely in nuclear families than in complex pedigrees. We demonstrate that in nuclear families log10 [(1-theta)/theta] gives an upper limit on the impact that a single offspring's change in status can have on the lod score at that recombination fraction (theta). These limits hold for a fully penetrant dominant condition and fully informative marker, in either phase-known or phase-unknown matings. Moreover, log10 [(1-theta)/theta] (where theta denotes the value of theta at which Zmax occurs) gives an upper limit on the impact of a single offspring's status change on the maximum lod score (Zmax). In extended pedigrees, in contrast to nuclear families, no comparable limit can be set on the impact of a single individual on the lod score. Complex pedigrees are subject to both stabilizing and destabilizing influences, and these are described. Finally, we describe a "sensitivity analysis," in which, after all linkage analysis is completed, every informative individual in the data set is changed, one at a time, to see the effect which each separate change has on the lod scores. The procedure includes identifying "critical individuals," i.e., those who would have the greatest impact on the lod scores, should their diagnostic status in fact change. To illustrate use of the sensitivity analysis, we apply it to the large bipolar pedigree reported by Egeland et al. and Kelsoe et al. We show that the changes in lod scores observed there, on the order of 1.1-1.2 per person, are not unusual. We recommend that investigators include a sensitivity analysis as a standard part of reporting the results of a linkage analysis.

Candidate genes for COPD in two large data sets.

PubMed

Bakke, P S; Zhu, G; Gulsvik, A; Kong, X; Agusti, A G N; Calverley, P M A; Donner, C F; Levy, R D; Make, B J; Paré, P D; Rennard, S I; Vestbo, J; Wouters, E F M; Anderson, W; Lomas, D A; Silverman, E K; Pillai, S G

2011-02-01

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV₁) % predicted and FEV₁/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV₁ % predicted and FEV₁/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

A pedigree-based proxy measure of genetic predisposition of drinking and alcohol use among female sex workers in China: a cross-sectional study.

PubMed

Zhang, Chen; Li, Xiaoming; Liu, Yu; Qiao, Shan; Su, Shaobing; Zhang, Liying; Zhou, Yuejiao

2017-02-01

Scientific evidence has suggested that genetic factors accounted for more than half of the vulnerability of developing alcohol use problems. However, collecting genetic data poses a significant challenge for most population-based behavioral studies. The aim of this study was to assess the utilities of a pedigree-based proxy measure of genetic predisposition of drinking (GPD) and its effect on alcohol use behaviors as well as its interactions with personal and environmental factors. In the current study, cross-sectional data were collected from 700 female sex workers (FSW) in Guangxi, China. Participants provided information on a pedigree-based proxy measure of GPD and their alcohol use behaviors. Chi-square and independent t-test was applied for examining the bivariate associations between GPD and alcohol use behaviors; multivariate and ordinal regression models were used to examine the effect of GPD on alcohol use. This study found that women with a higher composite score of GPD tended to have a higher risk of alcohol use problem compared to their counterparts (p < .05). GPD was a significant predictor of alcohol use problems (p < .05), especially among women who had mental health issues or lack of health cares. The pedigree-based measure provided a useful proxy of GPD among participants. Both FSW's mental health and health care access interact with GPD and affect their drinking patterns. By understanding the genetic basis of alcohol use, we can develop scalable and efficacious interventions that will take into consideration the individual risk profile and environmental influences.

Multitrait, Random Regression, or Simple Repeatability Model in High-Throughput Phenotyping Data Improve Genomic Prediction for Wheat Grain Yield.

PubMed

Sun, Jin; Rutkoski, Jessica E; Poland, Jesse A; Crossa, José; Jannink, Jean-Luc; Sorrells, Mark E

2017-07-01

High-throughput phenotyping (HTP) platforms can be used to measure traits that are genetically correlated with wheat ( L.) grain yield across time. Incorporating such secondary traits in the multivariate pedigree and genomic prediction models would be desirable to improve indirect selection for grain yield. In this study, we evaluated three statistical models, simple repeatability (SR), multitrait (MT), and random regression (RR), for the longitudinal data of secondary traits and compared the impact of the proposed models for secondary traits on their predictive abilities for grain yield. Grain yield and secondary traits, canopy temperature (CT) and normalized difference vegetation index (NDVI), were collected in five diverse environments for 557 wheat lines with available pedigree and genomic information. A two-stage analysis was applied for pedigree and genomic selection (GS). First, secondary traits were fitted by SR, MT, or RR models, separately, within each environment. Then, best linear unbiased predictions (BLUPs) of secondary traits from the above models were used in the multivariate prediction models to compare predictive abilities for grain yield. Predictive ability was substantially improved by 70%, on average, from multivariate pedigree and genomic models when including secondary traits in both training and test populations. Additionally, (i) predictive abilities slightly varied for MT, RR, or SR models in this data set, (ii) results indicated that including BLUPs of secondary traits from the MT model was the best in severe drought, and (iii) the RR model was slightly better than SR and MT models under drought environment. Copyright © 2017 Crop Science Society of America.

Disaster victim investigation recommendations from two simulated mass disaster scenarios utilized for user acceptance testing CODIS 6.0.

PubMed

Bradford, Laurie; Heal, Jennifer; Anderson, Jeff; Faragher, Nichole; Duval, Kristin; Lalonde, Sylvain

2011-08-01

Members of the National DNA Data Bank (NDDB) of Canada designed and searched two simulated mass disaster (MD) scenarios for User Acceptance Testing (UAT) of the Combined DNA Index System (CODIS) 6.0, developed by the Federal Bureau of Investigation (FBI) and the US Department of Justice. A simulated airplane MD and inland Tsunami MD were designed representing a closed and open environment respectively. An in-house software program was written to randomly generate DNA profiles from a mock Caucasian population database. As part of the UAT, these two MDs were searched separately using CODIS 6.0. The new options available for identity and pedigree searching in addition to the inclusion of mitochondrial DNA (mtDNA) and Y-STR (short tandem repeat) information in CODIS 6.0, led to rapid identification of all victims. A Joint Pedigree Likelihood Ratio (JPLR) was calculated from the pedigree searches and ranks were stored in Rank Manager providing confidence to the user in assigning an Unidentified Human Remain (UHR) to a pedigree tree. Analyses of the results indicated that primary relatives were more useful in Disaster Victim Identification (DVI) compared to secondary or tertiary relatives and that inclusion of mtDNA and/or Y-STR technologies helped to link family units together as shown by the software searches. It is recommended that UHRs have as many informative loci possible to assist with their identification. CODIS 6.0 is a valuable technological tool for rapidly and confidently identifying victims of mass disasters. Crown Copyright © 2010. Published by Elsevier Ireland Ltd. All rights reserved.

Pedigree construction and disease confirmation: a pilot study in Wales exploring the role of nonclinical personnel.

PubMed

Tempest, Vanessa; Iredale, Rachel; Gray, Jonathon; France, Liz; Anstey, Sally; Steward, John

2005-09-01

Pedigree construction and disease confirmation are the means by which reported family histories are translated into a verified clinical tool informing risk assessment and management decisions by clinical genetics staff. In this study, we hypothesised that pedigree generation data processes do not generally require the clinical expertise of genetic counsellors and that they could be successfully transferred to nonclinical data administrators. We made a pragmatic comparison of two processes of pedigree generation by different personnel from 14 consecutive family history questionnaires containing 88 living and decease affected individuals. The pedigrees generated by the genetic counsellor and the data administrator were compared; discrepancies were quantified and their source determined. The information gathered by the data administrator mirrored that of the genetic counsellors in 89% of cases. Time was saved by permitting direct access to cancer registry and local oncology centre databases. Constructing a pedigree is not always a case of transferring clear-cut data. Decisions need to be made about which cancers to confirm. Notable differences emerged in the number of pieces of information not transferred. Ambiguous information was often interpreted differently, suggesting the need for clinical staff to review pedigrees after their initial plotting by the data administrator. This study demonstrates a good degree of concordance between pedigrees constructed by a nonclinical data administrator and those of experienced genetic counsellors. However, the redirection of all pedigree activity to nonclinical personnel up to the point of risk review is not possible at present.

A mitochondrial DNA (mtDNA) mutation associated with maternally inherited Parkinson`s disease (PD) and deafness

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

Shoffner, J.M.; Brown, M.; Huoponen, K.

1994-09-01

A pedigree was characterized in which PD and deafness is expressed along the maternal lineage. The proband is 74 years old and has PD. Her mother and 3 of 7 siblings have PD and a maternal lineage cousin may have early signs of PD. The proband`s mother, a sibling, and all four of her daughters have premature deafness. Since manifestations of PD begin after 50 years of age, the 30-40 year old daughters have not reached an age where extrapyramidal symptoms are likely to appear. Although all 4 daughters have premature deafness, one daughter experienced a rapid reduction of hermore » hearing after receiving a short course during childhood of the aminoglycoside streptomycin. Muscle biopsies from the proband who has PD and 3 daughters with deafness revealed normal histology. Oxidative phosphorylation biochemistry showed Complex I and IV defects in the proband and 2 daughters and a Complex I defect in the other daughter. The proband`s mtDNA was sequenced. Of the nucleotide variants observed, the only significant nucleotide change was a homoplasmic A-to-G point mutation in the 12S rRNA gene at position 1555 of the mtDNA. This site is homologous to the E. coli aminoglycoside binding site and has been found in a large Arab-Israeli pedigree with spontaneously occurring deafness and three Chinese pedigrees with aminoglycoside-induced deafness. Hence, this family shows a direct link between PD, deafness, Complex I and IV defects, and a mutation in a gene that functions in mitochondrial protein synthesis. Furthermore, the interaction between aminoglycosides and the mtDNA in a manner that augments the pathogenic effects of this mutation provides an excellent example of how environmental toxins and mtDNA mutations can interact to give a spectrum of clinical presentations.« less

Mapping by admixture linkage disequilibrium in human populations: Limits and guidelines

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

Stephens, J.C.; Briscoe, D.; O`Brien, S.J.

1994-10-01

Certain human hereditary conditions, notably those with low penetrance and those which require an environmental event such as infectious disease exposure, are difficult to localize in pedigree analysis, because of uncertainty in the phenotype of an affected patient`s relatives. An approach to locating these genes in human cohort studies would be to use association analysis, which depends on linkage disequilibrium of flanking polymorphic DNA markers. In theory, a high degree of linkage disequilibrium between genes separated by 10-20 cM will be generated and persist in populations that have a history of recent (3-20 generations ago) admixture between genetically differentiated racialmore » groups, such as has occurred in African Americans and Hispanic populations. We have conducted analytic and computer simulations to quantify the effect of genetic, genomic, and population parameters that affect the amount and ascertainment of linkage disequilibrium in populations with a history of genetic admixture. Our goal is to thoroughly explore the ranges of all relevant parameters or factors (e.g., sample size and degree of genetic differentiation between populations) that may be involved in gene localization studies, in hopes of prescribing guidelines for an efficient mapping strategy. The results provide reasonable limits on sample size (200-300 patients), marker number (200-300 in 20-cM intervals), and allele differentiation (loci with allele frequency difference of {ge}.3 between admixed parent populations) to produce an efficient approach (>95% ascertainment) for locating genes not easily tracked in human pedigrees. 321 refs., 8 figs., 7 tabs.« less

Estimating Kinship in Admixed Populations

PubMed Central

Thornton, Timothy; Tang, Hua; Hoffmann, Thomas J.; Ochs-Balcom, Heather M.; Caan, Bette J.; Risch, Neil

2012-01-01

Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to appropriately account for both pedigree and population structure can lead to spurious association. A number of methods have been proposed for identifying relatives in samples from homogeneous populations. A strong assumption of population homogeneity, however, is often untenable, and many GWASs include samples from structured populations. Here, we consider the problem of estimating relatedness in structured populations with admixed ancestry. We propose a method, REAP (relatedness estimation in admixed populations), for robust estimation of identity by descent (IBD)-sharing probabilities and kinship coefficients in admixed populations. REAP appropriately accounts for population structure and ancestry-related assortative mating by using individual-specific allele frequencies at SNPs that are calculated on the basis of ancestry derived from whole-genome analysis. In simulation studies with related individuals and admixture from highly divergent populations, we demonstrate that REAP gives accurate IBD-sharing probabilities and kinship coefficients. We apply REAP to the Mexican Americans in Los Angeles, California (MXL) population sample of release 3 of phase III of the International Haplotype Map Project; in this sample, we identify third- and fourth-degree relatives who have not previously been reported. We also apply REAP to the African American and Hispanic samples from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe) study, in which hundreds of pairs of cryptically related individuals have been identified. PMID:22748210

Exclusion of linkage between RET and Neuronal Intestinal Dysplasia type B

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

Barone, V.; Yin Luo; Brancolini, V.

1996-03-15

Neuronal Intestinal Dysplasia type B (NID B) is a complex alteration of the enteric nervous system belonging to the group of intestinal dysganglionoses which may involve rectum, colon, and small intestine. Second only to Hirschsprung diseases (HSCR), NID B is one of the most frequent causes of chronic constipation and pseudo-obstructive intestinal dysmotility. Since NID B is often associated with HSCR and point mutations in the RET proto-oncogene have been identified in HSCR patients, we analyzed two NID B pedigrees to investigate if RET mutations might cause also the NID B phenotype. Linkage analysis demonstrated that the NID B locusmore » is not linked to RET in the pedigrees analysed. Further genetic analyses will possibility improve the understanding of the cause and facilitate diagnostic procedures in NID B. 20 refs., 1 fig., 2 tabs.« less

Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation.

PubMed

Elahi, Elahe; Shafaghati, Yousef; Asadi, Sareh; Absalan, Farnaz; Goodarzi, Hani; Gharaii, Nava; Karimi-Nejad, Mohammad Hassan; Shahram, Farhad; Hughes, Anne E

2007-01-01

Familial expansile osteolysis (FEO) is a rare disorder causing bone dysplasia. The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity. An 18-bp duplication in the first exon of the TNFRSF11A gene encoding RANK has been previously identified in four FEO pedigrees. Despite having the identical mutation, phenotypic variations among affected individuals of the same and different pedigrees were noted. Another 18-bp duplication, one base proximal to the duplication previously reported, was subsequently found in two unrelated FEO patients. Finally, mutations overlapping with the mutations found in the FEO pedigrees have been found in ESH and early-onset PDB pedigrees. An Iranian FEO pedigree that contains six affected individuals dispersed in three generations has previously been introduced; here, the clinical features of the proband are reported in greater detail, and the genetic defect of the pedigree is presented. Direct sequencing of the entire coding region and upstream and downstream noncoding regions of TNFRSF11A in her DNA revealed the same 18-bp duplication mutation as previously found in the four FEO pedigrees. Additionally, eight sequence variations as compared to the TNFRSF11A reference sequence were identified, and a haplotype linked to the mutation based on these variations was defined. Although the mutation in the Iranian and four of the previously described FEO pedigrees was the same, haplotypes based on the intragenic SNPs suggest that the mutations do not share a common descent.

Efficient Maximum Likelihood Estimation for Pedigree Data with the Sum-Product Algorithm.

PubMed

Engelhardt, Alexander; Rieger, Anna; Tresch, Achim; Mansmann, Ulrich

2016-01-01

We analyze data sets consisting of pedigrees with age at onset of colorectal cancer (CRC) as phenotype. The occurrence of familial clusters of CRC suggests the existence of a latent, inheritable risk factor. We aimed to compute the probability of a family possessing this risk factor as well as the hazard rate increase for these risk factor carriers. Due to the inheritability of this risk factor, the estimation necessitates a costly marginalization of the likelihood. We propose an improved EM algorithm by applying factor graphs and the sum-product algorithm in the E-step. This reduces the computational complexity from exponential to linear in the number of family members. Our algorithm is as precise as a direct likelihood maximization in a simulation study and a real family study on CRC risk. For 250 simulated families of size 19 and 21, the runtime of our algorithm is faster by a factor of 4 and 29, respectively. On the largest family (23 members) in the real data, our algorithm is 6 times faster. We introduce a flexible and runtime-efficient tool for statistical inference in biomedical event data with latent variables that opens the door for advanced analyses of pedigree data. © 2017 S. Karger AG, Basel.

Invited review: Inbreeding in the genomics era: Inbreeding, inbreeding depression, and management of genomic variability.

PubMed

Howard, Jeremy T; Pryce, Jennie E; Baes, Christine; Maltecca, Christian

2017-08-01

Traditionally, pedigree-based relationship coefficients have been used to manage the inbreeding and degree of inbreeding depression that exists within a population. The widespread incorporation of genomic information in dairy cattle genetic evaluations allows for the opportunity to develop and implement methods to manage populations at the genomic level. As a result, the realized proportion of the genome that 2 individuals share can be more accurately estimated instead of using pedigree information to estimate the expected proportion of shared alleles. Furthermore, genomic information allows genome-wide relationship or inbreeding estimates to be augmented to characterize relationships for specific regions of the genome. Region-specific stretches can be used to more effectively manage areas of low genetic diversity or areas that, when homozygous, result in reduced performance across economically important traits. The use of region-specific metrics should allow breeders to more precisely manage the trade-off between the genetic value of the progeny and undesirable side effects associated with inbreeding. Methods tailored toward more effectively identifying regions affected by inbreeding and their associated use to manage the genome at the herd level, however, still need to be developed. We have reviewed topics related to inbreeding, measures of relatedness, genetic diversity and methods to manage populations at the genomic level, and we discuss future challenges related to managing populations through implementing genomic methods at the herd and population levels. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

[Complex estimation of proliferative activity of epithelial cells of the large intestine damaged by polyps and cancer].

PubMed

Nalieskina, L A; Zabarko, L B; Polishchuk, L Z; Oliĭnichenko, G P; Zakhartseva, L M; Koshel', K V

2001-01-01

Peculiarities of mitotic regime and expression of proliferating cell nuclear antigen were investigated in 18 polyps and 35 cases of colorectal cancer. Direct relationship between spectrum and degree of manifestation of proliferative activity, level of morphological malignant tumors and accumulation of oncopathology in the patient pedigrees was established.

Monitoring changes in the demographic and genealogical structure of the main Spanish local beef breeds.

PubMed

Cañas-Álvarez, J J; Gónzalez-Rodríguez, A; Martín-Collado, D; Avilés, C; Altarriba, J; Baro, J A; De la Fuente, L F; Díaz, C; Molina, A; Varona, L; Piedrafita, J

2014-10-01

Demographic and pedigree analyses describe the structure and dynamics of livestock populations. We studied information recorded in the herdbooks of Asturiana de los Valles (AV; N = 458,806), Avileña-Negra Ibérica (ANI; N = 204,623), Bruna dels Pirineus (BP; N = 62,138), Morucha (Mo; N = 65,350), Pirenaica (Pi; N = 217,428), Retinta (Re; N = 135,300), and Rubia Gallega (RG; N = 235,511) beef breeds from their creation until 2009. All breeds have increased in the number of registered cows in recent years. In all breeds, herds do not behave as isolated entities and a high rate of exchange of breeding males between herds exists. A percentage of herds (12-52%) make some type of selection and sell bulls to other herds. There were large differences in average number of progeny per bull, ranging from 15.6 (AV) to 373.7 animals (RG, with a high incidence of AI). Generation interval estimates ranged from 4.7 (AV) to 7.6 (RG) yr in the sire pathway and from 5.95 (AV) to 7.8 (Mo) yr in the dam pathway. Density of pedigrees varied among breeds, with Pi, ANI, and Re having the more dense pedigrees, with average completeness indexes of more than 96% in the first generation and 80% when 6 generations were considered. A general increase in average inbreeding was observed in all breeds in the years analyzed. For animals born in 2009, average inbreeding coefficients ranged from 0.6 (BP) to 7.2% (Re) when all animals were considered and from 3.6 (Pi) to 17.6% (BP) when only inbred animals were considered. Due to the lack of completeness of pedigrees in most populations, inbreeding coefficients may be considered as a lower bound of the true parameters. The proportion of inbred animals tended to increase in the periods analyzed in all breeds. Differences between inbreeding and coancestry rates (except in RG) suggest the presence of population structure. Effective population size (Ne) based on the inbreeding rate estimated by regression ranged from 43 to 378 for Re and BP, whereas Ne estimates based on coancestry were greater, with a range of 100 for RG to 9,985 for BP. These facts suggest that an adequate mating policy can help to monitor inbreeding so as not to lose genetic variability. Effective number of ancestors in 2009 for 6 of the breeds ranged from 42 (RG) to 220 (AV), with BP having much a greater value, and was lower than was the effective number of founders in all breeds, suggesting the existence of bottlenecks.

Individualization and estimation of relatedness in crocodilians by DNA fingerprinting with a Bkm-derived probe.

PubMed

Lang, J W; Aggarwal, R K; Majumdar, K C; Singh, L

1993-04-01

Individual-specific DNA fingerprints of crocodilians were obtained by the use of Bkm-2(8) probe. Pedigree analyses of Crocodylus palustris, C. porosus and Caiman crocodilus revealed that the multiple bands (22-23 bands with Aludigest) thus obtained were inherited stably in a Mendelian fashion. Unique fingerprints permitted us to identify individuals, assign parentage, and reconstruct the DNA profile of a missing parent. Average band sharing between unrelated crocodiles was found to be 0.37. Band sharing between animals of known pedigrees increased predictably with relatedness and provided a basis for distinguishing relatives from non-relatives. Similar results obtained in other species/genera, using the same probe, suggest that this approach may be applicable to all species of crocodilians, and could facilitate genetic studies of wild and captive populations.

Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos

PubMed Central

Khorram, David; Choi, Michael; Roos, Ben R.; Stone, Edwin M.; Kopel, Teresa; Allen, Richard; Alward, Wallace L.M.; Scheetz, Todd E.

2015-01-01

Purpose Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees. Methods Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene. Results Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these “linked regions” were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3′ end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases. Conclusions A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos. PMID:26392740

Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos.

PubMed

Khorram, David; Choi, Michael; Roos, Ben R; Stone, Edwin M; Kopel, Teresa; Allen, Richard; Alward, Wallace L M; Scheetz, Todd E; Fingert, John H

2015-01-01

Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees. Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene. Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases. A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

Cortical Folding of the Primate Brain: An Interdisciplinary Examination of the Genetic Architecture, Modularity, and Evolvability of a Significant Neurological Trait in Pedigreed Baboons (Genus Papio)

PubMed Central

Atkinson, Elizabeth G.; Rogers, Jeffrey; Mahaney, Michael C.; Cox, Laura A.; Cheverud, James M.

2015-01-01

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ∼1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical–cortical connectivity, and gyrification’s potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution. PMID:25873632

Identification of novel TFG mutation in HMSN-P pedigree: Emphasis on variable clinical presentations.

PubMed

Khani, Marzieh; Shamshiri, Hosein; Alavi, Afagh; Nafissi, Shahriar; Elahi, Elahe

2016-10-15

We aimed to identify the genetic cause of neurological disease in an Iranian pedigree whose manifestations suggested hereditary motor and sensory neuropathy with proximal predominance (HMSN-P). Identification of a p.Gly269Val mutation in TFG, the known HMSN-P causative gene, provided supportive evidence. Subjective, biochemical, electrodiagnostic, and imaging data were compared with previously reported HMSN-P patients, including patients of an earlier described Iranian pedigree. Although notable clinical variability was found, comparable involvement of proximal and distal muscles was observed in both Iranian pedigrees. Interestingly, the same p.Gly269Val mutation was recently reported as cause of Charcot-Marie-Tooth disease type 2 in a Taiwanese pedigree. The likelihood that the two pedigrees with the p.Gly269Val mutation are not affected with different diseases is discussed. Identification of a second Iranian HMSN-P pedigree further confirms that HMSN-P is not confined to the Far East. Furthermore, p.Pro285Leu that has been the only TFG mutation thus far reported in HMSN-P patients is not the only mutation that can cause the disease. It is emphasized HMSN-P is a neuronopathy. Copyright © 2016 Elsevier B.V. All rights reserved.

Ethical issues in bipolar disorders pedigree research: privacy concerns, informed consent, and grounds for waiver.

PubMed

Parker, Lisa S

2002-02-01

Focusing on bipolar disorders research, this article considers ethical issues of informed consent and privacy arising in genetic pedigree research at two stages: the construction of tentative pedigrees to determine family eligibility for study and, subsequently, the enrollment of subjects in and conduct of the family study. Increasing concern to protect the privacy of family members of primary subjects or probands, following ethical controversy over a survey study at Virginia Commonwealth University, has led some researchers and Institutional Review Boards (IRBs) to apply informed consent requirements to those represented on a tentative pedigree at the initial stage of research. This article analyzes the possible benefits, risks, and burdens to prospective subjects of seeking prospective consent for pedigree construction at this initial stage. It argues that the likely risk-benefit ratio favors granting a waiver of consent requirements for this stage of pedigree research and presents grounds for IRBs to grant such a waiver. The article closes by considering particular ethical concerns that should be addressed in the informed consent discussion when enrolling subjects in pedigree studies of bipolar disorder, including concerns about subjects' competence to consent, management of interim and incidental findings, and issues particular to psychiatric research.

Identification of hereditary cancer in the general population: development and validation of a screening questionnaire for obtaining the family history of cancer.

PubMed

Campacci, Natalia; de Lima, Juliana O; Carvalho, André L; Michelli, Rodrigo D; Haikel, Rafael; Mauad, Edmundo; Viana, Danilo V; Melendez, Matias E; Vazquez, Fabiana de L; Zanardo, Cleyton; Reis, Rui M; Rossi, Benedito M; Palmero, Edenir I

2017-12-01

One of the challenges for Latin American countries is to include in their healthcare systems technologies that can be applied to hereditary cancer detection and management. The aim of the study is to create and validate a questionnaire to identify individuals with possible risk for hereditary cancer predisposition syndromes (HCPS), using different strategies in a Cancer Prevention Service in Brazil. The primary screening questionnaire (PSQ) was developed to identify families at-risk for HCPS. The PSQ was validated using discrimination measures, and the reproducibility was estimated through kappa coefficient. Patients with at least one affirmative answer had the pedigree drawn using three alternative interview approaches: in-person, by telephone, or letter. Validation of these approaches was done. Kappa and intraclass correlation coefficients were used to analyze data's reproducibility considering the presence of clinical criteria for HCPS. The PSQ was applied to a convenience sample of 20,000 women of which 3121 (15.6%) answered at least one affirmative question and 1938 had their pedigrees drawn. The PSQ showed sensitivity and specificity scores of 94.4% and 75%, respectively, and a kappa of 0.64. The strategies for pedigree drawing had reproducibility coefficients of 0.976 and 0.850 for the telephone and letter approaches, respectively. Pedigree analysis allowed us to identify 465 individuals (24.0%) fulfilling at least one clinical criterion for HCPS. The PSQ fulfills its function, allowing the identification of HCPS at-risk families. The use of alternative screening methods may reduce the number of excluded at-risk individuals/families who live in locations where oncogenetic services are not established. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Improving genetic evaluation of litter size and piglet mortality for both genotyped and nongenotyped individuals using a single-step method.

PubMed

Guo, X; Christensen, O F; Ostersen, T; Wang, Y; Lund, M S; Su, G

2015-02-01

A single-step method allows genetic evaluation using information of phenotypes, pedigree, and markers from genotyped and nongenotyped individuals simultaneously. This paper compared genomic predictions obtained from a single-step BLUP (SSBLUP) method, a genomic BLUP (GBLUP) method, a selection index blending (SELIND) method, and a traditional pedigree-based method (BLUP) for total number of piglets born (TNB), litter size at d 5 after birth (LS5), and mortality rate before d 5 (Mort; including stillbirth) in Danish Landrace and Yorkshire pigs. Data sets of 778,095 litters from 309,362 Landrace sows and 472,001 litters from 190,760 Yorkshire sows were used for the analysis. There were 332,795 Landrace and 207,255 Yorkshire animals in the pedigree data, among which 3,445 Landrace pigs (1,366 boars and 2,079 sows) and 3,372 Yorkshire pigs (1,241 boars and 2,131 sows) were genotyped with the Illumina PorcineSNP60 BeadChip. The results showed that the 3 methods with marker information (SSBLUP, GBLUP, and SELIND) produced more accurate predictions for genotyped animals than the pedigree-based method. For genotyped animals, the average of reliabilities for all traits in both breeds using traditional BLUP was 0.091, which increased to 0.171 w+hen using GBLUP and to 0.179 when using SELIND and further increased to 0.209 when using SSBLUP. Furthermore, the average reliability of EBV for nongenotyped animals was increased from 0.091 for traditional BLUP to 0.105 for the SSBLUP. The results indicate that the SSBLUP is a good approach to practical genomic prediction of litter size and piglet mortality in Danish Landrace and Yorkshire populations.

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism

PubMed Central

Salvatori, Roberto; Radian, Serban; Diekmann, Yoan; Iacovazzo, Donato; David, Alessia; Gabrovska, Plamena; Grassi, Giorgia; Bussell, Anna-Marie; Stals, Karen; Weber, Astrid; Quinton, Richard; Crowne, Elizabeth C; Corazzini, Valentina; Metherell, Lou; Kearney, Tara; Du Plessis, Daniel; Sinha, Ajay Kumar; Baborie, Atik; Lecoq, Anne-Lise; Chanson, Philippe; Ansorge, Olaf; Ellard, Sian; Trainer, Peter J; Balding, David; Thomas, Mark G

2017-01-01

Objective Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Design and methods Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Results Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. Conclusions The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability. PMID:28634279

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

PubMed

Salvatori, Roberto; Radian, Serban; Diekmann, Yoan; Iacovazzo, Donato; David, Alessia; Gabrovska, Plamena; Grassi, Giorgia; Bussell, Anna-Marie; Stals, Karen; Weber, Astrid; Quinton, Richard; Crowne, Elizabeth C; Corazzini, Valentina; Metherell, Lou; Kearney, Tara; Du Plessis, Daniel; Sinha, Ajay Kumar; Baborie, Atik; Lecoq, Anne-Lise; Chanson, Philippe; Ansorge, Olaf; Ellard, Sian; Trainer, Peter J; Balding, David; Thomas, Mark G; Korbonits, Márta

2017-09-01

Mutations in the aryl hydrocarbon receptor-interacting protein ( AIP ) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP -region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability. © 2017 The authors.

Response to five generations of selection for growth performance traits in rainbow trout (Oncorhynchus mykiss)

USDA-ARS?s Scientific Manuscript database

A pedigreed rainbow trout population (~100 families per generation) was selected for five generations to improve growth performance to the standard ~500-gram US market weight and beyond (greater than 1 kg). Body weights (BW) were recorded each generation at 5, 8, 10, and 13 months post-hatch. Selec...

Population-Specific Haplotype Association of the Postsynaptic Density Gene DLG4 with Schizophrenia, in Family-Based Association Studies

PubMed Central

Balan, Shabeesh; Yamada, Kazuo; Hattori, Eiji; Iwayama, Yoshimi; Toyota, Tomoko; Ohnishi, Tetsuo; Maekawa, Motoko; Toyoshima, Manabu; Iwata, Yasuhide; Suzuki, Katsuaki; Kikuchi, Mitsuru; Yoshikawa, Takeo

2013-01-01

The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes. PMID:23936182

Methods of fertility control in cats: Owner, breeder and veterinarian behavior and attitudes.

PubMed

Murray, Jane K; Mosteller, Jill R; Loberg, Jenny M; Andersson, Maria; Benka, Valerie A W

2015-09-01

Fertility control is important for population management of owned and unowned cats, provides health benefits at the individual level and can reduce unwanted sexually dimorphic behaviors such as roaming, aggression, spraying and calling. This article reviews the available evidence regarding European and American veterinarian, owner and pedigree cat breeder attitudes toward both surgical sterilization and non-surgical fertility control. It additionally presents new data on veterinarians' and pedigree cat breeders' use of, and attitudes toward, alternative modalities of fertility control. Within the United States and Europe, the proportion of cats reported to be sterilized varies widely. Published estimates range from 27-93% for owned cats and 2-5% for cats trapped as part of a trap-neuter-return (TNR) program. In some regions and populations of cats, non-surgical fertility control is also used. Social context, cultural norms, individual preferences, economic considerations, legislation and professional organizations may all influence fertility control decisions for cats. Particularly in Europe, a limited number of non-surgical temporary contraceptives are available for cats; these include products with regulatory approval for cats as well as some used 'off label'. Non-surgical methods remove the risk of complications related to surgery and offer potential to treat more animals in less time and at lower cost; they may also appeal to pedigree cat breeders seeking temporary contraception. However, concerns over efficacy, delivery methods, target species safety, duration and side effects exist with current non-surgical options. Research is under way to develop new methods to control fertility in cats without surgery. US and European veterinarians place high value on three perceived benefits of surgical sterilization: permanence, behavioral benefits and health benefits. Non-surgical options will likely need to share these benefits to be widely accepted by the veterinary community. © The Author(s) 2015.

High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus.

PubMed

Muchero, Wellington; Guo, Jianjun; DiFazio, Stephen P; Chen, Jin-Gui; Ranjan, Priya; Slavov, Gancho T; Gunter, Lee E; Jawdy, Sara; Bryan, Anthony C; Sykes, Robert; Ziebell, Angela; Klápště, Jaroslav; Porth, Ilga; Skyba, Oleksandr; Unda, Faride; El-Kassaby, Yousry A; Douglas, Carl J; Mansfield, Shawn D; Martin, Joel; Schackwitz, Wendy; Evans, Luke M; Czarnecki, Olaf; Tuskan, Gerald A

2015-01-23

QTL cloning for the discovery of genes underlying polygenic traits has historically been cumbersome in long-lived perennial plants like Populus. Linkage disequilibrium-based association mapping has been proposed as a cloning tool, and recent advances in high-throughput genotyping and whole-genome resequencing enable marker saturation to levels sufficient for association mapping with no a priori candidate gene selection. Here, multiyear and multienvironment evaluation of cell wall phenotypes was conducted in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree and two partially overlapping populations of unrelated P. trichocarpa genotypes using pyrolysis molecular beam mass spectrometry, saccharification, and/ or traditional wet chemistry. QTL mapping was conducted using a high-density genetic map with 3,568 SNP markers. As a fine-mapping approach, chromosome-wide association mapping targeting a QTL hot-spot on linkage group XIV was performed in the two P. trichocarpa populations. Both populations were genotyped using the 34 K Populus Infinium SNP array and whole-genome resequencing of one of the populations facilitated marker-saturation of candidate intervals for gene identification. Five QTLs ranging in size from 0.6 to 1.8 Mb were mapped on linkage group XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6-carbon sugars using the mapping pedigree. Six candidate loci exhibiting significant associations with phenotypes were identified within QTL intervals. These associations were reproducible across multiple environments, two independent genotyping platforms, and different plant growth stages. cDNA sequencing for allelic variants of three of the six loci identified polymorphisms leading to variable length poly glutamine (PolyQ) stretch in a transcription factor annotated as an ANGUSTIFOLIA C-terminus Binding Protein (CtBP) and premature stop codons in a KANADI transcription factor as well as a protein kinase. Results from protoplast transient expression assays suggested that each of the polymorphisms conferred allelic differences in the activation of cellulose, hemicelluloses, and lignin pathway marker genes. This study illustrates the utility of complementary QTL and association mapping as tools for gene discovery with no a priori candidate gene selection. This proof of concept in a perennial organism opens up opportunities for discovery of novel genetic determinants of economically important but complex traits in plants.

9 CFR 151.4 - Pedigree certificate.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 151.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS Certification of Purebred Animals § 151.4 Pedigree certificate. A pedigree certificate for an animal of a breed listed in...

9 CFR 151.4 - Pedigree certificate.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 151.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS Certification of Purebred Animals § 151.4 Pedigree certificate. A pedigree certificate for an animal of a breed listed in...

9 CFR 151.4 - Pedigree certificate.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 151.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS Certification of Purebred Animals § 151.4 Pedigree certificate. A pedigree certificate for an animal of a breed listed in...

9 CFR 151.4 - Pedigree certificate.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 151.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS Certification of Purebred Animals § 151.4 Pedigree certificate. A pedigree certificate for an animal of a breed listed in...

9 CFR 151.4 - Pedigree certificate.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 151.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS Certification of Purebred Animals § 151.4 Pedigree certificate. A pedigree certificate for an animal of a breed listed in...

Linkage of familial Alzheimer disease to chromosome 14 in two large early-onset pedigrees: effects of marker allele frequencies on lod scores.

PubMed

Nechiporuk, A; Fain, P; Kort, E; Nee, L E; Frommelt, E; Polinsky, R J; Korenberg, J R; Pulst, S M

1993-05-01

Alzheimer disease (AD) is a devastating neurodegenerative disease leading to global dementia. In addition to sporadic forms of AD, familial forms (FAD) have been recognized. Mutations in the amyloid precursor protein (APP) gene on chromosome (CHR) 21 have been shown to cause early-onset AD in a small number of pedigrees. Recently, linkage to markers on CHR 14 has been established in several early-onset FAD pedigrees. We now report lod scores for CHR 14 markers in two large early-onset FAD pedigrees. Pairwise linkage analysis suggested that in these pedigrees the mutation is tightly linked to the loci D14S43 and D14S53. However, assumptions regarding marker allele frequencies had a major and often unpredictable effect on calculated lod scores. Therefore, caution needs to be exercised when single pedigrees are analyzed with marker allele frequencies determined from the literature or from a pool of spouses.

Next Generation Sequencing Plus (NGS+) with Y-chromosomal Markers for Forensic Pedigree Searches.

PubMed

Qian, Xiaoqin; Hou, Jiayi; Wang, Zheng; Ye, Yi; Lang, Min; Gao, Tianzhen; Liu, Jing; Hou, Yiping

2017-09-12

There is high demand for forensic pedigree searches with Y-chromosome short tandem repeat (Y-STR) profiling in large-scale crime investigations. However, when two Y-STR haplotypes have a few mismatched loci, it is difficult to determine if they are from the same male lineage because of the high mutation rate of Y-STRs. Here we design a new strategy to handle cases in which none of pedigree samples shares identical Y-STR haplotype. We combine next generation sequencing (NGS), capillary electrophoresis and pyrosequencing under the term 'NGS+' for typing Y-STRs and Y-chromosomal single nucleotide polymorphisms (Y-SNPs). The high-resolution Y-SNP haplogroup and Y-STR haplotype can be obtained with NGS+. We further developed a new data-driven decision rule, FSindex, for estimating the likelihood for each retrieved pedigree. Our approach enables positive identification of pedigree from mismatched Y-STR haplotypes. It is envisaged that NGS+ will revolutionize forensic pedigree searches, especially when the person of interest was not recorded in forensic DNA database.

Allele frequency changes due to hitch-hiking in genomic selection programs

PubMed Central

2014-01-01

Background Genomic selection makes it possible to reduce pedigree-based inbreeding over best linear unbiased prediction (BLUP) by increasing emphasis on own rather than family information. However, pedigree inbreeding might not accurately reflect loss of genetic variation and the true level of inbreeding due to changes in allele frequencies and hitch-hiking. This study aimed at understanding the impact of using long-term genomic selection on changes in allele frequencies, genetic variation and level of inbreeding. Methods Selection was performed in simulated scenarios with a population of 400 animals for 25 consecutive generations. Six genetic models were considered with different heritabilities and numbers of QTL (quantitative trait loci) affecting the trait. Four selection criteria were used, including selection on own phenotype and on estimated breeding values (EBV) derived using phenotype-BLUP, genomic BLUP and Bayesian Lasso. Changes in allele frequencies at QTL, markers and linked neutral loci were investigated for the different selection criteria and different scenarios, along with the loss of favourable alleles and the rate of inbreeding measured by pedigree and runs of homozygosity. Results For each selection criterion, hitch-hiking in the vicinity of the QTL appeared more extensive when accuracy of selection was higher and the number of QTL was lower. When inbreeding was measured by pedigree information, selection on genomic BLUP EBV resulted in lower levels of inbreeding than selection on phenotype BLUP EBV, but this did not always apply when inbreeding was measured by runs of homozygosity. Compared to genomic BLUP, selection on EBV from Bayesian Lasso led to less genetic drift, reduced loss of favourable alleles and more effectively controlled the rate of both pedigree and genomic inbreeding in all simulated scenarios. In addition, selection on EBV from Bayesian Lasso showed a higher selection differential for mendelian sampling terms than selection on genomic BLUP EBV. Conclusions Neutral variation can be shaped to a great extent by the hitch-hiking effects associated with selection, rather than just by genetic drift. When implementing long-term genomic selection, strategies for genomic control of inbreeding are essential, due to a considerable hitch-hiking effect, regardless of the method that is used for prediction of EBV. PMID:24495634

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk

PubMed Central

Curtin, Karen; Rajamanickam, Venkatesh; Jayabalan, David; Atanackovic, Djordje; Rajkumar, S. Vincent; Kumar, Shaji; Slager, Susan; Galia, Perrine; Demangel, Delphine; Salama, Mohamed; Joseph, Vijai; Lipkin, Steven M.; Dumontet, Charles; Vachon, Celine M.

2018-01-01

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits. PMID:29389935

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

PubMed

Waller, Rosalie G; Darlington, Todd M; Wei, Xiaomu; Madsen, Michael J; Thomas, Alun; Curtin, Karen; Coon, Hilary; Rajamanickam, Venkatesh; Musinsky, Justin; Jayabalan, David; Atanackovic, Djordje; Rajkumar, S Vincent; Kumar, Shaji; Slager, Susan; Middha, Mridu; Galia, Perrine; Demangel, Delphine; Salama, Mohamed; Joseph, Vijai; McKay, James; Offit, Kenneth; Klein, Robert J; Lipkin, Steven M; Dumontet, Charles; Vachon, Celine M; Camp, Nicola J

2018-02-01

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

Temporal variation in the mating structure of Sanday, Orkney Islands.

PubMed

Brennan, E R; Relethford, J H

1983-01-01

Pedigree and vital statistics data from the population of Sanday, Orkney Islands, Scotland, were used to assess temporal changes in population structure. Secular trends in patterns of mate choice were analysed for three separate birth cohorts of spouses: 1855-1884, 1885-1924 and 1925-1964. The degree to which mating was random or assortative with respect to both genealogical and geographic distance was determined by comparing average characteristics of all potential mates of married males with those of actual wives. We integrated this procedure, originally developed by Dyke (1971), into a three-fold investigation of population structure: (1) comparison of random and non-random components of relatedness as measured from pedigree data; (2) an analysis of marital distance distributions for actual and potential mates of married males; and (3) the relationship between genealogical relatedness and geographic distance. As population size decreased from 1881 to the present, total kinship and spatial distances between spouses increased. Whereas the random component of relatedness increased over time, consanguinity avoidance was sufficient to decrease the total coefficient of kinship over time. Part of the increase in consanguinity avoidance was associated with isolate breakdown, as distances between island-born spouses, as well as the total amount of off-island migration, increased from the mid-nineteenth century to the present. Mate choice was influenced by geographic distance for all time periods, although this effect diminished over time. Since decreases in population size, concomitant with increases in consanguinity avoidance and community exogamy, have probably occurred quite frequently in small human populations, as well as in rural Western communities in the past century, observed secular trends illustrate the potential for change in population structure characteristic of isolate breakdown.

Allelic variation of the FRMD7 gene in congenital idiopathic nystagmus.

PubMed

Self, James E; Shawkat, Fatima; Malpas, Crispin T; Thomas, N Simon; Harris, Christopher M; Hodgkins, Peter R; Chen, Xiaoli; Trump, Dorothy; Lotery, Andrew J

2007-09-01

To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.

[Construction of haplotype and haplotype block based on tag single nucleotide polymorphisms and their applications in association studies].

PubMed

Gu, Ming-liang; Chu, Jia-you

2007-12-01

Human genome has structures of haplotype and haplotype block which provide valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to complex diseases. Haplotype block can be divided into discrete blocks of limited haplotype diversity. In each block, a small fraction of ptag SNPsq can be used to distinguish a large fraction of the haplotypes. These tag SNPs can be potentially useful for construction of haplotype and haplotype block, and association studies in complex diseases. There are two general classes of methods to construct haplotype and haplotype blocks based on genotypes on large pedigrees and statistical algorithms respectively. The author evaluate several construction methods to assess the power of different association tests with a variety of disease models and block-partitioning criteria. The advantages, limitations and applications of each method and the application in the association studies are discussed equitably. With the completion of the HapMap and development of statistical algorithms for addressing haplotype reconstruction, ideas of construction of haplotype based on combination of mathematics, physics, and computer science etc will have profound impacts on population genetics, location and cloning for susceptible genes in complex diseases, and related domain with life science etc.

Quantitative genetic analysis of the body composition and blood pressure association in two ethnically diverse populations.

PubMed

Ghosh, Sudipta; Dosaev, Tasbulat; Prakash, Jai; Livshits, Gregory

2017-04-01

The major aim of this study was to conduct comparative quantitative-genetic analysis of the body composition (BCP) and somatotype (STP) variation, as well as their correlations with blood pressure (BP) in two ethnically, culturally and geographically different populations: Santhal, indigenous ethnic group from India and Chuvash, indigenous population from Russia. Correspondently two pedigree-based samples were collected from 1,262 Santhal and1,558 Chuvash individuals, respectively. At the first stage of the study, descriptive statistics and a series of univariate regression analyses were calculated. Finally, multiple and multivariate regression (MMR) analyses, with BP measurements as dependent variables and age, sex, BCP and STP as independent variables were carried out in each sample separately. The significant and independent covariates of BP were identified and used for re-examination in pedigree-based variance decomposition analysis. Despite clear and significant differences between the populations in BCP/STP, both Santhal and Chuvash were found to be predominantly mesomorphic irrespective of their sex. According to MMR analyses variation of BP significantly depended on age and mesomorphic component in both samples, and in addition on sex, ectomorphy and fat mass index in Santhal and on fat free mass index in Chuvash samples, respectively. Additive genetic component contributes to a substantial proportion of blood pressure and body composition variance. Variance component analysis in addition to above mentioned results suggests that additive genetic factors influence BP and BCP/STP associations significantly. © 2017 Wiley Periodicals, Inc.

Advantages of using molecular coancestry in the removal of introgressed genetic material

PubMed Central

2013-01-01

Background When introgression of undesired exogenous genetic material occurs in a population intended to remain pure, actions are necessary to recover the original background. It has been shown that genome-wide information can replace pedigree information for different objectives and is a valuable tool in the fields of genetic conservation and breeding. In this simulation study, molecular information provided by 50 000 SNP was used to minimise the molecular coancestry between individuals of an admixed population and the foreign individuals that originally introgressed a native population in order to remove the exogenous DNA. Results This management method, which detects the ‘purest’ individuals to be used as parents for the next generation, allowed recovery of the native genetic background to a great extent in all simulated scenarios. However, it also caused an increase in inbreeding larger than expected because of the lower number of individuals selected as parents and the higher coancestry between them. In scenarios involving several introgression events the method was more efficient than in those involving a single introgression event because part of the genetic information was mixed with the native genetic material for a shorter period. Conclusions Genome-wide information can be used to identify the purest individuals via the minimisation of molecular coancestry between individuals of the admixed and exogenous populations. Removal of the undesired genetic material is more efficient with a molecular-based approach than with a pedigree-based approach. PMID:23634969

Clarifying sub-genomic positions of QTLs for flowering habit and fruit quality in U.S. strawberry (Fragaria ×ananassa) breeding populations using pedigree-based QTL analysis

USDA-ARS?s Scientific Manuscript database

Strawberry (Fragaria ×ananassa) is consumed worldwide for its flavor and nutritional health benefits. Several quantitative trait loci (QTL) were detected in the last two decades for fruit quality and flowering traits using low-density genetic maps. Recent discoveries in allo-octoploid strawberry gen...

More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

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

NONE

1995-11-06

This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

DCEG Symposium to Honor Joseph F. Fraumeni, Jr. | Poster

Cancer.gov

By Nancy Parrish, Staff Writer On May 6, the Division of Cancer Epidemiology and Genetics (DCEG) will sponsor a symposium to honor 50 years of leadership from its founding director, Joseph F. Fraumeni, Jr., M.D., who stepped down from the position in July 2012. The conference, entitled “Cancer Epidemiology: From Pedigrees to Populations,” will highlight critical findings in

Two Quantitative Trait Loci Influence Whipworm (Trichuris trichiura) Infection in a Nepalese Population

PubMed Central

Williams-Blangero, Sarah; VandeBerg, John L.; Subedi, Janardan; Jha, Bharat; Dyer, T.D.; Blangero, John

2014-01-01

Background Whipworm (Trichuris trichiura) is a soil-transmitted helminth which infects over a billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of a significant heritability for whipworm infection, we conducted the first genome scan for susceptibility to this important parasitic disease. Methods We assessed whipworm eggs per gram of feces in 1253 members of the Jirel population of eastern Nepal. All sampled individuals belonged to a single pedigree containing over 26,000 relative pairs that are informative for genetic analysis. Results Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for two quantitative trait loci influencing susceptibility to whipworm infection, one located on chromosome 9 (LOD = 3.35, genome-wide p = 0.0138) and the other located on chromosome 18 (LOD = 3.29, genome-wide p = 0.0159). There was also suggestive evidence for two loci located on chromosomes 12 and 13 influencing whipworm infection. Conclusion The results of this first genome scan for susceptibility to whipworm infection may ultimately lead to the identification of novel targets for vaccine and drug development efforts. PMID:18462166

Two quantitative trait loci influence whipworm (Trichuris trichiura) infection in a Nepalese population.

PubMed

Williams-Blangero, Sarah; Vandeberg, John L; Subedi, Janardan; Jha, Bharat; Dyer, Tom D; Blangero, John

2008-04-15

Whipworm (Trichuris trichiura) infection is a soil-transmitted helminth infection that affects >1 billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of significant heritability for whipworm infection, we conducted the first genome scan for quantitative trait loci (QTL) influencing the heritability of susceptibility to this important parasitic disease. Whipworm egg counts were determined for 1,253 members of the Jirel population of eastern Nepal. All individuals in the study sample belonged to a single pedigree including >26,000 pairs of relatives that are informative for genetic analysis. Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for 2 QTL influencing susceptibility to whipworm infection, one located on chromosome 9 (logarithm of the odds ratio [LOD] score, 3.35; genomewide P = .0138) and the other located on chromosome 18 (LOD score, 3.29; genomewide P = .0159). There was also suggestive evidence that 2 loci located on chromosomes 12 and 13 influenced whipworm infection. The results of this first genome scan for T. trichiura egg counts provides new information on the determinants of genetic predisposition to whipworm infection.

Female reproductive success variation in a Pseudotsuga menziesii seed orchard as revealed by pedigree reconstruction from a bulk seed collection.

PubMed

El-Kassaby, Yousry A; Funda, Tomas; Lai, Ben S K

2010-01-01

The impact of female reproductive success on the mating system, gene flow, and genetic diversity of the filial generation was studied using a random sample of 801 bulk seed from a 49-clone Pseudotsuga menziesii seed orchard. We used microsatellite DNA fingerprinting and pedigree reconstruction to assign each seed's maternal and paternal parents and directly estimated clonal reproductive success, selfing rate, and the proportion of seed sired by outside pollen sources. Unlike most family array mating system and gene flow studies conducted on natural and experimental populations, which used an equal number of seeds per maternal genotype and thus generating unbiased inferences only on male reproductive success, the random sample we used was a representative of the entire seed crop; therefore, provided a unique opportunity to draw unbiased inferences on both female and male reproductive success variation. Selfing rate and the number of seed sired by outside pollen sources were found to be a function of female fertility variation. This variation also substantially and negatively affected female effective population size. Additionally, the results provided convincing evidence that the use of clone size as a proxy to fertility is questionable and requires further consideration.

Impacts of Population Structure and Analytical Models in Genome-Wide Association Studies of Complex Traits in Forest Trees: A Case Study in Eucalyptus globulus

PubMed Central

Garcia, Martín N.; Acuña, Cintia; Borralho, Nuno M. G.; Grattapaglia, Dario; Marcucci Poltri, Susana N.

2013-01-01

The promise of association genetics to identify genes or genomic regions controlling complex traits has generated a flurry of interest. Such phenotype-genotype associations could be useful to accelerate tree breeding cycles, increase precision and selection intensity for late expressing, low heritability traits. However, the prospects of association genetics in highly heterozygous undomesticated forest trees can be severely impacted by the presence of cryptic population and pedigree structure. To investigate how to better account for this, we compared the GLM and five combinations of the Unified Mixed Model (UMM) on data of a low-density genome-wide association study for growth and wood property traits carried out in a Eucalyptus globulus population (n = 303) with 7,680 Diversity Array Technology (DArT) markers. Model comparisons were based on the degree of deviation from the uniform distribution and estimates of the mean square differences between the observed and expected p-values of all significant marker-trait associations detected. Our analysis revealed the presence of population and family structure. There was not a single best model for all traits. Striking differences in detection power and accuracy were observed among the different models especially when population structure was not accounted for. The UMM method was the best and produced superior results when compared to GLM for all traits. Following stringent correction for false discoveries, 18 marker-trait associations were detected, 16 for tree diameter growth and two for lignin monomer composition (S∶G ratio), a key wood property trait. The two DArT markers associated with S∶G ratio on chromosome 10, physically map within 1 Mbp of the ferulate 5-hydroxylase (F5H) gene, providing a putative independent validation of this marker-trait association. This study details the merit of collectively integrate population structure and relatedness in association analyses in undomesticated, highly heterozygous forest trees, and provides additional insights into the nature of complex quantitative traits in Eucalyptus. PMID:24282578

A Combinatorial Approach to Detecting Gene-Gene and Gene-Environment Interactions in Family Studies

PubMed Central

Lou, Xiang-Yang; Chen, Guo-Bo; Yan, Lei; Ma, Jennie Z.; Mangold, Jamie E.; Zhu, Jun; Elston, Robert C.; Li, Ming D.

2008-01-01

Widespread multifactor interactions present a significant challenge in determining risk factors of complex diseases. Several combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, have emerged as a promising tool for better detecting gene-gene (G × G) and gene-environment (G × E) interactions. We recently developed a general combinatorial approach, namely the generalized multifactor dimensionality reduction (GMDR) method, which can entertain both qualitative and quantitative phenotypes and allows for both discrete and continuous covariates to detect G × G and G × E interactions in a sample of unrelated individuals. In this article, we report the development of an algorithm that can be used to study G × G and G × E interactions for family-based designs, called pedigree-based GMDR (PGMDR). Compared to the available method, our proposed method has several major improvements, including allowing for covariate adjustments and being applicable to arbitrary phenotypes, arbitrary pedigree structures, and arbitrary patterns of missing marker genotypes. Our Monte Carlo simulations provide evidence that the PGMDR method is superior in performance to identify epistatic loci compared to the MDR-pedigree disequilibrium test (PDT). Finally, we applied our proposed approach to a genetic data set on tobacco dependence and found a significant interaction between two taste receptor genes (i.e., TAS2R16 and TAS2R38) in affecting nicotine dependence. PMID:18834969

CNGA3 mutations in two United Arab Emirates families with achromatopsia.

PubMed

Ahuja, Yachna; Kohl, Susanne; Traboulsi, Elias I

2008-07-10

ACHROMATOPSIA RESULTS FROM MUTATIONS IN ONE OF THREE GENES: cyclic nucleotide-gated channel, alpha-3 (CNGA3); cyclic nucleotide-gated channel, beta-3 (CNGB3); and guanine nucleotide-binding protein, alpha-transducing activity polypeptide 2 (GNAT2). We report the responsible mutations in two United Arab Emirates families who have this autosomal recessive disease. Clinical examinations were performed in seven patients from three nuclear families. Molecular genetic testing for common CNGA3 and CNGB3 mutations was undertaken using standard protocols. All patients were extremely light sensitive and had reduced visual acuity and no color perception. Fundus examinations did not show any visible abnormalities. After further pedigree analysis, two of the families were found to be linked through the paternal line. Two mutations in CNGA3 were identified: Arg283Trp and Gly397Val. Family A, the larger pedigree, had one branch in which two sisters and one brother were homozygous for the Gly397Val mutation and another branch in which a brother and sister were compound heterozygous for both aforenamed mutations. Family B, however, only had two brothers who were homozygous for the Arg283Trp mutation. Achromatopsia in these two United Arab Emirates families results from two different mutations in CNGA3. Two branches of the same pedigree had individuals with both homozygous and compound heterozygous disease, demonstrating a complex molecular pathology in this large family.

Genomic selection accuracies within and between environments and small breeding groups in white spruce.

PubMed

Beaulieu, Jean; Doerksen, Trevor K; MacKay, John; Rainville, André; Bousquet, Jean

2014-12-02

Genomic selection (GS) may improve selection response over conventional pedigree-based selection if markers capture more detailed information than pedigrees in recently domesticated tree species and/or make it more cost effective. Genomic prediction accuracies using 1748 trees and 6932 SNPs representative of as many distinct gene loci were determined for growth and wood traits in white spruce, within and between environments and breeding groups (BG), each with an effective size of Ne ≈ 20. Marker subsets were also tested. Model fits and/or cross-validation (CV) prediction accuracies for ridge regression (RR) and the least absolute shrinkage and selection operator models approached those of pedigree-based models. With strong relatedness between CV sets, prediction accuracies for RR within environment and BG were high for wood (r = 0.71-0.79) and moderately high for growth (r = 0.52-0.69) traits, in line with trends in heritabilities. For both classes of traits, these accuracies achieved between 83% and 92% of those obtained with phenotypes and pedigree information. Prediction into untested environments remained moderately high for wood (r ≥ 0.61) but dropped significantly for growth (r ≥ 0.24) traits, emphasizing the need to phenotype in all test environments and model genotype-by-environment interactions for growth traits. Removing relatedness between CV sets sharply decreased prediction accuracies for all traits and subpopulations, falling near zero between BGs with no known shared ancestry. For marker subsets, similar patterns were observed but with lower prediction accuracies. Given the need for high relatedness between CV sets to obtain good prediction accuracies, we recommend to build GS models for prediction within the same breeding population only. Breeding groups could be merged to build genomic prediction models as long as the total effective population size does not exceed 50 individuals in order to obtain high prediction accuracy such as that obtained in the present study. A number of markers limited to a few hundred would not negatively impact prediction accuracies, but these could decrease more rapidly over generations. The most promising short-term approach for genomic selection would likely be the selection of superior individuals within large full-sib families vegetatively propagated to implement multiclonal forestry.

Pedigree and herd characterization of a donkey breed vulnerable to extinction.

PubMed

Quaresma, M; Martins, A M F; Rodrigues, J B; Colaço, J; Payan-Carreira, R

2014-03-01

Most donkey and local horse breeds are vulnerable to extinction as mechanization of agriculture progress throughout the world. The present study analyzed the pedigree and herd records of the donkey Asinina de Miranda breed (RAM), identifying genealogical and human factors that may affect the breed genetic diversity in the future and suggesting suitable strategies to breed preservation, early on the conservation program. The breeding rate was very low, with a ratio of foaling/live animals of 0.23 (178/760). The estimated number of founders and ancestors contributing to the reference population was 128 and 121. The number of founder herds in the reference population was 64, with an effective number of founder herds for the reference population of 7.6. The mean age of herd owners was 65.50 ± 0.884 years, with a negative association among the herd size and owner's age (P<0.001). In contrast, the size of the herd and the ownership of a male were both positively associated (P<0.001) with the herd number of in-born foals. Both the owners' age and the herd location (RAM home region v. dispersal region) were negatively associated with the foaling number (P<0.001). The main identified risk factors were: low breeding rates; low number of males and their unequal contribution to the genetic pool; unequal contribution of the herds to genetic pool; and advanced age of herd owners.

A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds.

PubMed

Short, Andrea D; Boag, Alisdair; Catchpole, Brian; Kennedy, Lorna J; Massey, Jonathan; Rothwell, Simon; Husebye, Eystein; Ollier, Bill

2013-01-01

Canine hypoadrenocorticism is believed to be an immune-related condition. It is rare in the overall dog population but shows a breed-related predisposition with Standard poodles and Portuguese water dogs having a greater prevalence of the condition. It shares many similarities with human primary adrenal insufficiency and is believed to be a naturally occurring, spontaneous model for the human condition. Short haplotype blocks and low levels of linkage disequilibrium in the human genome mean that the identification of genetic contributors to the condition requires large sample numbers. Pedigree dogs have high linkage disequilibrium and long haplotypes within a breed, increasing the potential of identifying novel genes that contribute to canine genetic disease. We investigated 222 SNPs from 42 genes that have been associated or may be implicated in human Addison's disease. We conducted case-control analyses in 3 pedigree dog breeds (Labrador retriever: affected n = 30, unaffected = 76; Cocker Spaniel: affected n = 19, unaffected = 53; Springer spaniel: affected n = 26, unaffected = 46) and identified 8 associated alleles in genes COL4A4, OSBPL9, CTLA4, PTPN22, and STXBP5 in 3 pedigree breeds. Association with immune response genes PTPN22 and CTLA4 in certain breeds suggests an underlying immunopathogenesis of the disease. These results suggest that canine hypoadrenocorticism could be a useful model for studying comparative genetics relevant to human Addison's disease.

Perceptions of family history and genetic testing and feasibility of pedigree development among African Americans with hypertension

PubMed Central

Pettey, Christina M; McSweeney, Jean C; Stewart, Katharine E; Price, Elvin T; Cleves, Mario A; Heo, Seongkum; Souder, Elaine

2016-01-01

Background Pedigree development, family history, and genetic testing are thought to be useful in improving outcomes of chronic illnesses such as hypertension (HTN). However, the clinical utility of pedigree development is still unknown. Further, little is known about African Americans’ (AAs’) perceptions of family history and genetic testing. Aims This study examined the feasibility of developing pedigrees for AAs with HTN and explored perceptions of family history and genetic research among AAs with HTN. Methods The US Surgeon General’s My Family Health Portrait was administered, and 30–60 minute in-person individual interviews were conducted. Descriptive statistics were used to analyze pedigree data. Interview transcripts were analyzed with content analysis and constant comparison. Results Twenty-nine AAs with HTN were recruited from one free clinic (15 women, 14 men; mean age 49 years, SD 9.6). Twenty-six (90%) reported their family history in sufficient detail to develop a pedigree. Perceptions of family history included knowledge of HTN in the family, culturally influenced family teaching about HTN, and response to family history of HTN. Most participants agreed to future genetic testing and DNA collection because they wanted to help others; some said they needed more information and others expressed a concern for privacy. Conclusion The majority of AAs in this sample possessed extensive knowledge of HTN within their family and were able to develop a three generation pedigree with assistance. The majority were willing to participate in future genetic research. PMID:25322748

Perceptions of family history and genetic testing and feasibility of pedigree development among African Americans with hypertension.

PubMed

Pettey, Christina M; McSweeney, Jean C; Stewart, Katharine E; Price, Elvin T; Cleves, Mario A; Heo, Seongkum; Souder, Elaine

2015-02-01

Pedigree development, family history, and genetic testing are thought to be useful in improving outcomes of chronic illnesses such as hypertension (HTN). However, the clinical utility of pedigree development is still unknown. Further, little is known about the perceptions of African Americans (AAs) of family history and genetic testing. This study examined the feasibility of developing pedigrees for AAs with HTN and explored perceptions of family history and genetic research among AAs with HTN. The US Surgeon General's My Family Health Portrait was administered, and 30-60 min in-person individual interviews were conducted. Descriptive statistics were used to analyze pedigree data. Interview transcripts were analyzed with content analysis and constant comparison. Twenty-nine AAs with HTN were recruited from one free clinic (15 women, 14 men; mean age 49 years, standard deviation (SD) 9.6). Twenty-six (90%) reported their family history in sufficient detail to develop a pedigree. Perceptions of family history included knowledge of HTN in the family, culturally influenced family teaching about HTN, and response to family history of HTN. Most participants agreed to future genetic testing and DNA collection because they wanted to help others; some said they needed more information and others expressed a concern for privacy. The majority of AAs in this sample possessed extensive knowledge of HTN within their family and were able to develop a three-generation pedigree with assistance. The majority were willing to participate in future genetic research. © The European Society of Cardiology 2014.

A Consensus Map for Loblolly Pine (Pinus taeda L.). I. Construction and Integration of Individual Linkage Maps From TwoOutbred Three-Generation Pedigrees

Treesearch

Mitchell M. Sewell; Bradley K. Sherman; David B. Neale

1998-01-01

A consensus map for loblolly pine (Pinus taeda L.) was constructed from the integration of linkage data from two unrelated three-generation out bred pedigrees. The progeny segregation data from restriction fragment length polymorphism, random amplified polymorphic DNA, and isozyme genetic markers from each pedigree were recoded to reflect the two independent...

An exploration of attitudes towards pedigree dogs and their disorders as expressed by a sample of companion animal veterinarians in New Zealand.

PubMed

Farrow, T; Keown, A J; Farnworth, M J

2014-09-01

To explore veterinary perceptions of inherited disorders in pedigree dogs within New Zealand and how these affect animal health and welfare. An online questionnaire was distributed to the 647 members of the Companion Animal Society of the New Zealand Veterinary Association using an online survey system. The questionnaire collected details of practitioners, pedigree dog breeds and disorders most often encountered in practice, and responses to questions and statements regarding inherited disorders and pedigree dogs. Of the 216 respondents, 194 (89.8%) believed inherited disorders in dogs were a significant issue. The most commonly identified breeds presenting with inherited disorders were Boxer, Bulldog and German Shepherd dog. The most commonly reported inherited disorders were hip dysplasia, brachycephalic syndromes and elbow dysplasia. Of 207 respondents, 100 (48.3%) had advised clients against purchasing a pedigree dog due to common inherited disorders and 183 (85.6%) considered the health and welfare of some breeds to be too compromised to continue breeding. Of 199 respondents, 132 (66.3%) reported seeing no change in prevalence of inherited conditions, 103/204 (50.5%) reported seeing a positive change in attitudes towards inherited disorders among dog owners, and 81/207 (39.1%) thought legislative support would help decrease inherited disorders in pedigree dogs. Attitudes were not associated with time since graduation or ownership of a New Zealand Kennel Club registered breed of dog. The most common suggestions to decrease prevalence of inherited disorders were to alter breed standards, educate public or buyers and compulsory genetic testing. Among respondents, veterinarians considered inherited disorders as significant issues in a number of pedigree breeds. Veterinarians were concerned about inherited disorders in pedigree dogs, felt they had an obligation to treat such animals and were supportive of measures to make genetic testing for inheritable disorders a requirement for registration of pedigree breeds. Prevalence and perceived importance of inherited disorders influences how clinicians advise their clients. Respondents to this survey provided a number of mechanisms by which inherited disorders may be managed and these could form the basis of future discussions within the profession.

Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment.

PubMed

Gagnon, France; Jarvik, Gail P; Motulsky, Arno G; Deeb, Samir S; Brunzell, John D; Wijsman, Ellen M

2003-11-01

The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus.

[Genetic risk of families with t(1;2)(q42;q33) GTG, RHG, QFQ, FISH].

PubMed

Stasiewicz-Jarocka, B; Raczkiewicz, B; Kowalczyk, D; Zawada, M; Midro, A T

2000-10-01

A central concept in genetic counseling is the estimation of the probability of recurrence of unfavourable pregnancy outcomes (abortion, stillbirth and birth at malformed child). In case of chromosomal changes estimates are made on basis of segregation analyses in actual pedigree. If we have a few of pedigree members than risk estimate should be performed on basis combined our data and empiric data from literature. We present individual genetic risk for carriers of unique reciprocal translocation t(1;2)(q42;q33) detected through karyotyping of the patient with miscarriage. The pedigree consisted 5 families of t(1;2)(q42;q33) carriers with 15 members of progeny was evaluated according to Stene and Stengel-Rutkowski. Cytogenetic analysis of persons of these families (7 persons) was performed on blood samples using GTG, RHG, QFQ and FISH techniques. Additional RCT pedigree analysis of Stengel-Rutkowski et at Collection, Polish Collection, Lituanian Collection, Bielorussian Collection and an available literature cases were performed. The translocation was classified as translocation at risk for double segment imbalances for trisomy 1q42-->qter together with monosomy 2q33-->qter or monosomy 1q42-->qter together with trisomy 2q33-->qter after 2:2 disjunction after adjacent-1 segregation of the meiotic chromosomes. Two improved risk values for RCT with segments 1q42-->qter, 2q33-->qter were obtained i.e. 6/44 (13.6% +/- 5.2%) and 4/20 (20% +/- 8.9%). The probability of occurrence for this translocation carriers was estimated as 7% (medium risk). On basis of direct analysis at presented pedigree a risk for miscarriage was estimated as 2/9. 1. Carrierships of t(1;2)(q42;q33) increased population risk value for unbalanced progeny at birth by 7% (medium risk) and for miscarriage 2/9. 2. Causative relation between presence of t(1;2)(q42;q33) and miscarriages is suggested. 3. Updated, new genetic risk values for RCT at risk for single segment 1q42-->qter imbalance is 6/44 (13.6% +/- 5.2%) at birth and for single segment 2q33-->qter imbalance is 4/20 (20% +/- 8.9%).

Nonsense mutations in the PAX3 gene cause Waardenburg syndrome type I in two Chinese patients.

PubMed

Yang, Shu-Zhi; Cao, Ju-Yang; Zhang, Rui-Ning; Liu, Li-Xian; Liu, Xin; Zhang, Xin; Kang, Dong-Yang; Li, Mei; Han, Dong-Yi; Yuan, Hui-Jun; Yang, Wei-Yan

2007-01-05

Waardenburg syndrome type I (WS1) is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmental abnormalities of the eye, hair and skin, and dystopia canthorum. The gene mainly responsible for WS1 is PAX3 which is involved in melanocytic development and survival. Mutations of PAX3 have been reported in familiar or sporadic patients with WS1 in several populations of the world except Chinese. In order to explore the genetic background of Chinese WS1 patients, a mutation screening of PAX3 gene was carried out in four WS1 pedigrees. A questionnaire survey and comprehensive clinical examination were conducted in four Chinese pedigrees of WS1. Genomic DNA from each patient and their family members was extracted and exons of PAX3 were amplified by PCR. PCR fragments were ethanol-purified and sequenced in both directions on an ABI_Prism 3100 DNA sequencer with the BigDye Terminator Cycle Sequencing Ready Reaction Kit. The sequences were obtained and aligned to the wild type sequence of PAX3 with the GeneTool program. Two nonsense PAX3 mutations have been found in the study population. One is heterozygous for a novel nonsense mutation S209X. The other is heterozygous for a previously reported mutation in European population R223X. Both mutations create stop codons leading to truncation of the PAX3 protein. This is the first demonstration of PAX3 mutations in Chinese WS1 patients and one of the few examples of an identical mutation of PAX3 occurred in different populations.

A Consensus Genetic Map for Pinus taeda and Pinus elliottii and Extent of Linkage Disequilibrium in Two Genotype-Phenotype Discovery Populations of Pinus taeda

PubMed Central

Westbrook, Jared W.; Chhatre, Vikram E.; Wu, Le-Shin; Chamala, Srikar; Neves, Leandro Gomide; Muñoz, Patricio; Martínez-García, Pedro J.; Neale, David B.; Kirst, Matias; Mockaitis, Keithanne; Nelson, C. Dana; Peter, Gary F.; Echt, Craig S.

2015-01-01

A consensus genetic map for Pinus taeda (loblolly pine) and Pinus elliottii (slash pine) was constructed by merging three previously published P. taeda maps with a map from a pseudo-backcross between P. elliottii and P. taeda. The consensus map positioned 3856 markers via genotyping of 1251 individuals from four pedigrees. It is the densest linkage map for a conifer to date. Average marker spacing was 0.6 cM and total map length was 2305 cM. Functional predictions of mapped genes were improved by aligning expressed sequence tags used for marker discovery to full-length P. taeda transcripts. Alignments to the P. taeda genome mapped 3305 scaffold sequences onto 12 linkage groups. The consensus genetic map was used to compare the genome-wide linkage disequilibrium in a population of distantly related P. taeda individuals (ADEPT2) used for association genetic studies and a multiple-family pedigree used for genomic selection (CCLONES). The prevalence and extent of LD was greater in CCLONES as compared to ADEPT2; however, extended LD with LGs or between LGs was rare in both populations. The average squared correlations, r2, between SNP alleles less than 1 cM apart were less than 0.05 in both populations and r2 did not decay substantially with genetic distance. The consensus map and analysis of linkage disequilibrium establish a foundation for comparative association mapping and genomic selection in P. taeda and P. elliottii. PMID:26068575

A locus for isolated cataract on human Xp

PubMed Central

Francis, P; Berry, V; Hardcastle, A; Maher, E; Moore, A; Bhattacharya, S

2002-01-01

Purpose: To genetically map the gene causing isolated X linked cataract in a large European pedigree. Methods: Using the patient registers at Birmingham Women's Hospital, UK, we identified and examined 23 members of a four generation family with nuclear cataract. Four of six affected males also had complex congenital heart disease. Pedigree data were collated and leucocyte DNA extracted from venous blood. Linkage analysis by PCR based microsatellite marker genotyping was used to identify the disease locus and mutations within candidate genes screened by direct sequencing. Results: The disease locus was genetically refined to chromosome Xp22, within a 3 cM linkage interval flanked by markers DXS9902 and DXS999 (Zmax=3.64 at θ=0 for marker DXS8036). Conclusions: This is the first report of a locus for isolated inherited cataract on the X chromosome. The disease interval lies within the Nance-Horan locus suggesting allelic heterogeneity. The apparent association with congenital cardiac anomalies suggests a possible new oculocardiac syndrome. PMID:11836358

A locus for isolated cataract on human Xp.

PubMed

Francis, P J; Berry, V; Hardcastle, A J; Maher, E R; Moore, A T; Bhattacharya, S S

2002-02-01

To genetically map the gene causing isolated X linked cataract in a large European pedigree. Using the patient registers at Birmingham Women's Hospital, UK, we identified and examined 23 members of a four generation family with nuclear cataract. Four of six affected males also had complex congenital heart disease. Pedigree data were collated and leucocyte DNA extracted from venous blood. Linkage analysis by PCR based microsatellite marker genotyping was used to identify the disease locus and mutations within candidate genes screened by direct sequencing. The disease locus was genetically refined to chromosome Xp22, within a 3 cM linkage interval flanked by markers DXS9902 and DXS999 (Zmax=3.64 at theta=0 for marker DXS8036). This is the first report of a locus for isolated inherited cataract on the X chromosome. The disease interval lies within the Nance-Horan locus suggesting allelic heterogeneity. The apparent association with congenital cardiac anomalies suggests a possible new oculocardiac syndrome.

Genome-wide linkage in Utah autism pedigrees

PubMed Central

Allen-Brady, K; Robison, R; Cannon, D; Varvil, T; Villalobos, M; Pingree, C; Leppert, MF; Miller, J; McMahon, WM; Coon, H

2014-01-01

Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended pedigrees may offer valuable insight, as the relatively few susceptibility genes within single large families may be more easily discerned. This genome-wide screen of 70 families includes 20 large extended pedigrees of 6–9 generations, 6 moderate-sized families of 4–5 generations, and 44 smaller families of 2–3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single nucleotide polymorphism (SNP) platform. Results from 192 subjects with an Autism Spectrum Disorder (ASD), and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1-q14 (HLOD=4.09 at 29,459,872bp); 15q14-q21.1 (HLOD=3.59 at 36,837,208bp); and 15q21.1-q22.2 (HLOD=5.31 at 55,629,733bp). Two of these peaks replicate previous findings. There were additional suggestive results on chromosomes 2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97), and 13q12.11-q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups. PMID:19455147

Linkage results on 11q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia

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

Maziade, M.; Raymond, V.; Cliche, D.

The 11q21-22 region is of interest for schizophrenia because several candidate genes are located in this section of the genome. The 11q21-22 region, including DRD2, was surveyed by linkage analysis in a sample (N = 242) made of four large multigenerational pedigrees densely affected by schizophrenia (SZ) and eight others by bipolar disorder (BP). These pedigrees were ascertained in a large area of Eastern Quebec and Northern New Brunswick and are still being extended. Family members were administered a {open_quotes}consensus best-estimate diagnosis procedure{close_quotes} (DSM-III-R criteria) blind to probands and relatives` diagnosis and to pedigree assignment (SZ or BP). For linkagemore » analysis, 11 microsatellite polymorphism (CA repeat) markers, located at 11q21-22, and comprising DRD2, were genotyped. Results show no evidence of a major gene for schizophrenia. However, a maximum lod score of 3.41 at the D11S35 locus was observed in an affected-only analysis of one large SZ family, pedigree 255. Whether or not the positive linkage trend in pedigree 255 reflects a true linkage for a small proportion of SZ needs to be confirmed through the extension of this kindred and through replication. 36 refs., 2 tabs.« less

Within- and across-breed genomic predictions and genomic relationships for Western Pyrenees dairy sheep breeds Latxa, Manech, and Basco-Béarnaise.

PubMed

Legarra, A; Baloche, G; Barillet, F; Astruc, J M; Soulas, C; Aguerre, X; Arrese, F; Mintegi, L; Lasarte, M; Maeztu, F; Beltrán de Heredia, I; Ugarte, E

2014-05-01

Genotypes, phenotypes and pedigrees of 6 breeds of dairy sheep (including subdivisions of Latxa, Manech, and Basco-Béarnaise) from the Spain and France Western Pyrenees were used to estimate genetic relationships across breeds (together with genotypes from the Lacaune dairy sheep) and to verify by forward cross-validation single-breed or multiple-breed genetic evaluations. The number of rams genotyped fluctuated between 100 and 1,300 but generally represented the 10 last cohorts of progeny-tested rams within each breed. Genetic relationships were assessed by principal components analysis of the genomic relationship matrices and also by the conservation of linkage disequilibrium patterns at given physical distances in the genome. Genomic and pedigree-based evaluations used daughter yield performances of all rams, although some of them were not genotyped. A pseudo-single step method was used in this case for genomic predictions. Results showed a clear structure in blond and black breeds for Manech and Latxa, reflecting historical exchanges, and isolation of Basco-Béarnaise and Lacaune. Relatedness between any 2 breeds was, however, lower than expected. Single-breed genomic predictions had accuracies comparable with other breeds of dairy sheep or small breeds of dairy cattle. They were more accurate than pedigree predictions for 5 out of 6 breeds, with absolute increases in accuracy ranging from 0.05 to 0.30 points. They were significantly better, as assessed by bootstrapping of candidates, for 2 of the breeds. Predictions using multiple populations only marginally increased the accuracy for a couple of breeds. Pooling populations does not increase the accuracy of genomic evaluations in dairy sheep; however, single-breed genomic predictions are more accurate, even for small breeds, and make the consideration of genomic schemes in dairy sheep interesting. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Utilization of the Tablet Application Proband in Pedigree Construction and Assessment.

PubMed

McCarty, Andrew Joseph; Miller, Jeffrey M; Fecteau, Heather; Pennington, Jeffrey W; Kessler, Lisa

2018-04-01

Many medical institutions have converted to a digital model for record keeping due to the Health Information Technology for Economic and Clinical Health Act. This Act provides incentives to health care systems to accelerate and encourage the adoption of electronic health record (EHR) systems. The pedigree as a tool in medicine provides an efficient method to assess and represent an individual's health and family health risks that may otherwise not be apparent in the medical record in a clearly identifiable way (Schuette, J. L., & Bennett 2009). Many clinicians continue to construct pedigrees using pen and paper method despite findings of improved identification of at risk patients with similar electronic intake tools (Arar et al. in Personalized Medicine 2011 8:523-32). The goal of this study was to explore the patient and practitioner experience with electronic pedigree programs using Proband, an application developed at The Children's Hospital of Philadelphia for genetic counselors to construct pedigrees during genetic counseling sessions directly on iPads. The first part of this study looked at the patient experience and assessed time to take the pedigree and the impact of using an electronic pedigree tool on the relationship between participant and genetic counselor. This involved 50 participants and was compared with the traditional paper method of taking a pedigree. There was no statistical significance found between the two different mediums in accuracy, speed, and rapport with provider. The second part of the study assessed the usability of Proband by ten genetic counselors. Overall, the application received a system usability score of 90/100 with a majority (7/10) of counselors agreeing that they would use this application in their clinic. The positive outcome of this study encourages future work to assess the impact and usability of programs on a larger scale as they continue to integrate into current electronic health records.

Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors.

PubMed

Jones, Matthew L; Norman, Jane E; Morgan, Neil V; Mundell, Stuart J; Lordkipanidzé, Marie; Lowe, Gillian C; Daly, Martina E; Simpson, Michael A; Drake, Sian; Watson, Steve P; Mumford, Andrew D

2015-04-01

Platelet responses to activating agonists are influenced by common population variants within or near G protein-coupled receptor (GPCR) genes that affect receptor activity. However, the impact of rare GPCR gene variants is unknown. We describe the rare single nucleotide variants (SNVs) in the coding and splice regions of 18 GPCR genes in 7,595 exomes from the 1,000-genomes and Exome Sequencing Project databases and in 31 cases with inherited platelet function disorders (IPFDs). In the population databases, the GPCR gene target regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop gain and 6 splice region) of which 70 % had global minor allele frequency (MAF) < 0.05 %. Functional annotation using six computational algorithms, experimental evidence and structural data identified 156/740 (21 %) SNVs as potentially damaging to GPCR function, most commonly in regions encoding the transmembrane and C-terminal intracellular receptor domains. In 31 index cases with IPFDs (Gi-pathway defect n=15; secretion defect n=11; thromboxane pathway defect n=3 and complex defect n=2) there were 256 SNVs in the target regions of 15 stimulatory platelet GPCRs (34 unique; 12 with MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting R122H, P258T and V207A substitutions in the P2Y12 receptor that were annotated as potentially damaging, but only partially explained the platelet function defects in each case. Our data highlight that potentially damaging variants in platelet GPCR genes have low individual frequencies, but are collectively abundant in the population. Potentially damaging variants are also present in pedigrees with IPFDs and may contribute to complex laboratory phenotypes.

Novel autosomal recessive gene mutations in aquaporin-2 in two Chinese congenital nephrogenic diabetes insipidus pedigrees

PubMed Central

Cen, Jing; Nie, Min; Duan, Lian; Gu, Feng

2015-01-01

Recent evidence has linked novel mutations in the arginine vasopressin receptor 2 gene (AVPR2) and aquaporin-2 gene (AQP2) present in Southeast Asian populations to congenital nephrogenic diabetes insipidus (NDI). To investigate mutations in 2 distinct Chinese pedigrees with NDI patients, clinical data, laboratory findings, and genomic DNA sequences from peripheral blood leukocytes were analyzed in two 5.5- and 8-year-old boys (proband 1 and 2, respectively) and their first-degree relatives. Water intake, urinary volume, body weight and medication use were recorded. Mutations in coding regions and intron-exon borders of both AQP2 and AVPR2 gene were sequenced. Three mutations in AQP2 were detected, including previously reported heterozygous frameshift mutation (c.127_128delCA, p.Gln43Aspfs ×63) inherited from the mother, a novel frameshift mutation (c.501_502insC, p.Val168Argfs ×30, inherited from the father) in proband 1 and a novel missense mutation (c. 643G>A, p. G215S), inherited from both parents in proband 2. In family 2 both parents and one sister were heterozygous carriers of the novel missense mutation. Neither pedigree exhibited mutation in the AVPR2 gene. The patient with truncated AQP2 may present with much more severe NDI manifestations. Identification of these novel AQP2 gene mutations expands the AQP2 genotypic spectrum and may contribute to etiological diagnosis and genetic counseling. PMID:26064258

Brisk deep-tendon reflexes as a distinctive phenotype in an Argentinean spinocerebellar ataxia type 2 pedigree.

PubMed

Rosa, Alberto L; Molina, Irma; Kowaljow, Valeria; Conde, Cecilia B

2006-01-01

Slow saccades, postural/intention tremor, peripheral neuropathy, and decreased deep-tendon reflexes are valuable neurological signs for clinical suspicion of spinocerebellar ataxia type 2 (SCA2). We report the presence of abnormally brisk deep-tendon reflexes in nonsymptomatic carriers and mildly and severely affected subjects of a large Argentinean SCA2 pedigree. The identification of this distinctive SCA2 phenotype in an entire pedigree reinforces the current concept that clinical algorithms are of limited value as indicators for genetic testing in SCA. Combined with published pedigrees of SCA2 manifesting as levodopa-responsive parkinsonism, this finding suggests that modifier genes could influence the clinical phenotype of SCA2. Copyright (c) 2005 Movement Disorder Society.

Genetic analysis of the CHCHD2 gene in a cohort of Chinese patients with Parkinson disease.

PubMed

Wu, Hongwei; Lu, Xingjiao; Xie, Fei; Cen, Zhidong; Zheng, Xiaosheng; Luo, Wei

2016-08-26

CHCHD2 has been recently reported as a causative gene for autosomal dominant Parkinson disease (ADPD) in Japanese populations. Further genetic studies of CHCHD2 in other populations are needed. Herein, we sequenced CHCHD2 gene in 162 patients (90 from ADPD pedigrees, 72 with sporadic Parkinson disease) and 90 healthy controls in Chinese population. We observed 5 exonic variants (c.-34C>A, c.-9T>G, c.5C>T, c.*125G>A, c.*154A>G) including 1 novel variant. No pathogenic mutation was found, suggesting that CHCHD2 mutations may be rare in Chinese ADPD patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Familial auditory neuropathy.

PubMed

Wang, Qiuju; Gu, Rui; Han, Dongyi; Yang, Weiyan

2003-09-01

Auditory neuropathy is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses and normal cochlear outer hair cell function as measured by otoacoustic emission recordings. Many risk factors are thought to be involved in its etiology and pathophysiology. Four Chinese pedigrees with familial auditory neuropathy were presented to demonstrate involvement of genetic factors in the etiology of auditory neuropathy. Probands of the above-mentioned pedigrees, who had been diagnosed with auditory neuropathy, were evaluated and followed in the Department of Otolaryngology-Head and Neck Surgery, China People Liberation Army General Hospital (Beijing, China). Their family members were studied, and the pedigree maps established. History of illness, physical examination, pure-tone audiometry, acoustic reflex, auditory brainstem responses, and transient evoked and distortion-product otoacoustic emissions were obtained from members of these families. Some subjects received vestibular caloric testing, computed tomography scan of the temporal bone, and electrocardiography to exclude other possible neuropathic disorders. In most affected patients, hearing loss of various degrees and speech discrimination difficulties started at 10 to 16 years of age. Their audiological evaluation showed absence of acoustic reflex and auditory brainstem responses. As expected in auditory neuropathy, these patients exhibited near-normal cochlear outer hair cell function as shown in distortion product otoacoustic emission recordings. Pure-tone audiometry revealed hearing loss ranging from mild to profound in these patients. Different inheritance patterns were observed in the four families. In Pedigree I, 7 male patients were identified among 43 family members, exhibiting an X-linked recessive pattern. Affected brothers were found in Pedigrees II and III, whereas in pedigree IV, two sisters were affected. All the patients were otherwise normal without evidence of peripheral neuropathy at the time of writing. Patients with characteristics of nonsyndromic hereditary auditory neuropathy were identified in one large and three smaller Chinese families. Pedigree analysis suggested an X-linked, recessive hereditary pattern in one pedigree and autosomal recessive inheritances in the other three pedigrees. The phenotypes in the study were typical of auditory neuropathy; they were transmitted in different inheritance patterns, indicating clinical and genetic heterogeneity of this disorder. The observed inheritance and clinical audiological findings are different from those previously described for nonsyndromic low-frequency sensorineural hearing loss. This information should facilitate future molecular linkage analyses and positional cloning for the relative genes contributing to auditory neuropathy.

Elucidation of the ‘Honeycrisp’ pedigree through haplotype analysis with a multi-family integrated SNP linkage map and a large apple (Malus×domestica) pedigree-connected SNP data set

PubMed Central

Howard, Nicholas P; van de Weg, Eric; Bedford, David S; Peace, Cameron P; Vanderzande, Stijn; Clark, Matthew D; Teh, Soon Li; Cai, Lichun; Luby, James J

2017-01-01

The apple (Malus×domestica) cultivar Honeycrisp has become important economically and as a breeding parent. An earlier study with SSR markers indicated the original recorded pedigree of ‘Honeycrisp’ was incorrect and ‘Keepsake’ was identified as one putative parent, the other being unknown. The objective of this study was to verify ‘Keepsake’ as a parent and identify and genetically describe the unknown parent and its grandparents. A multi-family based dense and high-quality integrated SNP map was created using the apple 8 K Illumina Infinium SNP array. This map was used alongside a large pedigree-connected data set from the RosBREED project to build extended SNP haplotypes and to identify pedigree relationships. ‘Keepsake’ was verified as one parent of ‘Honeycrisp’ and ‘Duchess of Oldenburg’ and ‘Golden Delicious’ were identified as grandparents through the unknown parent. Following this finding, siblings of ‘Honeycrisp’ were identified using the SNP data. Breeding records from several of these siblings suggested that the previously unreported parent is a University of Minnesota selection, MN1627. This selection is no longer available, but now is genetically described through imputed SNP haplotypes. We also present the mosaic grandparental composition of ‘Honeycrisp’ for each of its 17 chromosome pairs. This new pedigree and genetic information will be useful in future pedigree-based genetic studies to connect ‘Honeycrisp’ with other cultivars used widely in apple breeding programs. The created SNP linkage map will benefit future research using the data from the Illumina apple 8 and 20 K and Affymetrix 480 K SNP arrays. PMID:28243452

Two novel CHN1 mutations in two families with Duane’s retraction syndrome

PubMed Central

Chan, Wai-Man; Miyake, Noriko; Zhu-Tam, Lily; Andrews, Caroline; Engle, Elizabeth C.

2012-01-01

Objective To determine the genetic cause of Duane’s retraction syndrome (DRS) in two families segregating DRS as an autosomal dominant trait. Method Members of two unrelated pedigrees were enrolled in an ongoing genetic study. Linkage analysis was performed using fluorescent microsatellite markers flanking the CHN1 locus. Probands and family members were screened for CHN1 mutations. Results Of the six clinically affected individuals in the two pedigrees, three have bilateral and three have unilateral DRS. Both pedigrees are consistent with linkage to the DURS2 locus, one with complete and one with incomplete penetrance. Sequence analysis revealed the pedigrees segregate novel heterozygous missense CHN1 mutations, c.422C>T and c.754C>T, predicted to result in α2-chimaerin amino acid substitutions P141L and P252S, respectively. Conclusion Genetic analysis of two pedigrees segregating nonsyndromic DRS reveals two novel mutations in CHN1, bringing the number of DRS pedigrees know to harbor CHN1 mutations, and the number of unique CHN1 mutations, from seven to nine. Both mutations identified in this study alter residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of α2-chimerin, and thus are predicted to result in its hyper-activation. Moreover, amino acid residue P252 was altered to a different residue in a previously reported DRS pedigree; thus, this is the first report of two CHN1 mutations altering the same residue, further supporting a gain-of-function etiology. Clinical Relevance Members of families segregating DRS as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis. PMID:21555619

Pedigree data analysis with crossover interference.

PubMed Central

Browning, Sharon

2003-01-01

We propose a new method for calculating probabilities for pedigree genetic data that incorporates crossover interference using the chi-square models. Applications include relationship inference, genetic map construction, and linkage analysis. The method is based on importance sampling of unobserved inheritance patterns conditional on the observed genotype data and takes advantage of fast algorithms for no-interference models while using reweighting to allow for interference. We show that the method is effective for arbitrarily many markers with small pedigrees. PMID:12930760

Targeted next generation sequencing identified a novel mutation in MYO7A causing Usher syndrome type 1 in an Iranian consanguineous pedigree.

PubMed

Kooshavar, Daniz; Razipour, Masoumeh; Movasat, Morteza; Keramatipour, Mohammad

2018-01-01

Usher syndrome (USH) is characterized by congenital hearing loss and retinitis pigmentosa (RP) with a later onset. It is an autosomal recessive trait with clinical and genetic heterogeneity which makes the molecular diagnosis much difficult. In this study, we introduce a pedigree with two affected members with USH type 1 and represent a cost and time effective approach for genetic diagnosis of USH as a genetically heterogeneous disorder. Target region capture in the genes of interest, followed by next generation sequencing (NGS) was used to determine the causative mutations in one of the probands. Then segregation analysis in the pedigree was conducted using PCR-Sanger sequencing. Targeted NGS detected a novel homozygous nonsense variant c.4513G > T (p.Glu1505Ter) in MYO7A. The variant is segregating in the pedigree with an autosomal recessive pattern. In this study, a novel stop gained variant c.4513G > T (p.Glu1505Ter) in MYO7A was found in an Iranian pedigree with two affected members with USH type 1. Bioinformatic as well as pedigree segregation analyses were in line with pathogenic nature of this variant. Targeted NGS panel was showed to be an efficient method for mutation detection in hereditary disorders with locus heterogeneity. Copyright © 2017 Elsevier B.V. All rights reserved.

Manila clam Venerupis philippinarum as a biomonitor to metal pollution

NASA Astrophysics Data System (ADS)

Wu, Huifeng; Ji, Chenglong; Wang, Qing; Liu, Xiaoli; Zhao, Jianmin; Feng, Jianghua

2013-01-01

The Manila clam Venerupis philippinarum is a good biomonitor/bioindicator to marine metal pollution and is frequently used in aquatic toxicology. Two dominant pedigrees (white and zebra) of clam are distributed in the Bohai Sea; however, little attention has been paid to potential biological differences between these two pedigrees. In this study, we tested the sensitivity of both pedigrees to marine metal (cadmium and zinc) pollution biomonitoring and marine environmental toxicology. Results demonstrate significant biological differences in gills of white and zebra clams based on metabolic profiles and antioxidant enzyme activities. In addition, we found that hypotaurine, malonate and homarine were relatively high in white clam gills, while alanine, arginine, glutamate, succinate, 4-aminobutyrate, taurine and betaine were high in zebra clam gills. Zebra clam gills were also more sensitive to a mixture of Cd and Zn, as shown by antioxidant enzyme activities and metabolic profiles, but white clam gills could accumulate more Zn. Therefore, we suggest that the white pedigree can be used as a biomonitor to marine Zn pollution, whereas the zebra pedigree can be used for toxicology studies on Cd and Zn mixed pollution.

SeqSIMLA2_exact: simulate multiple disease sites in large pedigrees with given disease status for diseases with low prevalence.

PubMed

Yao, Po-Ju; Chung, Ren-Hua

2016-02-15

It is difficult for current simulation tools to simulate sequence data in a pre-specified pedigree structure and pre-specified affection status. Previously, we developed a flexible tool, SeqSIMLA2, for simulating sequence data in either unrelated case-control or family samples with different disease and quantitative trait models. Here we extended the tool to efficiently simulate sequences with multiple disease sites in large pedigrees with a given disease status for each pedigree member, assuming that the disease prevalence is low. SeqSIMLA2_exact is implemented with C++ and is available at http://seqsimla.sourceforge.net. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

In Silico Genome Mismatch Scanning to Map Breast Cancer Genes in Extended Pedigrees

DTIC Science & Technology

2008-07-01

University College London Annals of Human Genetics (2008) 72,279–287 279 A. Thomas et al. Methods IBD sharing in pedigrees There is considerable literature...is sufficient to maintain interest in the region. 282 Annals of Human Genetics (2008) 72,279–287 C© 2007 The Authors Journal compilation C© 2007...for observed IBS instead of IBD, and for sporadic cases reducing the number of meioses, pedigrees with meiosis count d in the 25 to 30 range are

Population genetic structure analysis and effect of inbreeding on body weights at different ages in Iranian Mehraban sheep.

PubMed

Yavarifard, Roya; Ghavi Hossein-Zadeh, Navid; Shadparvar, Abdol Ahad

2014-01-01

The objective of this study was to describe the population structure and inbreeding, and to quantify their effects on weights at different ages of Mehraban sheep in Iran. The analysis was based on the pedigree information of 26990 animals and 10278 body weight records from birth to yearling age. Data and pedigree information were collected during 1994 to 2011 by the breeding station of Mehraban sheep. The population structure was analyzed using the CFC program. Inbreeding of all animals was calculated by INBUPGF90 program. All animals were grouped into three classes according to their inbreeding coefficients: the first class included non-inbred animals (F=0); and the second and third classes included inbred animals (0

Impact of reduced marker set estimation of genomic relationship matrices on genomic selection for feed efficiency in Angus cattle.

PubMed

Rolf, Megan M; Taylor, Jeremy F; Schnabel, Robert D; McKay, Stephanie D; McClure, Matthew C; Northcutt, Sally L; Kerley, Monty S; Weaber, Robert L

2010-04-19

Molecular estimates of breeding value are expected to increase selection response due to improvements in the accuracy of selection and a reduction in generation interval, particularly for traits that are difficult or expensive to record or are measured late in life. Several statistical methods for incorporating molecular data into breeding value estimation have been proposed, however, most studies have utilized simulated data in which the generated linkage disequilibrium may not represent the targeted livestock population. A genomic relationship matrix was developed for 698 Angus steers and 1,707 Angus sires using 41,028 single nucleotide polymorphisms and breeding values were estimated using feed efficiency phenotypes (average daily feed intake, residual feed intake, and average daily gain) recorded on the steers. The number of SNPs needed to accurately estimate a genomic relationship matrix was evaluated in this population. Results were compared to estimates produced from pedigree-based mixed model analysis of 862 Angus steers with 34,864 identified paternal relatives but no female ancestors. Estimates of additive genetic variance and breeding value accuracies were similar for AFI and RFI using the numerator and genomic relationship matrices despite fewer animals in the genomic analysis. Bootstrap analyses indicated that 2,500-10,000 markers are required for robust estimation of genomic relationship matrices in cattle. This research shows that breeding values and their accuracies may be estimated for commercially important sires for traits recorded in experimental populations without the need for pedigree data to establish identity by descent between members of the commercial and experimental populations when at least 2,500 SNPs are available for the generation of a genomic relationship matrix.

Meiotic and pedigree segregation analyses in carriers of t(4;8)(p16;p23.1) differing in localization of breakpoint positions at 4p subband 4p16.3 and 4p16.1.

PubMed

Midro, Alina T; Zollino, Marcella; Wiland, Ewa; Panasiuk, Barbara; Iwanowski, Piotr S; Murdolo, Marina; Śmigiel, Robert; Sąsiadek, Maria; Pilch, Jacek; Kurpisz, Maciej

2016-02-01

The purpose of this study was to compare meiotic segregation in sperm cells from two carriers with t(4;8)(p16;p23.1) reciprocal chromosome translocations (RCTs), differing in localization of the breakpoint positions at the 4p subband-namely, 4p16.3 (carrier 1) and 4p16.1 (carrier 2)-and to compare data of the pedigree analyses performed by direct method. Three-color fluorescent in situ hybridization (FISH) on sperm cells and FISH mapping for the evaluation of the breakpoint positions, data from pedigrees, and direct segregation analysis of the pedigrees were performed. Similar proportions of normal/balanced and unbalanced sperm cells were found in both carriers. The most common was an alternate type of segregation (about 52 % and about 48 %, respectively). Unbalanced adjacent I and adjacent II karyotypes were found in similar proportions about 15 %. The direct segregation analysis (following Stengel-Rutkowski) of the pedigree of carriers of t(4;8)(p16.1;p23.1) was performed and results were compared with the data of the pedigree segregation analysis obtained earlier through the indirect method. The probability of live-born progeny with unbalanced karyotype for carriers of t(4;8)(p16.1;p23.1) was moderately high at 18.8 %-comparable to the value obtained using the indirect method for the same carriership, which was 12 %. This was, however, markedly lower than the value of 41.2 % obtained through the pedigree segregation indirect analysis estimated for carriers of t(4;8)(p16.3;p23.1), perhaps due to the unique composition of genes present within the 4p16.1-4p 16.3 region. Revealed differences in pedigree segregation analysis did not correspond to the very similar profile of meiotic segregation patterns presented by carrier 1 and carrier 2. Most probably, such discordances may be due to differences in embryo survival rates arising from different genetic backgrounds.

Ischemic Stroke: From Next Generation Sequencing and GWAS to Community Genomics?

PubMed

Black, Michael; Wang, Wenzhi; Wang, Wei

2015-08-01

Stroke is a major cause of mortality and morbidity in both the developed and developing world. Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the way we research and understand stroke. These biotechnologies also signal a shift from genetics to genomics of stroke, which is highlighted in this review. Stroke is a focal neurological deficit resulting from disruption of the cerebral blood supply. There are two main types of common stroke, ischemic stroke (IS), which comprises 80% of cases, and hemorrhagic stroke (HS) that accounts for about 20% of cases. IS is a complex multi-factorial disease with multiple environmental and genomic determinants. We discuss here IS from genomics and bioinformatics perspectives, including the highlights of the genome wide association studies (GWAS), NGS progress to date, and exome studies. While both 'common variant, common disease' and 'rare variant, common disease' approaches need to be assessed in tandem, future studies into IS omics should also consider pedigree and/or community based sampling to take account of the complex diversity of IS genetics. We conclude by presenting an example of such community genomics research from China in an extended pedigree sample, and the ways in which the intersection of genomics and global society can usefully inform our understanding of IS pathophysiology and potential preventive medicine interventions in the future.

Evaluation of the major histocompatibility complex (Mhc) in cranes: applications to conservation efforts

USGS Publications Warehouse

Jarvi, S.I.; Miller, M.M.; Goto, R.M.; Gee, G.F.; Briles, W.E.

2001-01-01

Although there have been heated discussions concerning the relative importance of using Mhc diversity as a basis for selecting breeders in conservation projects, most parties agree that the genetic variability residual in an endangered species should be maintained through genetic management, if at all possible. Substantial evidence exists (particularly in birds) documenting the influences of specific Mhc haplotypes on disease outcome and also that those individuals which are heterozygous for Mhc alleles appear to have an advantage for survival over those that are homozygous. Thus, conservation of genetic variability of the Mhc is likely important for the preservation of fitness, especially in small breeding populations. More than half of the world's crane species are listed as endangered. Members of all 15 known species are represented among breeding animals for captive propagation at the International Crane Foundation (Wisconsin) and the USGS Patuxent Wildlife Research Center (Maryland). Collaborative multi-organization efforts and the availability of extensive pedigree records have allowed the study of Mhc variability in several species of cranes. We have found, for example, that Mhc diversity in the captive Florida sandhill crane (Grus canadensis pratensis) population appears high, whereas in the captive whooping crane (Grus americana), which has undergone a severe 'genetic bottleneck,? both the number of alleles and the levels of heterozygosity appear to be substantially reduced.

Linkage disequilibrium interval mapping of quantitative trait loci.

PubMed

Boitard, Simon; Abdallah, Jihad; de Rochambeau, Hubert; Cierco-Ayrolles, Christine; Mangin, Brigitte

2006-03-16

For many years gene mapping studies have been performed through linkage analyses based on pedigree data. Recently, linkage disequilibrium methods based on unrelated individuals have been advocated as powerful tools to refine estimates of gene location. Many strategies have been proposed to deal with simply inherited disease traits. However, locating quantitative trait loci is statistically more challenging and considerable research is needed to provide robust and computationally efficient methods. Under a three-locus Wright-Fisher model, we derived approximate expressions for the expected haplotype frequencies in a population. We considered haplotypes comprising one trait locus and two flanking markers. Using these theoretical expressions, we built a likelihood-maximization method, called HAPim, for estimating the location of a quantitative trait locus. For each postulated position, the method only requires information from the two flanking markers. Over a wide range of simulation scenarios it was found to be more accurate than a two-marker composite likelihood method. It also performed as well as identity by descent methods, whilst being valuable in a wider range of populations. Our method makes efficient use of marker information, and can be valuable for fine mapping purposes. Its performance is increased if multiallelic markers are available. Several improvements can be developed to account for more complex evolution scenarios or provide robust confidence intervals for the location estimates.

High-density linkage mapping in a pine tree reveals a genomic region associated with inbreeding depression and provides clues to the extent and distribution of meiotic recombination

PubMed Central

2013-01-01

Background The availability of a large expressed sequence tags (EST) resource and recent advances in high-throughput genotyping technology have made it possible to develop highly multiplexed SNP arrays for multi-objective genetic applications, including the construction of meiotic maps. Such approaches are particularly useful in species with a large genome size, precluding the use of whole-genome shotgun assembly with current technologies. Results In this study, a 12 k-SNP genotyping array was developed for maritime pine from an extensive EST resource assembled into a unigene set. The offspring of three-generation outbred and inbred mapping pedigrees were then genotyped. The inbred pedigree consisted of a classical F2 population resulting from the selfing of a single inter-provenance (Landes x Corsica) hybrid tree, whereas the outbred pedigree (G2) resulted from a controlled cross of two intra-provenance (Landes x Landes) hybrid trees. This resulted in the generation of three linkage maps based on SNP markers: one from the parental genotype of the F2 population (1,131 markers in 1,708 centimorgan (cM)), and one for each parent of the G2 population (1,015 and 1,110 markers in 1,447 and 1,425 cM for the female and male parents, respectively). A comparison of segregation patterns in the progeny obtained from the two types of mating (inbreeding and outbreeding) led to the identification of a chromosomal region carrying an embryo viability locus with a semi-lethal allele. Following selfing and segregation, zygote mortality resulted in a deficit of Corsican homozygous genotypes in the F2 population. This dataset was also used to study the extent and distribution of meiotic recombination along the length of the chromosomes and the effect of sex and/or genetic background on recombination. The genetic background of trees in which meiotic recombination occurred was found to have a significant effect on the frequency of recombination. Furthermore, only a small proportion of the recombination hot- and cold-spots were common to all three genotypes, suggesting that the spatial pattern of recombination was genetically variable. Conclusion This study led to the development of classical genomic tools for this ecologically and economically important species. It also identified a chromosomal region bearing a semi-lethal recessive allele and demonstrated the genetic variability of recombination rate over the genome. PMID:23597128

The Tennessee Mouse Genome Consortium: Identification of ocular mutants

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

Jablonski, Monica M.; Wang, Xiaofei; Lu, Lu

2005-06-01

The Tennessee Mouse Genome Consortium (TMGC) is in its fifth year of a ethylnitrosourea (ENU)-based mutagenesis screen to detect recessive mutations that affect the eye and brain. Each pedigree is tested by various phenotyping domains including the eye, neurohistology, behavior, aging, ethanol, drug, social behavior, auditory, and epilepsy domains. The utilization of a highly efficient breeding protocol and coordination of various universities across Tennessee makes it possible for mice with ENU-induced mutations to be evaluated by nine distinct phenotyping domains within this large-scale project known as the TMGC. Our goal is to create mutant lines that model human diseases andmore » disease syndromes and to make the mutant mice available to the scientific research community. Within the eye domain, mice are screened for anterior and posterior segment abnormalities using slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, eye weight, histology, and immunohistochemistry. As of January 2005, we have screened 958 pedigrees and 4800 mice, excluding those used in mapping studies. We have thus far identified seven pedigrees with primary ocular abnormalities. Six of the mutant pedigrees have retinal or subretinal aberrations, while the remaining pedigree presents with an abnormal eye size. Continued characterization of these mutant mice should in most cases lead to the identification of the mutated gene, as well as provide insight into the function of each gene. Mice from each of these pedigrees of mutant mice are available for distribution to researchers for independent study.« less

Primary broiler breeding--striking a balance between economic and well-being traits.

PubMed

Katanbaf, M N; Hardiman, J W

2010-04-01

Primary breeders are well aware that selecting for better health and well-being along with economic traits such as faster growth rate, higher levels of meat yield, and improved efficiency of feed utilization are critical to balanced long-term genetic progress of their pure lines as well as to increased production efficiency of broiler products for the broiler industry. Cobb collects and selects on over 50 phenotypic observations per pedigree candidate at various ages. Over 50% of these collections are involved with evaluation of each bird's health, welfare, and fitness. Some examples of these traits are various chick defects, various broiler age skeletal and leg abnormalities, feather cover, various physiological measures of heart and lung functions, and specific causes of mortality. Large pedigree populations, massive data collection infrastructure, integration of better technologies in evaluation of phenotypes, and sophisticated data analysis capability have allowed geneticists to perform selections that are balanced for both economic and welfare traits. Cobb's internal as well as worldwide sponsored research has facilitated geneticists to make science-based breeding decisions. Each pedigree line per product available to primary breeders exhibits their own unique characteristics that are enhanced by selective breeding and positioned in special mating schemes to produce the product and welfare performance that our customers demand. Additionally, most if not all primary breeding companies now offer different products for different markets that exhibit varying levels of performance and behavior to fit customer needs. Future expansion of these products and creation of new products by breeding companies will be in large dictated by both our customers and consumers.

Endogenous Retrovirus Insertion in the KIT Oncogene Determines White and White spotting in Domestic Cats

PubMed Central

David, Victor A.; Menotti-Raymond, Marilyn; Wallace, Andrea Coots; Roelke, Melody; Kehler, James; Leighty, Robert; Eizirik, Eduardo; Hannah, Steven S.; Nelson, George; Schäffer, Alejandro A.; Connelly, Catherine J.; O’Brien, Stephen J.; Ryugo, David K.

2014-01-01

The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively. PMID:25085922

Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats.

PubMed

David, Victor A; Menotti-Raymond, Marilyn; Wallace, Andrea Coots; Roelke, Melody; Kehler, James; Leighty, Robert; Eizirik, Eduardo; Hannah, Steven S; Nelson, George; Schäffer, Alejandro A; Connelly, Catherine J; O'Brien, Stephen J; Ryugo, David K

2014-08-01

The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively. Copyright © 2014 David et al.

Adjusting for founder relatedness in a linkage analysis using prior information.

PubMed

Sheehan, N A; Egeland, T

2008-01-01

In genetic linkage studies, while the pedigrees are generally known, background relatedness between the founding individuals, assumed by definition to be unrelated, can seriously affect the results of the analysis. Likelihood approaches to relationship estimation from genetic marker data can all be expressed in terms of finding the most likely pedigree connecting the individuals of interest. When the true relationship is the main focus, the set of all possible alternative pedigrees can be too large to consider. However, prior information is often available which, when incorporated in a formal and structured way, can restrict this set to a manageable size thus enabling the calculation of a posterior distribution from which inferences can be drawn. Here, the unknown relationships are more of a nuisance factor than of interest in their own right, so the focus is on adjusting the results of the analysis rather than on direct estimation. In this paper, we show how prior information on founder relationships can be exploited in some applications to generate a set of candidate extended pedigrees. We then weight the relevant pedigree-specific likelihoods by their posterior probabilities to adjust the lod score statistics. (c) 2007 S. Karger AG, Basel

Multilocus lod scores in large pedigrees: combination of exact and approximate calculations.

PubMed

Tong, Liping; Thompson, Elizabeth

2008-01-01

To detect the positions of disease loci, lod scores are calculated at multiple chromosomal positions given trait and marker data on members of pedigrees. Exact lod score calculations are often impossible when the size of the pedigree and the number of markers are both large. In this case, a Markov Chain Monte Carlo (MCMC) approach provides an approximation. However, to provide accurate results, mixing performance is always a key issue in these MCMC methods. In this paper, we propose two methods to improve MCMC sampling and hence obtain more accurate lod score estimates in shorter computation time. The first improvement generalizes the block-Gibbs meiosis (M) sampler to multiple meiosis (MM) sampler in which multiple meioses are updated jointly, across all loci. The second one divides the computations on a large pedigree into several parts by conditioning on the haplotypes of some 'key' individuals. We perform exact calculations for the descendant parts where more data are often available, and combine this information with sampling of the hidden variables in the ancestral parts. Our approaches are expected to be most useful for data on a large pedigree with a lot of missing data. (c) 2007 S. Karger AG, Basel

Multilocus Lod Scores in Large Pedigrees: Combination of Exact and Approximate Calculations

PubMed Central

Tong, Liping; Thompson, Elizabeth

2007-01-01

To detect the positions of disease loci, lod scores are calculated at multiple chromosomal positions given trait and marker data on members of pedigrees. Exact lod score calculations are often impossible when the size of the pedigree and the number of markers are both large. In this case, a Markov Chain Monte Carlo (MCMC) approach provides an approximation. However, to provide accurate results, mixing performance is always a key issue in these MCMC methods. In this paper, we propose two methods to improve MCMC sampling and hence obtain more accurate lod score estimates in shorter computation time. The first improvement generalizes the block-Gibbs meiosis (M) sampler to multiple meiosis (MM) sampler in which multiple meioses are updated jointly, across all loci. The second one divides the computations on a large pedigree into several parts by conditioning on the haplotypes of some ‘key’ individuals. We perform exact calculations for the descendant parts where more data are often available, and combine this information with sampling of the hidden variables in the ancestral parts. Our approaches are expected to be most useful for data on a large pedigree with a lot of missing data. PMID:17934317

Analyzing Association Mapping in Pedigree-Based GWAS Using a Penalized Multitrait Mixed Model

PubMed Central

Liu, Jin; Yang, Can; Shi, Xingjie; Li, Cong; Huang, Jian; Zhao, Hongyu; Ma, Shuangge

2017-01-01

Genome-wide association studies (GWAS) have led to the identification of many genetic variants associated with complex diseases in the past 10 years. Penalization methods, with significant numerical and statistical advantages, have been extensively adopted in analyzing GWAS. This study has been partly motivated by the analysis of Genetic Analysis Workshop (GAW) 18 data, which have two notable characteristics. First, the subjects are from a small number of pedigrees and hence related. Second, for each subject, multiple correlated traits have been measured. Most of the existing penalization methods assume independence between subjects and traits and can be suboptimal. There are a few methods in the literature based on mixed modeling that can accommodate correlations. However, they cannot fully accommodate the two types of correlations while conducting effective marker selection. In this study, we develop a penalized multitrait mixed modeling approach. It accommodates the two different types of correlations and includes several existing methods as special cases. Effective penalization is adopted for marker selection. Simulation demonstrates its satisfactory performance. The GAW 18 data are analyzed using the proposed method. PMID:27247027

Construction of a High-Density American Cranberry (Vaccinium macrocarpon Ait.) Composite Map Using Genotyping-by-Sequencing for Multi-pedigree Linkage Mapping

PubMed Central

Schlautman, Brandon; Covarrubias-Pazaran, Giovanny; Diaz-Garcia, Luis; Iorizzo, Massimo; Polashock, James; Grygleski, Edward; Vorsa, Nicholi; Zalapa, Juan

2017-01-01

The American cranberry (Vaccinium macrocarpon Ait.) is a recently domesticated, economically important, fruit crop with limited molecular resources. New genetic resources could accelerate genetic gain in cranberry through characterization of its genomic structure and by enabling molecular-assisted breeding strategies. To increase the availability of cranberry genomic resources, genotyping-by-sequencing (GBS) was used to discover and genotype thousands of single nucleotide polymorphisms (SNPs) within three interrelated cranberry full-sib populations. Additional simple sequence repeat (SSR) loci were added to the SNP datasets and used to construct bin maps for the parents of the populations, which were then merged to create the first high-density cranberry composite map containing 6073 markers (5437 SNPs and 636 SSRs) on 12 linkage groups (LGs) spanning 1124 cM. Interestingly, higher rates of recombination were observed in maternal than paternal gametes. The large number of markers in common (mean of 57.3) and the high degree of observed collinearity (mean Pair-wise Spearman rank correlations >0.99) between the LGs of the parental maps demonstrates the utility of GBS in cranberry for identifying polymorphic SNP loci that are transferable between pedigrees and populations in future trait-association studies. Furthermore, the high-density of markers anchored within the component maps allowed identification of segregation distortion regions, placement of centromeres on each of the 12 LGs, and anchoring of genomic scaffolds. Collectively, the results represent an important contribution to the current understanding of cranberry genomic structure and to the availability of molecular tools for future genetic research and breeding efforts in cranberry. PMID:28250016

HLA Haplotype Frequency Estimation from Real-Life Data with the Hapl-o-Mat Software.

PubMed

Sauter, Jürgen; Schäfer, Christian; Schmidt, Alexander H

2018-01-01

HLA haplotype frequencies are of use in a variety of settings. Such data is typically derived either from family pedigree data by targeted typing or statistical analysis of large population-specific genotype samples. As established tools for the latter approach lacked ability to treat the amount, ambiguity, and inhomogeneity found in genotype data in hematopoietic stem cell donor registries, we developed Hapl-o-Mat to alleviate these specific shortcomings.

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.

Accuracy of predicting genomic breeding values for residual feed intake in Angus and Charolais beef cattle.

PubMed

Chen, L; Schenkel, F; Vinsky, M; Crews, D H; Li, C

2013-10-01

In beef cattle, phenotypic data that are difficult and/or costly to measure, such as feed efficiency, and DNA marker genotypes are usually available on a small number of animals of different breeds or populations. To achieve a maximal accuracy of genomic prediction using the phenotype and genotype data, strategies for forming a training population to predict genomic breeding values (GEBV) of the selection candidates need to be evaluated. In this study, we examined the accuracy of predicting GEBV for residual feed intake (RFI) based on 522 Angus and 395 Charolais steers genotyped on SNP with the Illumina Bovine SNP50 Beadchip for 3 training population forming strategies: within breed, across breed, and by pooling data from the 2 breeds (i.e., combined). Two other scenarios with the training and validation data split by birth year and by sire family within a breed were also investigated to assess the impact of genetic relationships on the accuracy of genomic prediction. Three statistical methods including the best linear unbiased prediction with the relationship matrix defined based on the pedigree (PBLUP), based on the SNP genotypes (GBLUP), and a Bayesian method (BayesB) were used to predict the GEBV. The results showed that the accuracy of the GEBV prediction was the highest when the prediction was within breed and when the validation population had greater genetic relationships with the training population, with a maximum of 0.58 for Angus and 0.64 for Charolais. The within-breed prediction accuracies dropped to 0.29 and 0.38, respectively, when the validation populations had a minimal pedigree link with the training population. When the training population of a different breed was used to predict the GEBV of the validation population, that is, across-breed genomic prediction, the accuracies were further reduced to 0.10 to 0.22, depending on the prediction method used. Pooling data from the 2 breeds to form the training population resulted in accuracies increased to 0.31 and 0.43, respectively, for the Angus and Charolais validation populations. The results suggested that the genetic relationship of selection candidates with the training population has a greater impact on the accuracy of GEBV using the Illumina Bovine SNP50 Beadchip. Pooling data from different breeds to form the training population will improve the accuracy of across breed genomic prediction for RFI in beef cattle.

Recruitment of Yoruba families from Nigeria for genetic research: experience from a multisite keloid study.

PubMed

Olaitan, Peter B; Odesina, Victoria; Ademola, Samuel; Fadiora, Solomon O; Oluwatosin, Odunayo M; Reichenberger, Ernst J

2014-09-02

More involvement of sub-Saharan African countries in biomedical studies, specifically in genetic research, is needed to advance individualized medicine that will benefit non-European populations. Missing infrastructure, cultural and religious beliefs as well as lack of understanding of research benefits can pose a challenge to recruitment. Here we describe recruitment efforts for a large genetic study requiring three-generation pedigrees within the Yoruba homelands of Nigeria. The aim of the study was to identify genes responsible for keloids, a wound healing disorder. We also discuss ethical and logistical considerations that we encountered in preparation for this research endeavor. Protocols for this bi-national intercultural study were approved by the Institutional Review Board (IRB) in the US and the ethics committees of the Nigerian institutions for consideration of cultural differences. Principles of community based participatory research were employed throughout the recruitment process. Keloid patients (patient advisors), community leaders, kings/chiefs and medical directors were engaged to assist the research teams with recruitment strategies. Community meetings, church forums, and media outlets (study flyers, radio and TV announcements) were utilized to promote the study in Nigeria. Recruitment of research participants was conducted by trained staff from the local communities. Pedigree structures were re-analyzed on a regular basis as new family members were recruited and recruitment challenges were documented. Total recruitment surpassed 4200 study participants over a 7-year period including 79 families with complete three-generation pedigrees. In 9 families more than 20 family members participated, however, in 5 of these families, we encountered issues with pedigree structure as members from different branches presented inconsistent family histories. These issues were due to the traditional open family structure amongst the Yoruba and by beliefs in voodoo or in juju. In addition, family members living in other parts of the country or abroad complicated timely and complete family recruitment. Organizational, logistics and ethics challenges can be overcome by additional administrative efforts, good communication, community involvement and education of staff members. However, recruitment challenges due to infrastructural shortcomings or cultural and religious beliefs can lead to significant delays, which may negatively affect study time lines and expectations of funding agencies.

Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.

PubMed Central

Sobel, E.; Lange, K.

1996-01-01

The introduction of stochastic methods in pedigree analysis has enabled geneticists to tackle computations intractable by standard deterministic methods. Until now these stochastic techniques have worked by running a Markov chain on the set of genetic descent states of a pedigree. Each descent state specifies the paths of gene flow in the pedigree and the founder alleles dropped down each path. The current paper follows up on a suggestion by Elizabeth Thompson that genetic descent graphs offer a more appropriate space for executing a Markov chain. A descent graph specifies the paths of gene flow but not the particular founder alleles traveling down the paths. This paper explores algorithms for implementing Thompson's suggestion for codominant markers in the context of automatic haplotyping, estimating location scores, and computing gene-clustering statistics for robust linkage analysis. Realistic numerical examples demonstrate the feasibility of the algorithms. PMID:8651310

[Mutation analysis of beta myosin heavy chain gene in hypertrophic cardiomyopathy families].

PubMed

Fan, Xin-ping; Yang, Zhong-wei; Feng, Xiu-li; Yang, Fu-hui; Xiao, Bai; Liang, Yan

2011-08-01

To detect the gene mutations of beta-myosin heavy chain gene (MYH7) in Chinese pedigrees with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. Exons 3, 5, 7-9, 11-16 and 18-23 of the MYH7 gene were amplified with PCR in three Chinese pedigrees with HCM. The products were sequenced. Sequence alignment between the detected and the standard sequences was performed. A missense mutation of Thr441Met in exon 14 was identified in a pedigree, which was not detected in the controls. Several synonymous mutations of MYH7 gene were detected in the three pedigrees. The mutation of Thr441Met, located in the actin binding domain of the globular head, was first identified in Chinese. It probably caused HCM. HCM is a heterogeneous disease. Many factors are involved in the process of its occurrence and development.

A genealogical survey of Australian registered dog breeds.

PubMed

Shariflou, Mohammad R; James, John W; Nicholas, Frank W; Wade, Claire M

2011-08-01

Breeding practices were analysed for 32 registered dog breeds representing very small registries (120 Central Asian shepherd dogs) through to very large registries (252,521 German shepherd dogs) in Australia. The vast majority (91%) of registered kennels in Australia that were sampled did not regularly employ either close breeding or popular sire usage in their kennels and the weighted mean inbreeding coefficient of Australian pedigree dogs was <5%. Australian breed mean inbreeding coefficients ranged from 0% (Central Asian shepherd dog) to 10.1% (Bichon Frise). Breed effective population sizes ranged from 26 (Ibizan hound) to 1090 (Golden retriever), comparable with other species of domesticated animals. The relatively low levels of inbreeding suggest that pedigree dog disorders are unlikely to arise frequently from the use of popular sires or close breeding in Australian registered dog breeds. It is possible that deleterious allele fixation might be driven by founder effects, genetic drift or adverse selection practices, which were not assessed in this analysis. European popular sire definitions should be revisited for rare breeds. Copyright © 2011. Published by Elsevier Ltd.

Molecular investigation of mental retardation locus gene PRSS12 by linkage analysis

PubMed Central

Ali, Zafar; Babar, Masroor Ellahi; Ahmad, Jamil; Yousaf, Muhammad Zubair; Asif, Muhammad; Shah, Sajjad Ali

2011-01-01

The present study was carried out to determine the prevalence of families having mental retardation in Pakistani population. We enrolled seven mentally retarded (MR) families with two or more affected individuals. Family history was taken to minimize the chances of other abnormalities. Pedigrees were drawn using the Cyrillic software (version 2.1). The structure of pedigrees shows that all the marriages are consanguineous and the families have recessive mode of inheritance. All the families were studied by linkage analysis to mental retardation locus (MRT1)/gene PRSS12. Three STR markers (D4S191, D4S2392, and D4S3024) in vicinity of mental retardation (MR) locus (MRT1)/gene PRSS12 were amplified on all the sample of each family by PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). The Haplotype were constructed to determine the pattern of inheritance and also to determine that a family was linked or unlinked to gene PRSS12. One out of the seven families was potentially linked to gene PRSS12, while the other six families remain unlinked. PMID:22090715

Molecular investigation of mental retardation locus gene PRSS12 by linkage analysis.

PubMed

Ali, Zafar; Babar, Masroor Ellahi; Ahmad, Jamil; Yousaf, Muhammad Zubair; Asif, Muhammad; Shah, Sajjad Ali

2011-05-01

The present study was carried out to determine the prevalence of families having mental retardation in Pakistani population. We enrolled seven mentally retarded (MR) families with two or more affected individuals. Family history was taken to minimize the chances of other abnormalities. Pedigrees were drawn using the Cyrillic software (version 2.1). The structure of pedigrees shows that all the marriages are consanguineous and the families have recessive mode of inheritance. All the families were studied by linkage analysis to mental retardation locus (MRT1)/gene PRSS12. Three STR markers (D4S191, D4S2392, and D4S3024) in vicinity of mental retardation (MR) locus (MRT1)/gene PRSS12 were amplified on all the sample of each family by PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). The Haplotype were constructed to determine the pattern of inheritance and also to determine that a family was linked or unlinked to gene PRSS12. One out of the seven families was potentially linked to gene PRSS12, while the other six families remain unlinked.

A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.

PubMed

Savitz, Jonathan; van der Merwe, Lize; Solms, Mark; Ramesar, Rajkumar

2007-01-01

The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.

Efficient Breeding by Genomic Mating.

PubMed

Akdemir, Deniz; Sánchez, Julio I

2016-01-01

Selection in breeding programs can be done by using phenotypes (phenotypic selection), pedigree relationship (breeding value selection) or molecular markers (marker assisted selection or genomic selection). All these methods are based on truncation selection, focusing on the best performance of parents before mating. In this article we proposed an approach to breeding, named genomic mating, which focuses on mating instead of truncation selection. Genomic mating uses information in a similar fashion to genomic selection but includes information on complementation of parents to be mated. Following the efficiency frontier surface, genomic mating uses concepts of estimated breeding values, risk (usefulness) and coefficient of ancestry to optimize mating between parents. We used a genetic algorithm to find solutions to this optimization problem and the results from our simulations comparing genomic selection, phenotypic selection and the mating approach indicate that current approach for breeding complex traits is more favorable than phenotypic and genomic selection. Genomic mating is similar to genomic selection in terms of estimating marker effects, but in genomic mating the genetic information and the estimated marker effects are used to decide which genotypes should be crossed to obtain the next breeding population.

The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity.

PubMed

Christensen, G B; Knight, S; Camp, N J

2009-11-01

We present the "sumLINK" statistic--the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus--as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the "sumLOD" statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. sumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage-based statistics as well. Using 500 genome-wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome-wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta-analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak.

Genetic evaluation of the total hip score of four populous breeds of dog, as recorded by the New Zealand Veterinary Association Hip Dysplasia Scheme (1991-2011).

PubMed

Soo, M; Sneddon, N W; Lopez-Villalobos, N; Worth, A J

2015-03-01

To use estimated breeding value (EBV) analysis to investigate the genetic trend of the total hip score (to assess canine hip dysplasia) in four populous breeds of dogs using the records from the New Zealand Veterinary Association (NZVA) Canine Hip Dysplasia Scheme database (1991 to 2011). Estimates of heritability and EBV for the NZVA total hip score of individual dogs from the German Shepherd, Labrador Retriever, Golden Retriever and Rottweiler breeds were obtained using restricted maximum likelihood procedures with a within-breed linear animal model. The model included the fixed effects of gender, birth year, birth season, age at scoring and the random effect of animal. The pedigree file included animals recorded between 1990 and 2011. A total of 2,983 NZVA hip score records, from a pedigree of 3,172 animals, were available for genetic evaluation. Genetic trends of the NZVA total hip score were calculated as the regression coefficient of the EBV (weighted by reliabilities) on year of birth. The estimates of heritability for hip score were 0.32 (SE 0.08) in German Shepherd, 0.37 (SE 0.08) in Labrador Retriever, 0.29 (SE 0.08) in Golden Retriever and 0.52 (SE 0.18) in Rottweiler breeds. Genetic trend analysis revealed that only the German Shepherd breed exhibited a genetic trend towards better hip conformation over time, with a decline of 0.13 (SE 0.04) NZVA total hip score units per year (p<0.001). The genetic trends of total hip score for the remaining three breeds were not significantly different from zero (p>0.1). Despite moderate heritability of the NZVA total hip score, there has not been substantial improvement of this trait for the four breeds analysed in the study period. Greater improvement in reducing the prevalence of canine hip dysplasia may be possible if screening were to be compulsory as a requirement for registration of pedigree breeding stock, greater selection pressure were to be applied and selection of breeding stock made on the basis on an individual's EBV rather than the NZVA total hip score alone.

Using the Animal Model to Accelerate Response to Selection in a Self-Pollinating Crop

PubMed Central

Cowling, Wallace A.; Stefanova, Katia T.; Beeck, Cameron P.; Nelson, Matthew N.; Hargreaves, Bonnie L. W.; Sass, Olaf; Gilmour, Arthur R.; Siddique, Kadambot H. M.

2015-01-01

We used the animal model in S0 (F1) recurrent selection in a self-pollinating crop including, for the first time, phenotypic and relationship records from self progeny, in addition to cross progeny, in the pedigree. We tested the model in Pisum sativum, the autogamous annual species used by Mendel to demonstrate the particulate nature of inheritance. Resistance to ascochyta blight (Didymella pinodes complex) in segregating S0 cross progeny was assessed by best linear unbiased prediction over two cycles of selection. Genotypic concurrence across cycles was provided by pure-line ancestors. From cycle 1, 102/959 S0 plants were selected, and their S1 self progeny were intercrossed and selfed to produce 430 S0 and 575 S2 individuals that were evaluated in cycle 2. The analysis was improved by including all genetic relationships (with crossing and selfing in the pedigree), additive and nonadditive genetic covariances between cycles, fixed effects (cycles and spatial linear trends), and other random effects. Narrow-sense heritability for ascochyta blight resistance was 0.305 and 0.352 in cycles 1 and 2, respectively, calculated from variance components in the full model. The fitted correlation of predicted breeding values across cycles was 0.82. Average accuracy of predicted breeding values was 0.851 for S2 progeny of S1 parent plants and 0.805 for S0 progeny tested in cycle 2, and 0.878 for S1 parent plants for which no records were available. The forecasted response to selection was 11.2% in the next cycle with 20% S0 selection proportion. This is the first application of the animal model to cyclic selection in heterozygous populations of selfing plants. The method can be used in genomic selection, and for traits measured on S0-derived bulks such as grain yield. PMID:25943522

Novel mutations in CRB1 gene identified in a chinese pedigree with retinitis pigmentosa by targeted capture and next generation sequencing

PubMed Central

Lo, David; Weng, Jingning; Liu, xiaohong; Yang, Juhua; He, Fen; Wang, Yun; Liu, Xuyang

2016-01-01

PURPOSE To detect the disease-causing gene in a Chinese pedigree with autosomal-recessive retinitis pigmentosa (ARRP). METHODS All subjects in this family underwent a complete ophthalmic examination. Targeted-capture next generation sequencing (NGS) was performed on the proband to detect variants. All variants were verified in the remaining family members by PCR amplification and Sanger sequencing. RESULTS All the affected subjects in this pedigree were diagnosed with retinitis pigmentosa (RP). The compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations in the Crumbs homolog 1 (CRB1) gene were identified in all the affected patients but not in the unaffected individuals in this family. These mutations were inherited from their parents, respectively. CONCLUSION The novel compound heterozygous mutations in CRB1 were identified in a Chinese pedigree with ARRP using targeted-capture next generation sequencing. After evaluating the significant heredity and impaired protein function, the compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations are the causal genes of early onset ARRP in this pedigree. To the best of our knowledge, there is no previous report regarding the compound mutations. PMID:27806333

Modelling uncertain paternity to address differential pedigree accuracy

USDA-ARS?s Scientific Manuscript database

The objective was to implement uncertain parentage models to account for differences in daughter pedigree accuracy. Elite sires have nearly all daughters genotyped resulting in correct paternity assignment. Bulls of lesser genetic merit have fewer daughters genotyped creating the possibility for mor...

A genome-wide linkage and association study of musical aptitude identifies loci containing genes related to inner ear development and neurocognitive functions

PubMed Central

Oikkonen, J.; Huang, Y.; Onkamo, P.; Ukkola-Vuoti, L.; Raijas, P.; Karma, K.; Vieland, V. J.; Järvelä, I.

2014-01-01

Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several SNPs near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude. PMID:24614497

A genome-wide linkage and association study of musical aptitude identifies loci containing genes related to inner ear development and neurocognitive functions.

PubMed

Oikkonen, J; Huang, Y; Onkamo, P; Ukkola-Vuoti, L; Raijas, P; Karma, K; Vieland, V J; Järvelä, I

2015-02-01

Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several single nucleotide polymorphisms (SNPs) near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia-related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude.

Genomic Quantitative Genetics to Study Evolution in the Wild.

PubMed

Gienapp, Phillip; Fior, Simone; Guillaume, Frédéric; Lasky, Jesse R; Sork, Victoria L; Csilléry, Katalin

2017-12-01

Quantitative genetic theory provides a means of estimating the evolutionary potential of natural populations. However, this approach was previously only feasible in systems where the genetic relatedness between individuals could be inferred from pedigrees or experimental crosses. The genomic revolution opened up the possibility of obtaining the realized proportion of genome shared among individuals in natural populations of virtually any species, which could promise (more) accurate estimates of quantitative genetic parameters in virtually any species. Such a 'genomic' quantitative genetics approach relies on fewer assumptions, offers a greater methodological flexibility, and is thus expected to greatly enhance our understanding of evolution in natural populations, for example, in the context of adaptation to environmental change, eco-evolutionary dynamics, and biodiversity conservation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prediction of whole-genome risk for selection and management of hyperketonemia in Holstein dairy cattle.

PubMed

Weigel, K A; Pralle, R S; Adams, H; Cho, K; Do, C; White, H M

2017-06-01

Hyperketonemia (HYK), a common early postpartum health disorder characterized by elevated blood concentrations of β-hydroxybutyrate (BHB), affects millions of dairy cows worldwide and leads to significant economic losses and animal welfare concerns. In this study, blood concentrations of BHB were assessed for 1,453 Holstein cows using electronic handheld meters at four time points between 5 and 18 days postpartum. Incidence rates of subclinical (1.2 ≤ maximum BHB ≤ 2.9 mmol/L) and clinical ketosis (maximum BHB ≥ 3.0 mmol/L) were 24.0 and 2.4%, respectively. Variance components, estimated breeding values, and predicted HYK phenotypes were computed on the original, square-root, and binary scales. Heritability estimates for HYK ranged from 0.058 to 0.072 in pedigree-based analyses, as compared to estimates that ranged from 0.071 to 0.093 when pedigrees were augmented with 60,671 single nucleotide polymorphism genotypes of 959 cows and 801 male ancestors. On average, predicted HYK phenotypes from the genome-enhanced analysis ranged from 0.55 mmol/L for first-parity cows in the best contemporary group to 1.40 mmol/L for fourth-parity cows in the worst contemporary group. Genome-enhanced predictions of HYK phenotypes were more closely associated with actual phenotypes than pedigree-based predictions in five-fold cross-validation, and transforming phenotypes to reduce skewness and kurtosis also improved predictive ability. This study demonstrates the feasibility of using repeated cowside measurement of blood BHB concentration in early lactation to construct a reference population that can be used to estimate HYK breeding values for genomic selection programmes and predict HYK phenotypes for genome-guided management decisions. © 2017 Blackwell Verlag GmbH.

Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

PubMed Central

Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

2013-01-01

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10−7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis.

PubMed

Herdewyn, Sarah; Zhao, Hui; Moisse, Matthieu; Race, Valérie; Matthijs, Gert; Reumers, Joke; Kusters, Benno; Schelhaas, Helenius J; van den Berg, Leonard H; Goris, An; Robberecht, Wim; Lambrechts, Diether; Van Damme, Philip

2012-06-01

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has a familial cause in 10% of patients. Despite significant advances in the genetics of the disease, many families remain unexplained. We performed whole-genome sequencing in five family members from a pedigree with autosomal-dominant classical ALS. A family-based elimination approach was used to identify novel coding variants segregating with the disease. This list of variants was effectively shortened by genotyping these variants in 2 additional unaffected family members and 1500 unrelated population-specific controls. A novel rare coding variant in SPAG8 on chromosome 9p13.3 segregated with the disease and was not observed in controls. Mutations in SPAG8 were not encountered in 34 other unexplained ALS pedigrees, including 1 with linkage to chromosome 9p13.2-23.3. The shared haplotype containing the SPAG8 variant in this small pedigree was 22.7 Mb and overlapped with the core 9p21 linkage locus for ALS and frontotemporal dementia. Based on differences in coverage depth of known variable tandem repeat regions between affected and non-affected family members, the shared haplotype was found to contain an expanded hexanucleotide (GGGGCC)(n) repeat in C9orf72 in the affected members. Our results demonstrate that rare coding variants identified by whole-genome sequencing can tag a shared haplotype containing a non-coding pathogenic mutation and that changes in coverage depth can be used to reveal tandem repeat expansions. It also confirms (GGGGCC)n repeat expansions in C9orf72 as a cause of familial ALS.

Bayesian Statistics for Biological Data: Pedigree Analysis

ERIC Educational Resources Information Center

Stanfield, William D.; Carlton, Matthew A.

2004-01-01

The use of Bayes' formula is applied to the biological problem of pedigree analysis to show that the Bayes' formula and non-Bayesian or "classical" methods of probability calculation give different answers. First year college students of biology can be introduced to the Bayesian statistics.

Privacy protection and public goods: building a genetic database for health research in Newfoundland and Labrador

PubMed Central

Pullman, Daryl; Perrot-Daley, Astrid; Hodgkinson, Kathy; Street, Catherine; Rahman, Proton

2013-01-01

Objective To provide a legal and ethical analysis of some of the implementation challenges faced by the Population Therapeutics Research Group (PTRG) at Memorial University (Canada), in using genealogical information offered by individuals for its genetics research database. Materials and methods This paper describes the unique historical and genetic characteristics of the Newfoundland and Labrador founder population, which gave rise to the opportunity for PTRG to build the Newfoundland Genealogy Database containing digitized records of all pre-confederation (1949) census records of the Newfoundland founder population. In addition to building the database, PTRG has developed the Heritability Analytics Infrastructure, a data management structure that stores genotype, phenotype, and pedigree information in a single database, and custom linkage software (KINNECT) to perform pedigree linkages on the genealogy database. Discussion A newly adopted legal regimen in Newfoundland and Labrador is discussed. It incorporates health privacy legislation with a unique research ethics statute governing the composition and activities of research ethics boards and, for the first time in Canada, elevating the status of national research ethics guidelines into law. The discussion looks at this integration of legal and ethical principles which provides a flexible and seamless framework for balancing the privacy rights and welfare interests of individuals, families, and larger societies in the creation and use of research data infrastructures as public goods. Conclusion The complementary legal and ethical frameworks that now coexist in Newfoundland and Labrador provide the legislative authority, ethical legitimacy, and practical flexibility needed to find a workable balance between privacy interests and public goods. Such an approach may also be instructive for other jurisdictions as they seek to construct and use biobanks and related research platforms for genetic research. PMID:22859644

Privacy protection and public goods: building a genetic database for health research in Newfoundland and Labrador.

PubMed

Kosseim, Patricia; Pullman, Daryl; Perrot-Daley, Astrid; Hodgkinson, Kathy; Street, Catherine; Rahman, Proton

2013-01-01

To provide a legal and ethical analysis of some of the implementation challenges faced by the Population Therapeutics Research Group (PTRG) at Memorial University (Canada), in using genealogical information offered by individuals for its genetics research database. This paper describes the unique historical and genetic characteristics of the Newfoundland and Labrador founder population, which gave rise to the opportunity for PTRG to build the Newfoundland Genealogy Database containing digitized records of all pre-confederation (1949) census records of the Newfoundland founder population. In addition to building the database, PTRG has developed the Heritability Analytics Infrastructure, a data management structure that stores genotype, phenotype, and pedigree information in a single database, and custom linkage software (KINNECT) to perform pedigree linkages on the genealogy database. A newly adopted legal regimen in Newfoundland and Labrador is discussed. It incorporates health privacy legislation with a unique research ethics statute governing the composition and activities of research ethics boards and, for the first time in Canada, elevating the status of national research ethics guidelines into law. The discussion looks at this integration of legal and ethical principles which provides a flexible and seamless framework for balancing the privacy rights and welfare interests of individuals, families, and larger societies in the creation and use of research data infrastructures as public goods. The complementary legal and ethical frameworks that now coexist in Newfoundland and Labrador provide the legislative authority, ethical legitimacy, and practical flexibility needed to find a workable balance between privacy interests and public goods. Such an approach may also be instructive for other jurisdictions as they seek to construct and use biobanks and related research platforms for genetic research.

[A total of 362 HLA different haplotypes and HLA recombination haplotypes based on analysis of their family pedigree in Chinese partial Han populations].

PubMed

Gao, Su-Qing; Cheng, Xi; Li, Qian; Li, Yu-Zhu; Deng, Zhi-Hui

2009-06-01

This study was aimed to discover the novel HLA recombination haplotypes and investigate the distribution of haplotypes in Chinese Han population. Based on the HLA-A, B, DRB1 typing results of 179 family members, 791 haplotypes were assigned by the mode of inheritance. The results showed that a total of 4 novel recombinant haplotypes in HLA-DRB1 locus region were observed in 4 families, which ratio of paternal to maternal chromosomes was 3:1. The recombination ratio between HLA-DRB1 and HLA-A or B loci was 0.92% (4/433). There were a total of 362 kinds of HLA-A, -B, -DRB1 haplotypes to be confirmed in Chinese Han partial population. A33-B58-DR17, A2-B46-DR9, A30-B13-DR7, A11-B13-DR15, A11-B75-DR12 and A2-B46-DR14 were the most common haplotypes that was consistent with the distribution of HLA alleles in unrelated donors. There were A1-B63-DR12, A29-B46-DR15, A1-B61-DR10, A34-B35-DR9, A29-B54-DR4, A23-B13-DR16 and A34-B62-DR15 haplotypes and so on, which were rare haplotypes not yet reported in Chinese. It is concluded that the HLA-A-B-DRB1 haplotypes would be confirmed by analysis of their family pedigree. The results obtained in this study are basic data for study of Chinese anthropology, organ transplantation and disease correlation analysis.

Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.

PubMed

Visscher, P M; Haley, C S; Ewald, H; Mors, O; Egeland, J; Thiel, B; Ginns, E; Muir, W; Blackwood, D H

2005-02-05

To test the hypothesis that the same genetic loci confer susceptibility to, or protection from, disease in different populations, and that a combined analysis would improve the map resolution of a common susceptibility locus, we analyzed data from three studies that had reported linkage to bipolar disorder in a small region on chromosome 4p. Data sets comprised phenotypic information and genetic marker data on Scottish, Danish, and USA extended pedigrees. Across the three data sets, 913 individuals appeared in the pedigrees, 462 were classified, either as unaffected (323) or affected (139) with unipolar or bipolar disorder. A consensus linkage map was created from 14 microsatellite markers in a 33 cM region. Phenotypic and genetic data were analyzed using a variance component (VC) and allele sharing method. All previously reported elevated test statistics in the region were confirmed with one or both analysis methods, indicating the presence of one or more susceptibility genes to bipolar disorder in the three populations in the studied chromosome segment. When the results from both the VC and allele sharing method were considered, there was strong evidence for a susceptibility locus in the data from Scotland, some evidence in the data from Denmark and relatively less evidence in the data from the USA. The test statistics from the Scottish data set dominated the test statistics from the other studies, and no improved map resolution for a putative genetic locus underlying susceptibility in all three studies was obtained. Studies reporting linkage to the same region require careful scrutiny and preferably joint or meta analysis on the same basis in order to ensure that the results are truly comparable. (c) 2004 Wiley-Liss, Inc.

Construction of a High-Density American Cranberry (Vaccinium macrocarpon Ait.) Composite Map Using Genotyping-by-Sequencing for Multi-pedigree Linkage Mapping.

PubMed

Schlautman, Brandon; Covarrubias-Pazaran, Giovanny; Diaz-Garcia, Luis; Iorizzo, Massimo; Polashock, James; Grygleski, Edward; Vorsa, Nicholi; Zalapa, Juan

2017-04-03

The American cranberry ( Vaccinium macrocarpon Ait.) is a recently domesticated, economically important, fruit crop with limited molecular resources. New genetic resources could accelerate genetic gain in cranberry through characterization of its genomic structure and by enabling molecular-assisted breeding strategies. To increase the availability of cranberry genomic resources, genotyping-by-sequencing (GBS) was used to discover and genotype thousands of single nucleotide polymorphisms (SNPs) within three interrelated cranberry full-sib populations. Additional simple sequence repeat (SSR) loci were added to the SNP datasets and used to construct bin maps for the parents of the populations, which were then merged to create the first high-density cranberry composite map containing 6073 markers (5437 SNPs and 636 SSRs) on 12 linkage groups (LGs) spanning 1124 cM. Interestingly, higher rates of recombination were observed in maternal than paternal gametes. The large number of markers in common (mean of 57.3) and the high degree of observed collinearity (mean Pair-wise Spearman rank correlations >0.99) between the LGs of the parental maps demonstrates the utility of GBS in cranberry for identifying polymorphic SNP loci that are transferable between pedigrees and populations in future trait-association studies. Furthermore, the high-density of markers anchored within the component maps allowed identification of segregation distortion regions, placement of centromeres on each of the 12 LGs, and anchoring of genomic scaffolds. Collectively, the results represent an important contribution to the current understanding of cranberry genomic structure and to the availability of molecular tools for future genetic research and breeding efforts in cranberry. Copyright © 2017 Schlautman et al.

Genetic Variance Partitioning and Genome-Wide Prediction with Allele Dosage Information in Autotetraploid Potato.

PubMed

Endelman, Jeffrey B; Carley, Cari A Schmitz; Bethke, Paul C; Coombs, Joseph J; Clough, Mark E; da Silva, Washington L; De Jong, Walter S; Douches, David S; Frederick, Curtis M; Haynes, Kathleen G; Holm, David G; Miller, J Creighton; Muñoz, Patricio R; Navarro, Felix M; Novy, Richard G; Palta, Jiwan P; Porter, Gregory A; Rak, Kyle T; Sathuvalli, Vidyasagar R; Thompson, Asunta L; Yencho, G Craig

2018-05-01

As one of the world's most important food crops, the potato ( Solanum tuberosum L.) has spurred innovation in autotetraploid genetics, including in the use of SNP arrays to determine allele dosage at thousands of markers. By combining genotype and pedigree information with phenotype data for economically important traits, the objectives of this study were to (1) partition the genetic variance into additive vs. nonadditive components, and (2) determine the accuracy of genome-wide prediction. Between 2012 and 2017, a training population of 571 clones was evaluated for total yield, specific gravity, and chip fry color. Genomic covariance matrices for additive ( G ), digenic dominant ( D ), and additive × additive epistatic ( G # G ) effects were calculated using 3895 markers, and the numerator relationship matrix ( A ) was calculated from a 13-generation pedigree. Based on model fit and prediction accuracy, mixed model analysis with G was superior to A for yield and fry color but not specific gravity. The amount of additive genetic variance captured by markers was 20% of the total genetic variance for specific gravity, compared to 45% for yield and fry color. Within the training population, including nonadditive effects improved accuracy and/or bias for all three traits when predicting total genotypic value. When six F 1 populations were used for validation, prediction accuracy ranged from 0.06 to 0.63 and was consistently lower (0.13 on average) without allele dosage information. We conclude that genome-wide prediction is feasible in potato and that it will improve selection for breeding value given the substantial amount of nonadditive genetic variance in elite germplasm. Copyright © 2018 by the Genetics Society of America.

Generalized disequilibrium test for association in qualitative traits incorporating imprinting effects based on extended pedigrees.

PubMed

Li, Jian-Long; Wang, Peng; Fung, Wing Kam; Zhou, Ji-Yuan

2017-10-16

For dichotomous traits, the generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method. Genomic imprinting is an important epigenetic phenomenon and currently, there has been increasing interest of incorporating imprinting to improve the test power of association analysis. However, GDT-ME does not take imprinting effects into account, and it has not been investigated whether it can be used for association analysis when the effects indeed exist. In this article, based on a novel decomposition of the genotype score according to the paternal or maternal source of the allele, we propose the generalized disequilibrium test with imprinting (GDTI) for complete pedigrees without any missing genotypes. Then, we extend GDTI and GDT-ME to accommodate incomplete pedigrees with some pedigrees having missing genotypes, by using a Monte Carlo (MC) sampling and estimation scheme to infer missing genotypes given available genotypes in each pedigree, denoted by MCGDTI and MCGDT-ME, respectively. The proposed GDTI and MCGDTI methods evaluate the differences of the paternal as well as maternal allele scores for all discordant relative pairs in a pedigree, including beyond first-degree relative pairs. Advantages of the proposed GDTI and MCGDTI test statistics over existing methods are demonstrated by simulation studies under various simulation settings and by application to the rheumatoid arthritis dataset. Simulation results show that the proposed tests control the size well under the null hypothesis of no association, and outperform the existing methods under various imprinting effect models. The existing GDT-ME and the proposed MCGDT-ME can be used to test for association even when imprinting effects exist. For the application to the rheumatoid arthritis data, compared to the existing methods, MCGDTI identifies more loci statistically significantly associated with the disease. Under complete and incomplete imprinting effect models, our proposed GDTI and MCGDTI methods, by considering the information on imprinting effects and all discordant relative pairs within each pedigree, outperform all the existing test statistics and MCGDTI can recapture much of the missing information. Therefore, MCGDTI is recommended in practice.

The effect of rare alleles on estimated genomic relationships from whole genome sequence data.

PubMed

Eynard, Sonia E; Windig, Jack J; Leroy, Grégoire; van Binsbergen, Rianne; Calus, Mario P L

2015-03-12

Relationships between individuals and inbreeding coefficients are commonly used for breeding decisions, but may be affected by the type of data used for their estimation. The proportion of variants with low Minor Allele Frequency (MAF) is larger in whole genome sequence (WGS) data compared to Single Nucleotide Polymorphism (SNP) chips. Therefore, WGS data provide true relationships between individuals and may influence breeding decisions and prioritisation for conservation of genetic diversity in livestock. This study identifies differences between relationships and inbreeding coefficients estimated using pedigree, SNP or WGS data for 118 Holstein bulls from the 1000 Bull genomes project. To determine the impact of rare alleles on the estimates we compared three scenarios of MAF restrictions: variants with a MAF higher than 5%, variants with a MAF higher than 1% and variants with a MAF between 1% and 5%. We observed significant differences between estimated relationships and, although less significantly, inbreeding coefficients from pedigree, SNP or WGS data, and between MAF restriction scenarios. Computed correlations between pedigree and genomic relationships, within groups with similar relationships, ranged from negative to moderate for both estimated relationships and inbreeding coefficients, but were high between estimates from SNP and WGS (0.49 to 0.99). Estimated relationships from genomic information exhibited higher variation than from pedigree. Inbreeding coefficients analysis showed that more complete pedigree records lead to higher correlation between inbreeding coefficients from pedigree and genomic data. Finally, estimates and correlations between additive genetic (A) and genomic (G) relationship matrices were lower, and variances of the relationships were larger when accounting for allele frequencies than without accounting for allele frequencies. Using pedigree data or genomic information, and including or excluding variants with a MAF below 5% showed significant differences in relationship and inbreeding coefficient estimates. Estimated relationships and inbreeding coefficients are the basis for selection decisions. Therefore, it can be expected that using WGS instead of SNP can affect selection decision. Inclusion of rare variants will give access to the variation they carry, which is of interest for conservation of genetic diversity.

Evolution of the genetic variability of eight French dairy cattle breeds assessed by pedigree analysis.

PubMed

Danchin-Burge, C; Leroy, G; Brochard, M; Moureaux, S; Verrier, E

2012-06-01

A pedigree analysis was performed on eight French dairy cattle breeds to assess their change in genetic variability since a first analysis completed in 1996. The Holstein, Normande and Montbéliarde breeds are selected internationally with over hundreds of thousands cows registered in the performance recording system. Three breeds are internationally selected but with limited numbers of cows in France (Brown Swiss, French Simmental and French Red Pied). The last two remaining breeds (Abondance and Tarentaise) are raised at regional level. The effective numbers of ancestors of cows born between 2004 and 2007 varied between 15 (Abondance and Tarentaise) and 51 (French Red Pied). The effective population sizes (classical approach) varied between 53 (Abondance) and 197 (French Red Pied). This article also compares the genetic variability of the ex situ (collections of the French National Cryobank) and in situ populations. The results were commented in regard to the recent history of gene flows in the different breeds as well as the existence of more or less stringent bottlenecks. Our results showed that whatever the size of the breeds, their genetic diversity impoverished quite rapidly since 1996 and they all could be considered as quite poor from a genetic diversity point of view. It shows the need for setting up cryobanks as gene reservoirs as well as sustainable breeding programmes that include loss of genetic diversity as an integrated control parameter. © 2011 Blackwell Verlag GmbH.

An assessment of the reliability of quantitative genetics estimates in study systems with high rate of extra-pair reproduction and low recruitment.

PubMed

Bourret, A; Garant, D

2017-03-01

Quantitative genetics approaches, and particularly animal models, are widely used to assess the genetic (co)variance of key fitness related traits and infer adaptive potential of wild populations. Despite the importance of precision and accuracy of genetic variance estimates and their potential sensitivity to various ecological and population specific factors, their reliability is rarely tested explicitly. Here, we used simulations and empirical data collected from an 11-year study on tree swallow (Tachycineta bicolor), a species showing a high rate of extra-pair paternity and a low recruitment rate, to assess the importance of identity errors, structure and size of the pedigree on quantitative genetic estimates in our dataset. Our simulations revealed an important lack of precision in heritability and genetic-correlation estimates for most traits, a low power to detect significant effects and important identifiability problems. We also observed a large bias in heritability estimates when using the social pedigree instead of the genetic one (deflated heritabilities) or when not accounting for an important cause of resemblance among individuals (for example, permanent environment or brood effect) in model parameterizations for some traits (inflated heritabilities). We discuss the causes underlying the low reliability observed here and why they are also likely to occur in other study systems. Altogether, our results re-emphasize the difficulties of generalizing quantitative genetic estimates reliably from one study system to another and the importance of reporting simulation analyses to evaluate these important issues.

Direct estimate of the spontaneous germ line mutation rate in African green monkeys.

PubMed

Pfeifer, Susanne P

2017-12-01

Here, I provide the first direct estimate of the spontaneous mutation rate in an Old World monkey, using a seven individual, three-generation pedigree of African green monkeys. Eight de novo mutations were identified within ∼1.5 Gbp of accessible genome, corresponding to an estimated point mutation rate of 0.94 × 10 -8 per site per generation, suggesting an effective population size of ∼12000 for the species. This estimation represents a significant improvement in our knowledge of the population genetics of the African green monkey, one of the most important nonhuman primate models in biomedical research. Furthermore, by comparing mutation rates in Old World monkeys with the only other direct estimates in primates to date-humans and chimpanzees-it is possible to uniquely address how mutation rates have evolved over longer time scales. While the estimated spontaneous mutation rate for African green monkeys is slightly lower than the rate of 1.2 × 10 -8 per base pair per generation reported in chimpanzees, it is similar to the lower range of rates of 0.96 × 10 -8 -1.28 × 10 -8 per base pair per generation recently estimated from whole genome pedigrees in humans. This result suggests a long-term constraint on mutation rate that is quite different from similar evidence pertaining to recombination rate evolution in primates. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

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

9 CFR 151.5 - Alteration of pedigree certificate.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Alteration of pedigree certificate. 151.5 Section 151.5 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS...

9 CFR 151.5 - Alteration of pedigree certificate.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Alteration of pedigree certificate. 151.5 Section 151.5 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS...

Collaborative project to identify direct and distant pedigree relationships in apple

USDA-ARS?s Scientific Manuscript database

Pedigree information is fundamentally important in breeding programs, enabling breeders to know the source of valuable attributes and underlying alleles and to enlarge genetic diversity in a directed way. Many apple cultivars are related to each other through both recent and distant common ancestors...

Cattle sex-specific recombination and genetic control from a very large pedigree

USDA-ARS?s Scientific Manuscript database

Meiotic recombination is an essential biological process that generates novel genetic variants and ensures proper segregation of chromosomes during meiosis. From a large USDA dairy cattle pedigree with over half million genotyped animals, we extracted 186,927 three-generation families, identified ov...

9 CFR 151.5 - Alteration of pedigree certificate.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Alteration of pedigree certificate. 151.5 Section 151.5 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS...

9 CFR 151.5 - Alteration of pedigree certificate.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Alteration of pedigree certificate. 151.5 Section 151.5 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS...

9 CFR 151.5 - Alteration of pedigree certificate.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Alteration of pedigree certificate. 151.5 Section 151.5 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL BREEDS RECOGNITION OF BREEDS AND BOOKS OF RECORD OF PUREBRED ANIMALS...

Bound Volatile Precursors in Genotypes in the Pedigree of 'Marion' Blackberry (Rubus Sp.)

USDA-ARS?s Scientific Manuscript database

Glycosidically bound volatiles and precursors in genotypes representing the pedigree for 'Marion' blackberry were investigated over two growing seasons. The volatile precursors were isolated using a C18 solid-phase extraction column. After enzymatic hydrolysis, the released volatiles were analyzed u...

The Genetic Blues: Understanding Genetic Principles Using a Practical Approach and a Historical Perspective.

ERIC Educational Resources Information Center

Mysliwiec, Tami H.

2003-01-01

Incorporates history and genetics to explain how genetic traits are passed on to the next generation by focusing on methemoglobinemia, a rare genetic disease, and discusses how oxygen is carried by hemoglobin. Includes individual pedigree analysis and class pedigree analysis. (YDS)

Online System for Faster Multipoint Linkage Analysis via Parallel Execution on Thousands of Personal Computers

PubMed Central

Silberstein, M.; Tzemach, A.; Dovgolevsky, N.; Fishelson, M.; Schuster, A.; Geiger, D.

2006-01-01

Computation of LOD scores is a valuable tool for mapping disease-susceptibility genes in the study of Mendelian and complex diseases. However, computation of exact multipoint likelihoods of large inbred pedigrees with extensive missing data is often beyond the capabilities of a single computer. We present a distributed system called “SUPERLINK-ONLINE,” for the computation of multipoint LOD scores of large inbred pedigrees. It achieves high performance via the efficient parallelization of the algorithms in SUPERLINK, a state-of-the-art serial program for these tasks, and through the use of the idle cycles of thousands of personal computers. The main algorithmic challenge has been to efficiently split a large task for distributed execution in a highly dynamic, nondedicated running environment. Notably, the system is available online, which allows computationally intensive analyses to be performed with no need for either the installation of software or the maintenance of a complicated distributed environment. As the system was being developed, it was extensively tested by collaborating medical centers worldwide on a variety of real data sets, some of which are presented in this article. PMID:16685644

MMACHC gene mutation in familial hypogonadism with neurological symptoms.

PubMed

Shi, Changhe; Shang, Dandan; Sun, Shilei; Mao, Chengyuan; Qin, Jie; Luo, Haiyang; Shao, Mingwei; Chen, Zhengguang; Liu, Yutao; Liu, Xinjing; Song, Bo; Xu, Yuming

2015-12-15

Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison on genomic predictions using three GBLUP methods and two single-step blending methods in the Nordic Holstein population

PubMed Central

2012-01-01

Background A single-step blending approach allows genomic prediction using information of genotyped and non-genotyped animals simultaneously. However, the combined relationship matrix in a single-step method may need to be adjusted because marker-based and pedigree-based relationship matrices may not be on the same scale. The same may apply when a GBLUP model includes both genomic breeding values and residual polygenic effects. The objective of this study was to compare single-step blending methods and GBLUP methods with and without adjustment of the genomic relationship matrix for genomic prediction of 16 traits in the Nordic Holstein population. Methods The data consisted of de-regressed proofs (DRP) for 5 214 genotyped and 9 374 non-genotyped bulls. The bulls were divided into a training and a validation population by birth date, October 1, 2001. Five approaches for genomic prediction were used: 1) a simple GBLUP method, 2) a GBLUP method with a polygenic effect, 3) an adjusted GBLUP method with a polygenic effect, 4) a single-step blending method, and 5) an adjusted single-step blending method. In the adjusted GBLUP and single-step methods, the genomic relationship matrix was adjusted for the difference of scale between the genomic and the pedigree relationship matrices. A set of weights on the pedigree relationship matrix (ranging from 0.05 to 0.40) was used to build the combined relationship matrix in the single-step blending method and the GBLUP method with a polygenetic effect. Results Averaged over the 16 traits, reliabilities of genomic breeding values predicted using the GBLUP method with a polygenic effect (relative weight of 0.20) were 0.3% higher than reliabilities from the simple GBLUP method (without a polygenic effect). The adjusted single-step blending and original single-step blending methods (relative weight of 0.20) had average reliabilities that were 2.1% and 1.8% higher than the simple GBLUP method, respectively. In addition, the GBLUP method with a polygenic effect led to less bias of genomic predictions than the simple GBLUP method, and both single-step blending methods yielded less bias of predictions than all GBLUP methods. Conclusions The single-step blending method is an appealing approach for practical genomic prediction in dairy cattle. Genomic prediction from the single-step blending method can be improved by adjusting the scale of the genomic relationship matrix. PMID:22455934

Genetic linkage map of a wild genome: genomic structure, recombination and sexual dimorphism in bighorn sheep

PubMed Central

2010-01-01

Background The construction of genetic linkage maps in free-living populations is a promising tool for the study of evolution. However, such maps are rare because it is difficult to develop both wild pedigrees and corresponding sets of molecular markers that are sufficiently large. We took advantage of two long-term field studies of pedigreed individuals and genomic resources originally developed for domestic sheep (Ovis aries) to construct a linkage map for bighorn sheep, Ovis canadensis. We then assessed variability in genomic structure and recombination rates between bighorn sheep populations and sheep species. Results Bighorn sheep population-specific maps differed slightly in contiguity but were otherwise very similar in terms of genomic structure and recombination rates. The joint analysis of the two pedigrees resulted in a highly contiguous map composed of 247 microsatellite markers distributed along all 26 autosomes and the X chromosome. The map is estimated to cover about 84% of the bighorn sheep genome and contains 240 unique positions spanning a sex-averaged distance of 3051 cM with an average inter-marker distance of 14.3 cM. Marker synteny, order, sex-averaged interval lengths and sex-averaged total map lengths were all very similar between sheep species. However, in contrast to domestic sheep, but consistent with the usual pattern for a placental mammal, recombination rates in bighorn sheep were significantly greater in females than in males (~12% difference), resulting in an autosomal female map of 3166 cM and an autosomal male map of 2831 cM. Despite differing genome-wide patterns of heterochiasmy between the sheep species, sexual dimorphism in recombination rates was correlated between orthologous intervals. Conclusions We have developed a first-generation bighorn sheep linkage map that will facilitate future studies of the genetic architecture of trait variation in this species. While domestication has been hypothesized to be responsible for the elevated mean recombination rate observed in domestic sheep, our results suggest that it is a characteristic of Ovis species. However, domestication may have played a role in altering patterns of heterochiasmy. Finally, we found that interval-specific patterns of sexual dimorphism were preserved among closely related Ovis species, possibly due to the conserved position of these intervals relative to the centromeres and telomeres. This study exemplifies how transferring genomic resources from domesticated species to close wild relative can benefit evolutionary ecologists while providing insights into the evolution of genomic structure and recombination rates of domesticated species. PMID:20920197

Breeder survey, tools, and resources to visualize diversity and pedigree relationships at MaizeGDB

USDA-ARS?s Scientific Manuscript database

In collaboration with maize researchers, the MaizeGDB Team prepared a survey to identify breeder needs for visualizing pedigrees, diversity data, and haplotypes, and distributed it to the maize community on behalf of the Maize Genetics Executive Committee (Summer 2015). We received 48 responses from...

[Genetic aspects of genealogy].

PubMed

Tetushkin, E Iu

2011-11-01

The supplementary historical discipline genealogy is also a supplementary genetic discipline. In its formation, genetics borrowed from genealogy some methods of pedigree analysis. In the 21th century, it started receiving contribution from computer-aided genealogy and genetic (molecular) genealogy. The former provides novel tools for genetics, while the latter, which employing genetic methods, enriches genetics with new evidence. Genealogists formulated three main laws ofgenealogy: the law of three generations, the law of doubling the ancestry number, and the law of declining ancestry. The significance and meaning of these laws can be fully understood only in light of genetics. For instance, a controversy between the exponential growth of the number of ancestors of an individual, i.e., the law of doubling the ancestry number, and the limited number of the humankind is explained by the presence of weak inbreeding because of sibs' interference; the latter causes the pedigrees' collapse, i.e., explains also the law of diminishing ancestry number. Mathematic modeling of pedigrees' collapse presented in a number of studies showed that the number of ancestors of each individual attains maximum in a particular generation termed ancestry saturated generation. All representatives of this and preceding generation that left progeny are common ancestors of all current members of the population. In subdivided populations, these generations are more ancient than in panmictic ones, whereas in small isolates and social strata with limited numbers of partners, they are younger. The genealogical law of three generations, according to which each hundred years contain on average three generation intervals, holds for generation lengths for Y-chromosomal DNA, typically equal to 31-32 years; for autosomal and mtDNA, this time is somewhat shorter. Moving along ascending lineas, the number of genetically effective ancestors transmitting their DNA fragment to descendants increases far slower than the number of common ancestors, because the time to the nearest common ancestor is proportional to log2N, and the time to genetically effective ancestor, to N, where N is the population size. In relatively young populations, the number of genetically effective ancestors does not exceed the number of recombination hot spots, which is equal to 25000-50000. In ancient African populations with weaker linkage disequilibrium, their number may be higher. In genealogy, the degree of kinship is measured by the number of births separating the individuals under comparison, and in genetics, by Wright's coefficients of relationship (R). Genetic frames of a "large family" are limited by the average genomic differences among the members of the human population, which constitute approximately 0.1%. Conventionally it can be assumed that it is limited by relatives, associated with the members of the given nuclear family by the 7th degree of relatedness (R approximately 0.78%). However, in the course of the HapMap project it was established that 10-30% of pairs of individuals from the same population have at least one common genome region, which they inherited from a recent common ancestor. A nuclear family, if it is not consanguinous, unites two lineages, and indirectly, a multitude of them, constituting a "suprafamily" equivalent to a population. Some problems ofgenealogy and related historical issues can be resolved only with the help of genetics. These problems include identification of "true" and "false" Rurikids and the problem of continuity of the Y-chromosomal lineage of the Romanov dynasty. On the other hand, computer-aided genealogy and molecular genealogy seem to be promising in resolving genetic problems connected to recombination and coalescence ofgenomic regions.

The timing of UV mutagenesis in yeast: a pedigree analysis of induced recessive mutation.

PubMed

James, A P; Kilbey, B J

1977-10-01

The mechanism of UV-induced mutation in eukaryotes was studied in individual yeast cells by a procedure that combined pedigree analysis and tetrad analysis. The technique involved the induction of recessive lethals and semilethals in G1 diploid cells. Induced frequencies were 25 and 61 percent at survival levels of 90 and 77 percent, respectively. No evidence of gross chromosome aberrations was detected. Recessive mutations that affect only one strand or that affect both strands of the DNA molecule are induced much at random among a population of cells, and both types can occur within the same cell. However, the data confirm that two-strand mutations are in the majority after a low level of irradiation. The simplest explanation involves a mechanism whereby most mutations are fixed in both strands prior to the first round of post-irradiation DNA replication. The recessive mutational consequences of irradiation are exhausted at the conclusion of the first post-irradiation cell division, although dominant-lethal sectoring continues at a high level through the second post-irradiation division. It is concluded that pyrimidine dimers that persist to the second round of DNA replication are rare or ineffective.

Statistical fingerprinting for malware detection and classification

DOEpatents

Prowell, Stacy J.; Rathgeb, Christopher T.

2015-09-15

A system detects malware in a computing architecture with an unknown pedigree. The system includes a first computing device having a known pedigree and operating free of malware. The first computing device executes a series of instrumented functions that, when executed, provide a statistical baseline that is representative of the time it takes the software application to run on a computing device having a known pedigree. A second computing device executes a second series of instrumented functions that, when executed, provides an actual time that is representative of the time the known software application runs on the second computing device. The system detects malware when there is a difference in execution times between the first and the second computing devices.

Recruitment of Yoruba families from Nigeria for genetic research: experience from a multisite keloid study

PubMed Central

2014-01-01

Background More involvement of sub-Saharan African countries in biomedical studies, specifically in genetic research, is needed to advance individualized medicine that will benefit non-European populations. Missing infrastructure, cultural and religious beliefs as well as lack of understanding of research benefits can pose a challenge to recruitment. Here we describe recruitment efforts for a large genetic study requiring three-generation pedigrees within the Yoruba homelands of Nigeria. The aim of the study was to identify genes responsible for keloids, a wound healing disorder. We also discuss ethical and logistical considerations that we encountered in preparation for this research endeavor. Methods Protocols for this bi-national intercultural study were approved by the Institutional Review Board (IRB) in the US and the ethics committees of the Nigerian institutions for consideration of cultural differences. Principles of community based participatory research were employed throughout the recruitment process. Keloid patients (patient advisors), community leaders, kings/chiefs and medical directors were engaged to assist the research teams with recruitment strategies. Community meetings, church forums, and media outlets (study flyers, radio and TV announcements) were utilized to promote the study in Nigeria. Recruitment of research participants was conducted by trained staff from the local communities. Pedigree structures were re-analyzed on a regular basis as new family members were recruited and recruitment challenges were documented. Results Total recruitment surpassed 4200 study participants over a 7-year period including 79 families with complete three-generation pedigrees. In 9 families more than 20 family members participated, however, in 5 of these families, we encountered issues with pedigree structure as members from different branches presented inconsistent family histories. These issues were due to the traditional open family structure amongst the Yoruba and by beliefs in voodoo or in juju. In addition, family members living in other parts of the country or abroad complicated timely and complete family recruitment. Conclusions Organizational, logistics and ethics challenges can be overcome by additional administrative efforts, good communication, community involvement and education of staff members. However, recruitment challenges due to infrastructural shortcomings or cultural and religious beliefs can lead to significant delays, which may negatively affect study time lines and expectations of funding agencies. PMID:25182071

A fast indirect method to compute functions of genomic relationships concerning genotyped and ungenotyped individuals, for diversity management.

PubMed

Colleau, Jean-Jacques; Palhière, Isabelle; Rodríguez-Ramilo, Silvia T; Legarra, Andres

2017-12-01

Pedigree-based management of genetic diversity in populations, e.g., using optimal contributions, involves computation of the [Formula: see text] type yielding elements (relationships) or functions (usually averages) of relationship matrices. For pedigree-based relationships [Formula: see text], a very efficient method exists. When all the individuals of interest are genotyped, genomic management can be addressed using the genomic relationship matrix [Formula: see text]; however, to date, the computational problem of efficiently computing [Formula: see text] has not been well studied. When some individuals of interest are not genotyped, genomic management should consider the relationship matrix [Formula: see text] that combines genotyped and ungenotyped individuals; however, direct computation of [Formula: see text] is computationally very demanding, because construction of a possibly huge matrix is required. Our work presents efficient ways of computing [Formula: see text] and [Formula: see text], with applications on real data from dairy sheep and dairy goat breeding schemes. For genomic relationships, an efficient indirect computation with quadratic instead of cubic cost is [Formula: see text], where Z is a matrix relating animals to genotypes. For the relationship matrix [Formula: see text], we propose an indirect method based on the difference between vectors [Formula: see text], which involves computation of [Formula: see text] and of products such as [Formula: see text] and [Formula: see text], where [Formula: see text] is a working vector derived from [Formula: see text]. The latter computation is the most demanding but can be done using sparse Cholesky decompositions of matrix [Formula: see text], which allows handling very large genomic and pedigree data files. Studies based on simulations reported in the literature show that the trends of average relationships in [Formula: see text] and [Formula: see text] differ as genomic selection proceeds. When selection is based on genomic relationships but management is based on pedigree data, the true genetic diversity is overestimated. However, our tests on real data from sheep and goat obtained before genomic selection started do not show this. We present efficient methods to compute elements and statistics of the genomic relationships [Formula: see text] and of matrix [Formula: see text] that combines ungenotyped and genotyped individuals. These methods should be useful to monitor and handle genomic diversity.

Flaunting One's Academic Pedigree? Self-Presentation of Students from Elite French Schools

ERIC Educational Resources Information Center

Draelants, Hugues; Darchy-Koechlin, Brigitte

2011-01-01

This article starts from the puzzle that although French elite institutions enjoy extremely positive and attractive images, students from these schools generally choose to conceal their academic pedigree in their daily interactions. We show that, in a context of growing inequalities of access to "grandes ecoles," the strategy of hiding…

Inheritance of RFLP loci in a loblolly pine three-generation pedigree

Treesearch

M.D. Devey; K.D. Jermstad; C.G. Tauer; D.B. Neale

1991-01-01

A high-density restriction fragment length polymorphism (RFLP) linkage map is being constructed for loblolly pine (Pinus taeda L.). Loblolly pine cDNA and genomic DNA clones were used as probes in hybridizations to genomic DNAs prepared from grandparents, parents, and progeny of a three-generation outbred pedigree. Approximately 200 probes were...

Trust Networks: A New Perspective on Pedigree and the Ambiguities of Admissions

ERIC Educational Resources Information Center

Posselt, Julie R.

2018-01-01

Privileging elite academic pedigrees in graduate admissions preserves racial and socioeconomic inequities that many institutions say they wish to reduce. To understand this preference, I integrate across perspectives on trust in rational choice, social capital, and social network theories, and use the resulting framework to interpret 68 interviews…

Surveying the maize community for their diversity and pedigree visualization needs to prioritize tool development and curation

USDA-ARS?s Scientific Manuscript database

The Maize Genetics and Genomics Database (MaizeGDB) team prepared a survey to identify breeders’ needs for visualizing pedigrees, diversity data, and haplotypes in order to prioritize tool development and curation efforts at MaizeGDB. The survey was distributed to the maize research community on beh...

[Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China].

PubMed

2018-01-23

Hereditary colorectal cancer can be divded into two categories based on the presence or absence of polyps. The first category is characterized by the development of polyposis, which includes familial adenomatous polyposis (FAP); The second category is nonpolyposis colorectal cancer, which is represented by Lynch syndrome. "Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China" developed by the Genetics Group of the Committee of Colorectal Cancer, Chinese Anti-cancer Association, is composed of three sections, including hereditary nonpolyposis syndrome, polyposis syndrome as well as genetic evaluation of hereditary colorectal cancer. The consensus aims to provide recommendations on management of the respective hereditary syndromes in terms of definition, clinical and pathological features, diagnostic standards, treatment, and follow-ups. In addition to describing diagnostic and treatment strategies, prophylactic treatment as well as genetic screening and pedigree monitoring is highly recommended. Through the establishment of this expert consensus, we hope to promote better understanding of hereditary colorectal cancer for clinicians and encourage standardized treatment through multidisciplinery approaches, eventually improving clinical treatment and pedigree management of hereditary colorectal cancer in China.

Machado-Joseph disease in pedigrees of Azorean descent is linked to chromosome 14.

PubMed

St George-Hyslop, P; Rogaeva, E; Huterer, J; Tsuda, T; Santos, J; Haines, J L; Schlumpf, K; Rogaev, E I; Liang, Y; McLachlan, D R

1994-07-01

A locus for Machado-Joseph disease (MJD) has recently been mapped to a 30-cM region of chromosome 14q in five pedigrees of Japanese descent. MJD is a clinically pleomorphic neurodegenerative disease that was originally described in subjects of Azorean descent. In light of the nonallelic heterogeneity in other inherited spinocerebellar ataxias, we were interested to determine if the MJD phenotype in Japanese and Azorean pedigrees arose from mutations at the same locus. We provide evidence that MJD in five pedigrees of Azorean descent is also linked to chromosome 14q in an 18-cM region between the markers D14S67 and AACT (multipoint lod score +7.00 near D14S81). We also report molecular evidence for homozygosity at the MJD locus in an MJD-affected subject with severe, early-onset symptoms. These observations confirm the initial report of linkage of MJD to chromosome 14; suggest that MJD in Japanese and Azorean subjects may represent allelic or identical mutations at the same locus; and provide one possible explanation (MJD gene dosage) for the observed phenotypic heterogeneity in this disease.

[Analysis of clinical phenotype and CGH1 gene mutations in a family affected with dopa-responsive dystonia].

PubMed

Yan, Yaping; Chen, Xiaohong; Luo, Wei

2017-04-10

To explore genetic mutations and clinical features of a pedigree affected with dopa-responsive dystonia. PCR and Sanger sequencing were applied to detect mutations of the GCH1 gene among 7 members from the pedigree. The family was detected to have a known heterozygous mutation of the GCH1 gene (c.550C>T). For the 7 members from the pedigree, the age of onset has ranged from 13 to 60 years. The mother of the proband has carried the same mutation but was still healthy at 80. The symptoms of the other three patients were in slow progression, with diurnal fluctuation which can be improved with sleeping, dystonias of lower limbs, and tremor of both hands. Treatment with small dose of levodopa has resulted in significant improvement of clinical symptoms. By database analysis, the c.550C>T mutation was predicted as probably pathological. The c.550C>T mutation probably underlies the disease in this pedigree. The clinical phenotypes of family members may be variable for their ages of onset. Some may even be symptom free.

Clinical and genetic investigation of families with type II Waardenburg syndrome.

PubMed

Chen, Yong; Yang, Fuwei; Zheng, Hexin; Zhou, Jianda; Zhu, Ganghua; Hu, Peng; Wu, Weijing

2016-03-01

The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia‑associated transcription factor (MITF), sex‑determining region Y‑box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease‑causing mutation in pedigree 1. However, there are novel disease‑causing genes in Waardenburg syndrome type II, which require further research.

Development and pilot evaluation of novel genetic educational materials designed for an underserved patient population.

PubMed

Lubitz, Rebecca Jean; Komaromy, Miriam; Crawford, Beth; Beattie, Mary; Lee, Robin; Luce, Judith; Ziegler, John

2007-01-01

Genetic counseling for BRCA1 and BRCA2 mutations involves teaching about hereditary cancer, genetics and risk, subjects that are difficult to grasp and are routinely misunderstood. Supported by a grant from the Avon Foundation, the UCSF Cancer Risk Program started the first genetic testing and counseling service for a population of traditionally underserved women of varied ethnic and social backgrounds at the San Francisco General Hospital (SFGH). Informed by educational theory and clinical experience, we devised and piloted two simplified explanations of heredity and genetic risk, with the aim of uncovering how to best communicate genetics and risk to this underserved population. A "conventional" version comprised pictures of genes, pedigrees, and quantitative representations of risk. A "colloquial" pictorial version used an analogy of the "information book" of genes, family stories and vignettes, and visual representations of risk, without using scientific words such as genes or chromosomes. A verbal narrative accompanied each picture. We presented these modules to four focus groups of five to eight women recruited from the SFGH Family Practice Clinic. Overall, women preferred a picture-based approach and commented that additional text would have been distracting. The majority of women preferred the colloquial version because it was easier to understand and better conveyed a sense of comfort and hope. We conclude that simplicity, analogies, and familiarity support comprehension while vignettes, family stories, and photos of real people provide comfort and hope. These elements may promote understanding of complex scientific topics in healthcare, particularly when communicating with patients who come from disadvantaged backgrounds.

The genome of the vervet (Chlorocebus aethiops sabaeus)

PubMed Central

Warren, Wesley C.; Jasinska, Anna J.; García-Pérez, Raquel; Svardal, Hannes; Tomlinson, Chad; Rocchi, Mariano; Archidiacono, Nicoletta; Capozzi, Oronzo; Minx, Patrick; Montague, Michael J.; Kyung, Kim; Hillier, LaDeana W.; Kremitzki, Milinn; Graves, Tina; Chiang, Colby; Hughes, Jennifer; Tran, Nam; Huang, Yu; Ramensky, Vasily; Choi, Oi-wa; Jung, Yoon J.; Schmitt, Christopher A.; Juretic, Nikoleta; Wasserscheid, Jessica; Turner, Trudy R.; Wiseman, Roger W.; Tuscher, Jennifer J.; Karl, Julie A.; Schmitz, Jörn E.; Zahn, Roland; O'Connor, David H.; Redmond, Eugene; Nisbett, Alex; Jacquelin, Béatrice; Müller-Trutwin, Michaela C.; Brenchley, Jason M.; Dione, Michel; Antonio, Martin; Schroth, Gary P.; Kaplan, Jay R.; Jorgensen, Matthew J.; Thomas, Gregg W.C.; Hahn, Matthew W.; Raney, Brian J.; Aken, Bronwen; Nag, Rishi; Schmitz, Juergen; Churakov, Gennady; Noll, Angela; Stanyon, Roscoe; Webb, David; Thibaud-Nissen, Francoise; Nordborg, Magnus; Marques-Bonet, Tomas; Dewar, Ken; Weinstock, George M.; Wilson, Richard K.; Freimer, Nelson B.

2015-01-01

We describe a genome reference of the African green monkey or vervet (Chlorocebus aethiops). This member of the Old World monkey (OWM) superfamily is uniquely valuable for genetic investigations of simian immunodeficiency virus (SIV), for which it is the most abundant natural host species, and of a wide range of health-related phenotypes assessed in Caribbean vervets (C. a. sabaeus), whose numbers have expanded dramatically since Europeans introduced small numbers of their ancestors from West Africa during the colonial era. We use the reference to characterize the genomic relationship between vervets and other primates, the intra-generic phylogeny of vervet subspecies, and genome-wide structural variations of a pedigreed C. a. sabaeus population. Through comparative analyses with human and rhesus macaque, we characterize at high resolution the unique chromosomal fission events that differentiate the vervets and their close relatives from most other catarrhine primates, in whom karyotype is highly conserved. We also provide a summary of transposable elements and contrast these with the rhesus macaque and human. Analysis of sequenced genomes representing each of the main vervet subspecies supports previously hypothesized relationships between these populations, which range across most of sub-Saharan Africa, while uncovering high levels of genetic diversity within each. Sequence-based analyses of major histocompatibility complex (MHC) polymorphisms reveal extremely low diversity in Caribbean C. a. sabaeus vervets, compared to vervets from putatively ancestral West African regions. In the C. a. sabaeus research population, we discover the first structural variations that are, in some cases, predicted to have a deleterious effect; future studies will determine the phenotypic impact of these variations. PMID:26377836

Leber's hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families

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

Zhou Xiangtian; Wei Qiping; Yang Li

2006-02-03

We report here the clinical, genetic, and molecular characterization of five Chinese families with Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical ND4 G11696A mutation associated with LHON. Indeed, this mutation is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families. In fact,more » the occurrence of the G11696A mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Furthermore, the N405D in the ND5 and G5820A in the tRNA{sup Cys}, showing high evolutional conservation, may contribute to the phenotypic expression of G11696A mutation in the WZ10 pedigree. However, there was the absence of functionally significant mtDNA mutations in other four Chinese pedigrees carrying the G11696A mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated G11696A mutation in these Chinese pedigrees.« less

[Molecular genetic analysis for a pedigree with severe hereditary coagulation factor VII deficiency].

PubMed

Ding, Qiu-lan; Wang, Hong-li; Wang, Xue-feng; Wang, Ming-shan; Fu, Qi-hua; Wu, Wen-man; Hu, Yi-qun; Wang, Zhen-yi

2003-10-01

To identify the genetic mutations of a severe inherited coagulation factor VII (FVII) deficiency pedigree. The diagnosis was validated by coagulant and haemostatic parameters. FVII gene mutations were screened in the propositus and his family members by DNA direct sequencing and confirmed by digestions of the restriction enzymes of the PCR production. Two heterozygous missense mutations were found in the propositus of the pedigree: a G to T transversion at position 9482 in exon 6 and a C to T mutation at position 11348 in exon 8 resulting in the amino acid substitution of Arg152 with Leu and Arg304 with Trp, respectively. A heterozygous single nucleotide deletion (C) at position 11487-11489(CCC) within exon 8 was identified, which predicted the frameshift mutation at position His351 followed by the changes of six corresponding amino acids and appearance of a premature protein caused by stop codon. The heterozygous mutations identified in the proband were derived from his father (Arg152 to Leu) and his mother (Arg304 to Trp mutation) and a heterozygous deletion (C) at position 11487-9(CCC). By tracing the other pedigree members, it was found that his grandmother had a heterozygous mutation of Arg304Trp and a heterozygous polymorphism of Arg353Gln and his grandfather had a heterozygous Arg152Leu mutation. Three heterozygous mutations were found in a pedigree with hereditary coagulation factor VII deficiency. Arg152Leu and deletion C at position 11487-9(CCC) were novel mutations.

f-treeGC: a questionnaire-based family tree-creation software for genetic counseling and genome cohort studies.

PubMed

Tokutomi, Tomoharu; Fukushima, Akimune; Yamamoto, Kayono; Bansho, Yasushi; Hachiya, Tsuyoshi; Shimizu, Atsushi

2017-07-14

The Tohoku Medical Megabank project aims to create a next-generation personalized healthcare system by conducting large-scale genome-cohort studies involving three generations of local residents in the areas affected by the Great East Japan Earthquake. We collected medical and genomic information for developing a biobank to be used for this healthcare system. We designed a questionnaire-based pedigree-creation software program named "f-treeGC," which enables even less experienced medical practitioners to accurately and rapidly collect family health history and create pedigree charts. f-treeGC may be run on Adobe AIR. Pedigree charts are created in the following manner: 1) At system startup, the client is prompted to provide required information on the presence or absence of children; f-treeGC is capable of creating a pedigree up to three generations. 2) An interviewer fills out a multiple-choice questionnaire on genealogical information. 3) The information requested includes name, age, gender, general status, infertility status, pregnancy status, fetal status, and physical features or health conditions of individuals over three generations. In addition, information regarding the client and the proband, and birth order information, including multiple gestation, custody, multiple individuals, donor or surrogate, adoption, and consanguinity may be included. 4) f-treeGC shows only marriages between first cousins via the overlay function. 5) f-treeGC automatically creates a pedigree chart, and the chart-creation process is visible for inspection on the screen in real time. 6) The genealogical data may be saved as a file in the original format. The created/modified date and time may be changed as required, and the file may be password-protected and/or saved in read-only format. To enable sorting or searching from the database, the file name automatically contains the terms typed into the entry fields, including physical features or health conditions, by default. 7) Alternatively, family histories are collected using a completed foldable interview paper sheet named "f-sheet", which is identical to the questionnaire in f-treeGC. We developed a questionnaire-based family tree-creation software, named f-treeGC, which is fully compliant with international recommendations for standardized human pedigree nomenclature. The present software simplifies the process of collecting family histories and pedigrees, and has a variety of uses, from genome cohort studies or primary care to genetic counseling.

The genetic composition of populations of cynomolgus macaques (Macaca fascicularis) used in biomedical research.

PubMed

Kanthaswamy, S; Ng, J; Satkoski Trask, J; George, D A; Kou, A J; Hoffman, L N; Doherty, T B; Houghton, P; Smith, D G

2013-06-01

The genetic composition of cynomolgus macaques used in biomedical research is not as well-characterized as that of rhesus macaques. Populations of cynomolgus macaques from Sumatra, Corregidor, Mauritius, Singapore, Cambodia, and Zamboanga were analyzed using 24 STRs. The Sumatran and Cambodian populations exhibited the highest allelic diversity, while the Mauritian population exhibited the lowest. Sumatran cynomolgus macaques were the most genetically similar to all others, consistent with an Indonesian origin of the species. The high diversity among Cambodian animals may result from interbreeding with rhesus macaques. The Philippine and Mauritian samples were the most divergent from other populations, the former due to separation from the Sunda Shelf by deepwater and the latter due to anthropogenic translocation and extreme founder effects. Investigators should verify their research subjects' origin, ancestry, and pedigree to minimize risks to biomedical experimentation from genetic variance stemming from close kinship and mixed ancestry as these can obscure treatment effects. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations.

PubMed

Iype, Thomas; Alakbarzade, Vafa; Iype, Mary; Singh, Royana; Sreekantan-Nair, Ajith; Chioza, Barry A; Mohapatra, Tribhuvan M; Baple, Emma L; Patton, Michael A; Warner, Thomas T; Proukakis, Christos; Kulkarni, Abhi; Crosby, Andrew H

2015-11-10

The deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typically results in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit and dysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance. We investigated a large Indian five-generation pedigree with ten affected family members in which chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication in three individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentation of WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1 duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or 4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features. We present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.

Complex segregation analysis of craniomandibular osteopathy in Deutsch Drahthaar dogs.

PubMed

Vagt, J; Distl, O

2018-01-01

This study investigated familial relationships among Deutsch Drahthaar dogs with craniomandibular osteopathy and examined the most likely mode of inheritance. Sixteen Deutsch Drahthaar dogs with craniomandibular osteopathy were diagnosed using clinical findings, radiography or computed tomography. All 16 dogs with craniomandibular osteopathy had one common ancestor. Complex segregation analyses rejected models explaining the segregation of craniomandibular osteopathy through random environmental variation, monogenic inheritance or an additive sex effect. Polygenic and mixed major gene models sufficiently explained the segregation of craniomandibular osteopathy in the pedigree analysis and offered the most likely hypotheses. The SLC37A2:c.1332C>T variant was not found in a sample of Deutsch Drahthaar dogs with craniomandibular osteopathy, nor in healthy controls. Craniomandibular osteopathy is an inherited condition in Deutsch Drahthaar dogs and the inheritance seems to be more complex than a simple Mendelian model. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rooster Semen Cryopreservation: Effect of Pedigree Line and Male Age on Post-Thaw Sperm Function

USDA-ARS?s Scientific Manuscript database

The fertility rates of cryopreserved poultry semen are highly variable and not reliable for use in preservation of commercial genetic stocks. Our objective was to evaluate the cryosurvival of semen from 8 pedigreed layer lines at the onset and end of production. Semen from 160 roosters (20/line) was...

Cultivar identification, pedigree verification, and diversity analysis among Peach (Prunus persica L. Batsch) Cultivars based on Simple Sequence Repeat markers

USDA-ARS?s Scientific Manuscript database

The genetic relationships and pedigree inferences among peach (Prunus persica (L.) Batsch) accessions and breeding lines used in genetic improvement were evaluated using 15 simple sequence repeat (SSR) markers. A total of 80 alleles were detected among the 37 peach accessions with an average of 5.53...

Genomic rearrangements and signatures of breeding in the allo-octoploid strawberry as revealed through an allele dose based SSR linkage map

PubMed Central

2014-01-01

Background Breeders in the allo-octoploid strawberry currently make little use of molecular marker tools. As a first step of a QTL discovery project on fruit quality traits and resistance to soil-borne pathogens such as Phytophthora cactorum and Verticillium we built a genome-wide SSR linkage map for the cross Holiday x Korona. We used the previously published MADCE method to obtain full haplotype information for both of the parental cultivars, facilitating in-depth studies on their genomic organisation. Results The linkage map incorporates 508 segregating loci and represents each of the 28 chromosome pairs of octoploid strawberry, spanning an estimated length of 2050 cM. The sub-genomes are denoted according to their sequence divergence from F. vesca as revealed by marker performance. The map revealed high overall synteny between the sub-genomes, but also revealed two large inversions on LG2C and LG2D, of which the latter was confirmed using a separate mapping population. We discovered interesting breeding features within the parental cultivars by in-depth analysis of our haplotype data. The linkage map-derived homozygosity level of Holiday was similar to the pedigree-derived inbreeding level (33% and 29%, respectively). For Korona we found that the observed homozygosity level was over three times higher than expected from the pedigree (13% versus 3.6%). This could indicate selection pressure on genes that have favourable effects in homozygous states. The level of kinship between Holiday and Korona derived from our linkage map was 2.5 times higher than the pedigree-derived value. This large difference could be evidence of selection pressure enacted by strawberry breeders towards specific haplotypes. Conclusion The obtained SSR linkage map provides a good base for QTL discovery. It also provides the first biologically relevant basis for the discernment and notation of sub-genomes. For the first time, we revealed genomic rearrangements that were verified in a separate mapping population. We believe that haplotype information will become increasingly important in identifying marker-trait relationships and regions that are under selection pressure within breeding material. Our attempt at providing a biological basis for the discernment of sub-genomes warrants follow-up studies to streamline the naming of the sub-genomes among different octoploid strawberry maps. PMID:24581289

Improving empirical evidence on differentiating closely related men with RM Y-STRs: A comprehensive pedigree study from Pakistan.

PubMed

Adnan, Atif; Ralf, Arwin; Rakha, Allah; Kousouri, Nefeli; Kayser, Manfred

2016-11-01

Y-chromosomal short tandem repeat (Y-STR) markers are commonly used in forensic genetics. Male-specific haplotypes provided by commercial Y-STR kits allow discriminating between many - but not all - unrelated men, while they mostly fail to separate related ones. Aiming to improve male relative and paternal lineage differentiation, a set of 13 rapidly-mutating (RM) Y-STRs was previously identified and introduced to forensic Y-chromosome analysis. Recently, their value was highlighted by separating 99% of over 12,200 unrelated men from 111 global populations, as well as 29% of over 2500 male relative pairs, the vast majority were father-sons. Here, we provide improved empirical evidence on differentiating closely related men with RM Y-STRs, most notably beyond father-sons, where previous data were limited. After careful quality control including genetic relationship testing, we used 572 Pakistani men belonging to 99 2-4 generation pedigrees covering 1568 pairs of men related by 1-6 meioses. Of those, 45% were differentiated by one or more of the 13 RM Y-STR markers. In contrast, only 14.7% of a subset of 1484 pairs from 94 pedigrees were separated by the commercial AmpFlSTR Y-filer kit. Combining previously published and new data, an overall differentiation rate of 35.3% was revealed for the RM Y-STR set based on 4096 pairs of men related by 1-20 meioses, compared to 9.6% with Y-filer based on 3645 pairs. Using father-son pair data from the present and previous studies, we provide updated RM Y-STR mutation rates. Locus-specific mutation rates ranged from 2.0×10 -3 (7.0×10 -4 -4.3×10 -3 ) to 6.9×10 -2 (6.1×10 -2 -7.9×10 -2 ) based on 2741-3143 meioses, with an average rate across all 13 RM Y-STR markers of 1.8×10 -2 (1.7×10 -2 -1.9×10 -2 ) based on 800 mutations from 44,922 meioses. The high haplotype diversity (h=0.9996) we observed among the unrelated men (N=105) underlines the value of this RM Y-STR set to differentiate paternal lineages even from endogamous populations such as from Pakistan. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genomic rearrangements and signatures of breeding in the allo-octoploid strawberry as revealed through an allele dose based SSR linkage map.

PubMed

van Dijk, Thijs; Pagliarani, Giulia; Pikunova, Anna; Noordijk, Yolanda; Yilmaz-Temel, Hulya; Meulenbroek, Bert; Visser, Richard G F; van de Weg, Eric

2014-03-01

Breeders in the allo-octoploid strawberry currently make little use of molecular marker tools. As a first step of a QTL discovery project on fruit quality traits and resistance to soil-borne pathogens such as Phytophthora cactorum and Verticillium we built a genome-wide SSR linkage map for the cross Holiday x Korona. We used the previously published MADCE method to obtain full haplotype information for both of the parental cultivars, facilitating in-depth studies on their genomic organisation. The linkage map incorporates 508 segregating loci and represents each of the 28 chromosome pairs of octoploid strawberry, spanning an estimated length of 2050 cM. The sub-genomes are denoted according to their sequence divergence from F. vesca as revealed by marker performance. The map revealed high overall synteny between the sub-genomes, but also revealed two large inversions on LG2C and LG2D, of which the latter was confirmed using a separate mapping population. We discovered interesting breeding features within the parental cultivars by in-depth analysis of our haplotype data. The linkage map-derived homozygosity level of Holiday was similar to the pedigree-derived inbreeding level (33% and 29%, respectively). For Korona we found that the observed homozygosity level was over three times higher than expected from the pedigree (13% versus 3.6%). This could indicate selection pressure on genes that have favourable effects in homozygous states. The level of kinship between Holiday and Korona derived from our linkage map was 2.5 times higher than the pedigree-derived value. This large difference could be evidence of selection pressure enacted by strawberry breeders towards specific haplotypes. The obtained SSR linkage map provides a good base for QTL discovery. It also provides the first biologically relevant basis for the discernment and notation of sub-genomes. For the first time, we revealed genomic rearrangements that were verified in a separate mapping population. We believe that haplotype information will become increasingly important in identifying marker-trait relationships and regions that are under selection pressure within breeding material. Our attempt at providing a biological basis for the discernment of sub-genomes warrants follow-up studies to streamline the naming of the sub-genomes among different octoploid strawberry maps.

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.

PubMed

Lee, M H; Hazard, S; Carpten, J D; Yi, S; Cohen, J; Gerhardt, G T; Salen, G; Patel, S B

2001-02-01

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.

Canopy Temperature and Vegetation Indices from High-Throughput Phenotyping Improve Accuracy of Pedigree and Genomic Selection for Grain Yield in Wheat

PubMed Central

Rutkoski, Jessica; Poland, Jesse; Mondal, Suchismita; Autrique, Enrique; Pérez, Lorena González; Crossa, José; Reynolds, Matthew; Singh, Ravi

2016-01-01

Genomic selection can be applied prior to phenotyping, enabling shorter breeding cycles and greater rates of genetic gain relative to phenotypic selection. Traits measured using high-throughput phenotyping based on proximal or remote sensing could be useful for improving pedigree and genomic prediction model accuracies for traits not yet possible to phenotype directly. We tested if using aerial measurements of canopy temperature, and green and red normalized difference vegetation index as secondary traits in pedigree and genomic best linear unbiased prediction models could increase accuracy for grain yield in wheat, Triticum aestivum L., using 557 lines in five environments. Secondary traits on training and test sets, and grain yield on the training set were modeled as multivariate, and compared to univariate models with grain yield on the training set only. Cross validation accuracies were estimated within and across-environment, with and without replication, and with and without correcting for days to heading. We observed that, within environment, with unreplicated secondary trait data, and without correcting for days to heading, secondary traits increased accuracies for grain yield by 56% in pedigree, and 70% in genomic prediction models, on average. Secondary traits increased accuracy slightly more when replicated, and considerably less when models corrected for days to heading. In across-environment prediction, trends were similar but less consistent. These results show that secondary traits measured in high-throughput could be used in pedigree and genomic prediction to improve accuracy. This approach could improve selection in wheat during early stages if validated in early-generation breeding plots. PMID:27402362

Pedigree-based analysis of derivation of genome segments of an elite rice reveals key regions during its breeding.

PubMed

Zhou, Degui; Chen, Wei; Lin, Zechuan; Chen, Haodong; Wang, Chongrong; Li, Hong; Yu, Renbo; Zhang, Fengyun; Zhen, Gang; Yi, Junliang; Li, Kanghuo; Liu, Yaoguang; Terzaghi, William; Tang, Xiaoyan; He, Hang; Zhou, Shaochuan; Deng, Xing Wang

2016-02-01

Analyses of genome variations with high-throughput assays have improved our understanding of genetic basis of crop domestication and identified the selected genome regions, but little is known about that of modern breeding, which has limited the usefulness of massive elite cultivars in further breeding. Here we deploy pedigree-based analysis of an elite rice, Huanghuazhan, to exploit key genome regions during its breeding. The cultivars in the pedigree were resequenced with 7.6× depth on average, and 2.1 million high-quality single nucleotide polymorphisms (SNPs) were obtained. Tracing the derivation of genome blocks with pedigree and information on SNPs revealed the chromosomal recombination during breeding, which showed that 26.22% of Huanghuazhan genome are strictly conserved key regions. These major effect regions were further supported by a QTL mapping of 260 recombinant inbred lines derived from the cross of Huanghuazhan and a very dissimilar cultivar, Shuanggui 36, and by the genome profile of eight cultivars and 36 elite lines derived from Huanghuazhan. Hitting these regions with the cloned genes revealed they include numbers of key genes, which were then applied to demonstrate how Huanghuazhan were bred after 30 years of effort and to dissect the deficiency of artificial selection. We concluded the regions are helpful to the further breeding based on this pedigree and performing breeding by design. Our study provides genetic dissection of modern rice breeding and sheds new light on how to perform genomewide breeding by design. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Ignoring Intermarker Linkage Disequilibrium Induces False-Positive Evidence of Linkage for Consanguineous Pedigrees when Genotype Data Is Missing for Any Pedigree Member

PubMed Central

Li, Bingshan; Leal, Suzanne M.

2008-01-01

Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents in the analysis. PMID:18073490

A 2-step penalized regression method for family-based next-generation sequencing association studies.

PubMed

Ding, Xiuhua; Su, Shaoyong; Nandakumar, Kannabiran; Wang, Xiaoling; Fardo, David W

2014-01-01

Large-scale genetic studies are often composed of related participants, and utilizing familial relationships can be cumbersome and computationally challenging. We present an approach to efficiently handle sequencing data from complex pedigrees that incorporates information from rare variants as well as common variants. Our method employs a 2-step procedure that sequentially regresses out correlation from familial relatedness and then uses the resulting phenotypic residuals in a penalized regression framework to test for associations with variants within genetic units. The operating characteristics of this approach are detailed using simulation data based on a large, multigenerational cohort.

Identification of quantitative trait loci influencing wood specific gravity in an outbred pedigree of loblolly pine

Treesearch

A. Groover; M. Devey; T. Fiddler; J. Lee; R. Megraw; T. Mitchel-Olds; B. Sherman; S. Vujcic; C. Williams; D. Neale

1994-01-01

We report the identification of quantitative trait loci (QTL) influencing wood specific gravity (WSG) in an outbred pedigree of loblolly pine (Pinus taeda L.) . QTL mapping in an outcrossing species is complicated by the presence of multiple alleles (>2) at QTL and marker loci. Multiple alleles at QTL allow the examination of interaction among...

Feasibility of pedigree recording and genetic selection in village sheep flocks of smallholder farmers.

PubMed

Gizaw, Solomon; Goshme, Shenkute; Getachew, Tesfaye; Haile, Aynalem; Rischkowsky, Barbara; van Arendonk, Johan; Valle-Zárate, Anne; Dessie, Tadelle; Mwai, Ally Okeyo

2014-06-01

Pedigree recording and genetic selection in village flocks of smallholder farmers have been deemed infeasible by researchers and development workers. This is mainly due to the difficulty of sire identification under uncontrolled village breeding practices. A cooperative village sheep-breeding scheme was designed to achieve controlled breeding and implemented for Menz sheep of Ethiopia in 2009. In this paper, we evaluated the reliability of pedigree recording in village flocks by comparing genetic parameters estimated from data sets collected in the cooperative village and in a nucleus flock maintained under controlled breeding. Effectiveness of selection in the cooperative village was evaluated based on trends in breeding values over generations. Heritability estimates for 6-month weight recorded in the village and the nucleus flock were very similar. There was an increasing trend over generations in average estimated breeding values for 6-month weight in the village flocks. These results have a number of implications: the pedigree recorded in the village flocks was reliable; genetic parameters, which have so far been estimated based on nucleus data sets, can be estimated based on village recording; and appreciable genetic improvement could be achieved in village sheep selection programs under low-input smallholder farming systems.

Using genetic pedigree reconstruction to estimate effective spawner abundance from redd surveys: an example involving Pacific lamprey (Entosphenus tridentatus)

USGS Publications Warehouse

Whitlock, S.L.; Schultz, L.D.; Schreck, Carl B.; Hess, J.E.

2017-01-01

Redd surveys are a commonly used technique for indexing the abundance of sexually mature fish in streams; however, substantial effort is often required to link redd counts to actual spawner abundance. In this study, we describe how genetic pedigree reconstruction can be used to estimate effective spawner abundance in a stream reach, using Pacific lamprey (Entosphenus tridentatus) as an example. Lamprey embryos were sampled from redds within a 2.5 km reach of the Luckiamute River, Oregon, USA. Embryos were found in only 20 of the 48 redds sampled (suggesting 58% false redds); however, multiple sets of parents were detected in 44% of the true redds. Estimates from pedigree reconstruction suggested that there were 0.48 (95% CI: 0.29–0.88) effective spawners per redd and revealed that individual lamprey contributed gametes to a minimum of between one and six redds, and in one case, spawned in patches that were separated by over 800 m. Our findings demonstrate the utility of pedigree reconstruction techniques for both inferring spawning-ground behaviors and providing useful information for refining lamprey redd survey methodologies.

Machado-Joseph Disease in Pedigrees of Azorean descent is Linked to Chromosome 14

PubMed Central

George-Hyslop, P. St; Rogaeva, E.; Huterer, J.; Tsuda, T.; Santos, J.; Haines, J. L.; Schlumpf, K.; Rogaev, E. I.; Liang, Y.; McLachlan, D. R. Crapper; Kennedy, J.; Weissenbach, J.; Billingsley, G. D.; Cox, D. W.; Lang, A. E.; Wherrett, J. R.

1994-01-01

A locus for Machado-Joseph disease (MJD) has recently been mapped to a 30-cM region of chromosome 14q in five pedigrees of Japanese descent. MJD is a clinically pleomorphic neurodegenerative disease that was originally described in subjects of Azorean descent. In light of the nonallelic heterogeneity in other inherited spinocere-bellar ataxias, we were interested to determine if the MJD phenotype in Japanese and Azorean pedigrees arose from mutations at the same locus. We provide evidence that MJD in five pedigrees of Azorean descent is also linked to chromosome 14q in an 18-cM region between the markers D14S67 and AACT (multipoint lod score +7.00 near D14S81). We also report molecular evidence for homozy-gosity at the MJD locus in an MJD-affected subject with severe, early-onset symptoms. These observations confirm the initial report of linkage of MJD to chromosome 14; suggest that MJD in Japanese and Azorean subjects may represent allelic or identical mutations at the same locus; and provide one possible explanation (MJD gene dosage) for the observed phenotypic heterogeneity in this disease. PMID:8023841

Partitioning the variability of fasting plasma glucose levels in pedigrees. Genetic and environmental factors.

PubMed

Boehnke, M; Moll, P P; Kottke, B A; Weidman, W H

1987-04-01

Fasting plasma glucose measurements made in 1972-1977 on normoglycemic individuals in three-generation Caucasian pedigrees from Rochester, Minnesota were analyzed. The authors determined the contributions of polygenic loci and environmental factors to fasting plasma glucose variability in these pedigrees. To that end, fasting plasma glucose measurements were normalized by an inverse normal scores transformation and then regressed separately for males and females on measured concomitants including age, body mass index (weight/height2), season of measurement, sex hormone use, and diuretic use. The authors found that 27.7% of the variability in normalized fasting plasma glucose in these pedigrees is explained by these measured concomitants. Subsequent variance components analysis suggested that unmeasured polygenic loci and unmeasured shared environmental factors together account for at least an additional 36.7% of the variability in normalized fasting plasma glucose, with genes alone accounting for at least 27.3%. These results are consistent with the known familiality of diabetes, for which fasting plasma glucose level is an important predictor. Further, these familial factors provide an explanation for at least half the variability in normalized fasting plasma glucose which remains after regression on known concomitants.

Clinical and genetic investigation of families with type II Waardenburg syndrome

PubMed Central

CHEN, YONG; YANG, FUWEI; ZHENG, HEXIN; ZHOU, JIANDA; ZHU, GANGHUA; HU, PENG; WU, WEIJING

2016-01-01

The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia-associated transcription factor (MITF), sex-determining region Y-box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease-causing mutation in pedigree 1. However, there are novel disease-causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

Reparameterization of PAM50 Expression Identifies Novel Breast Tumor Dimensions and Leads to Discovery of a Genome-Wide Significant Breast Cancer Locus at 12q15.

PubMed

Madsen, Michael J; Knight, Stacey; Sweeney, Carol; Factor, Rachel; Salama, Mohamed; Stijleman, Inge J; Rajamanickam, Venkatesh; Welm, Bryan E; Arunachalam, Sasi; Jones, Brandt; Rachamadugu, Rakesh; Rowe, Kerry; Cessna, Melissa H; Thomas, Alun; Kushi, Lawrence H; Caan, Bette J; Bernard, Philip S; Camp, Nicola J

2018-06-01

Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene finding. Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared with the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis. Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genome-wide significant region at 12q15 This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors ( P = 2.6 × 10 -8 ). Conclusions: PC analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene mapping. Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity. Cancer Epidemiol Biomarkers Prev; 27(6); 644-52. ©2018 AACR . ©2018 American Association for Cancer Research.

Opportunities for international collaboration in dog breeding from the sharing of pedigree and health data.

PubMed

Fikse, W F; Malm, S; Lewis, T W

2013-09-01

Pooling of pedigree and phenotype data from different countries may improve the accuracy of derived indicators of both genetic diversity and genetic merit of traits of interest. This study demonstrates significant migration of individuals of four pedigree dog breeds between Sweden and the United Kingdom. Correlations of estimates of genetic merit (estimated breeding values, EBVs) for the Fédération Cynologique Internationale and the British Veterinary Association and Kennel Club evaluations of hip dysplasia (HD) were strong and favourable, indicating that both scoring schemes capture substantially the same genetic trait. Therefore pooled use of phenotypic data on hip dysplasia would be expected to improve the accuracy of EBV for HD in both countries due to increased sample data. Copyright © 2013. Published by Elsevier Ltd.

Identification of two novel pathogenic compound heterozygous MYO7A mutations in Usher syndrome by whole exome sequencing.

PubMed

Jia, Ying; Li, Xiaoge; Yang, Dong; Xu, Yi; Guo, Ying; Li, Xin

2018-01-01

The current study aims to identify the pathogenic sites in a core pedigree of Usher syndrome (USH). A core pedigree of USH was analyzed by whole exome sequencing (WES). Mutations were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing. Two pathogenic variations (c.849+2T>C and c.5994G>A) in MYO7A were successfully identified and individually separated from parents. One variant (c.849+2T>C) was nonsense mutation, causing the protein terminated in advance, and the other one (c.5994G>A) located near the boundary of exon could cause aberrant splicing. This study provides a meaningful exploration for identification of clinical core genetic pedigrees. Copyright © 2017 Elsevier B.V. All rights reserved.

Identifiability of tree-child phylogenetic networks under a probabilistic recombination-mutation model of evolution.

PubMed

Francis, Andrew; Moulton, Vincent

2018-06-07

Phylogenetic networks are an extension of phylogenetic trees which are used to represent evolutionary histories in which reticulation events (such as recombination and hybridization) have occurred. A central question for such networks is that of identifiability, which essentially asks under what circumstances can we reliably identify the phylogenetic network that gave rise to the observed data? Recently, identifiability results have appeared for networks relative to a model of sequence evolution that generalizes the standard Markov models used for phylogenetic trees. However, these results are quite limited in terms of the complexity of the networks that are considered. In this paper, by introducing an alternative probabilistic model for evolution along a network that is based on some ground-breaking work by Thatte for pedigrees, we are able to obtain an identifiability result for a much larger class of phylogenetic networks (essentially the class of so-called tree-child networks). To prove our main theorem, we derive some new results for identifying tree-child networks combinatorially, and then adapt some techniques developed by Thatte for pedigrees to show that our combinatorial results imply identifiability in the probabilistic setting. We hope that the introduction of our new model for networks could lead to new approaches to reliably construct phylogenetic networks. Copyright © 2018 Elsevier Ltd. All rights reserved.

Short communication: Improving accuracy of predicting breeding values in Brazilian Holstein population by adding data from Nordic and French Holstein populations.

PubMed

Li, X; Lund, M S; Zhang, Q; Costa, C N; Ducrocq, V; Su, G

2016-06-01

The present study investigated the improvement of prediction reliabilities for 3 production traits in Brazilian Holsteins that had no genotype information by adding information from Nordic and French Holstein bulls that had genotypes. The estimated across-country genetic correlations (ranging from 0.604 to 0.726) indicated that an important genotype by environment interaction exists between Brazilian and Nordic (or Nordic and French) populations. Prediction reliabilities for Brazilian genotyped bulls were greatly increased by including data of Nordic and French bulls, and a 2-trait single-step genomic BLUP performed much better than the corresponding pedigree-based BLUP. However, only a minor improvement in prediction reliabilities was observed in nongenotyped Brazilian cows. The results indicate that although there is a large genotype by environment interaction, inclusion of a foreign reference population can improve accuracy of genetic evaluation for the Brazilian Holstein population. However, a Brazilian reference population is necessary to obtain a more accurate genomic evaluation. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Estimation of Additive, Dominance, and Imprinting Genetic Variance Using Genomic Data

PubMed Central

Lopes, Marcos S.; Bastiaansen, John W. M.; Janss, Luc; Knol, Egbert F.; Bovenhuis, Henk

2015-01-01

Traditionally, exploration of genetic variance in humans, plants, and livestock species has been limited mostly to the use of additive effects estimated using pedigree data. However, with the development of dense panels of single-nucleotide polymorphisms (SNPs), the exploration of genetic variation of complex traits is moving from quantifying the resemblance between family members to the dissection of genetic variation at individual loci. With SNPs, we were able to quantify the contribution of additive, dominance, and imprinting variance to the total genetic variance by using a SNP regression method. The method was validated in simulated data and applied to three traits (number of teats, backfat, and lifetime daily gain) in three purebred pig populations. In simulated data, the estimates of additive, dominance, and imprinting variance were very close to the simulated values. In real data, dominance effects account for a substantial proportion of the total genetic variance (up to 44%) for these traits in these populations. The contribution of imprinting to the total phenotypic variance of the evaluated traits was relatively small (1–3%). Our results indicate a strong relationship between additive variance explained per chromosome and chromosome length, which has been described previously for other traits in other species. We also show that a similar linear relationship exists for dominance and imprinting variance. These novel results improve our understanding of the genetic architecture of the evaluated traits and shows promise to apply the SNP regression method to other traits and species, including human diseases. PMID:26438289

Determination of maternal pedigree and ewe-lamb spatial relationships by application of Bluetooth technology in extensive farming systems.

PubMed

Sohi, R; Trompf, J; Marriott, H; Bervan, A; Godoy, B I; Weerasinghe, M; Desai, A; Jois, M

2017-11-01

The objectives of this study were to validate the application of Bluetooth technology to determine maternal pedigree and to determine ewe-lamb spatial relationships in extensive farming systems. A total of 35 first-cross Merino ewes (Merino × Border Leicester and East Friesian) and 23 of their lambs aged 1 to 3 wk were fitted with activity monitors equipped with Bluetooth (BT) technology (ActiGraph wGT3X-BT) by means of halters and collars, respectively. The BT devices on lambs were programmed to receive wireless signals once every minute from nearby BT units on ewes, which were programmed as beacons sending BT signals 4 times every second. Ewes and lambs fitted with sensors were dispatched into the paddocks, and after 10 d, the sensor units were retrieved and the BT signals received by lambs were downloaded using the ActiGraph software. The maternal pedigree of the lambs was determined as the ewe from which the lamb received the most BT signals. The distance between the lamb receiving the signal and the ewe sending the signal was estimated from the strength of BT signal received. The pedigree determined by BT was compared with the pedigree determined by DNA profiling and verification. The results showed that the accuracy of maternal pedigree determined by BT signals reached 100% within the first 15 min of returning animals to pasture of ewes and lambs fitted with sensors. Maternal signals (counts/d) received by 1-, 2-, and 3-wk-old lambs were 617 ± 102, 603 ± 54, and 498 ± 36, respectively, and the corresponding nonmaternal signals received were 140 ± 27, 106 ± 30, and 155 ± 39, respectively. Maternal signals received during the dark period were significantly higher than the maternal signals received during the light period ( < 0.05). Maternal signals received during the light period by 3-wk-old lambs were significantly lower when compared with those received by 1- and 2-wk-old lambs. Over 90% of the BT signals received from within 2 m of the lamb were from its mother. The maternal BT signals expressed as a portion of total BT signals decreased with increasing distance from the lamb. The results show that BT wireless networking is a fast and reliable method for the determination of maternal pedigree of lambs in extensive farming systems. In addition, wireless BT technology is also useful in determining mother-offspring spatial relationships.

Ethnic identities and lifestyles in a multi-ethnic cancer patient population.

PubMed

Gotay, Carolyn Cook; Holup, Joan

2004-09-01

This report examined ethnic identity in 367 recently diagnosed cancer patients in Hawai'i's primary ethnic groups: Japanese, Hawaiians, Europeans, and Filipinos. The study assessed ethnic self-identify; definitions of and participation in different ethnic lifestyles; and relationships between measures of ethnic self-identity, lifestyle, and other indicators of ethnic and cultural affiliations. Results indicated that medical record-based ethnic indicators were well linked to individual self-reports of family pedigree. Self-descriptors included non-standard terms such as "American" and "Local," and respondents reported following between five and six different ethnically-associated ways of life. Multivariate analysis indicated that ethnic self-identity made a unique contribution that went beyond standard ethnic and acculturative markers in explaining lifestyles. This study provides strong support for multiculturalism in this ethnically heterogeneous population.

Prevalence and risk factor analysis for feline haemoplasmas in cats from Northern Serbia, with molecular subtyping of feline immunodeficiency virus.

PubMed

Sarvani, Elpida; Tasker, Séverine; Kovacˇević Filipović, Milica; Francuski Andrić, Jelena; Andrić, Nenad; Aquino, Larissa; English, Sarah; Attipa, Charalampos; Leutenegger, Christian M; Helps, Chris R; Papasouliotis, Kostas

2018-01-01

The objectives of this study were to estimate the prevalence of feline haemoplasma infections in Northern Serbia, identify potential risk factors and perform molecular subtyping of feline immunodeficiency virus (FIV). PCR analysis for feline haemoplasmas was performed on surplus EDTA blood samples from 373 cats from the Belgrade region, Serbia. An ELISA was used to determine the prevalence of feline leukaemia virus (FeLV) and FIV; PCR was performed on a subpopulation of these cats. FIV subtyping was performed using PCR. Within this population, 64/373 cats (17.2%) were infected with one or more haemoplasma species. Mycoplasma haemofelis was detected in 20/373 cats (5.4%), ' Candidatus Mycoplasma haemominutum' in 47/373 cats (12.6%) and ' Candidatus Mycoplasma turicensis' in 23/373 cats (6.2%). Coinfections were observed in 21/373 cats (5.6%). Based on ELISA serological retroviral testing, 4/310 cats (1.3%) were infected with FeLV, whereas 78/331 (23.6%) were infected with FIV. Multivariable analysis identified significant associations between haemoplasma infection and anaemia (anaemic/non-anaemic, odds ratio [OR] 2.7, 95% confidence interval [CI] 1.04-7.1; P = 0.041]), male gender (male/female, OR 4.5, 95% CI 2.22-9.03; P <0.0005), outdoor access (yes/no, OR 5.2, 95% CI 2.28-11.92; P <0.0005), non-pedigree breed (non-pedigree/pedigree, OR 5.5, 95% CI 1.24-24.84; P = 0.025) and FIV seropositive status (positive/negative, OR 2.4, 95% CI 1.21-4.83; P = 0.012). PCR analysis of the FIV ELISA-positive samples revealed clade D as being the most prevalent. All three known species of feline haemoplasma were detected, confirming their presence in Serbia; ' Candidatus Mycoplasma haemominutum' was the most prevalent. We found a high prevalence of FIV-infected cats and FIV clade D was most prevalent.

Modification of family size in families reporting history of haemophilia from Maharashtra, India.

PubMed

Potnis-Lele, Mugdha; Kar, Anita

2003-04-01

In India, genetic counselling services are largely unavailable. The question of whether awareness of the hereditary nature of the disorder leads to modified family size in affected families remains unanswered. The objective of this study was to determine whether family history of haemophilia resulted in modification of family size in families reporting haemophilia in the State of Maharashtra, India. The study was a retrospective cohort analysis from pedigrees collected from an earlier survey on haemophilia in Maharashtra. Pedigree data were manually defined into families with or without experience of haemophilia. Family size was defined as the number of live births per woman as documented in the pedigree. The data were analysed using Microsoft Excel package (version 2000) and SPSS package (version 10). Family size of obligate carriers who were daughters of patients was significantly less than the family size of obligate carriers who reported haemophilia in a brother or maternal relative (z = 7.14, P < 0.001). As compared with parents from an older generation, a significant reduction in the number of children born to younger families with haemophilia was observed, irrespective of family history of the condition. In families with history of haemophilia, there was no significant reduction in the number of families with more than one affected son in between two generations of parents (chi(2) = 1.43). The results revealed a reduction in size of families with haemophilia over a generation, which possibly reflected the reducing fertility trends observed in the Indian population. Reduction in the number of children born to women with a haemophilic father suggested a comprehension of father to daughter transmission of haemophilia. This was not true when relatives other than the father were affected. The lack of significant reduction in the number of families with history of haemophilia of having more than one affected son may suggest a compensatory response to the high mortality associated with the disorder in India.

Contribution of domestic production records, Interbull estimated breeding values, and single nucleotide polymorphism genetic markers to the single-step genomic evaluation of milk production.

PubMed

Přibyl, J; Madsen, P; Bauer, J; Přibylová, J; Simečková, M; Vostrý, L; Zavadilová, L

2013-03-01

Estimated breeding values (EBV) for first-lactation milk production of Holstein cattle in the Czech Republic were calculated using a conventional animal model and by single-step prediction of the genomic enhanced breeding value. Two overlapping data sets of milk production data were evaluated: (1) calving years 1991 to 2006, with 861,429 lactations and 1,918,901 animals in the pedigree and (2) calving years 1991 to 2010, with 1,097,319 lactations and 1,906,576 animals in the pedigree. Global Interbull (Uppsala, Sweden) deregressed proofs of 114,189 bulls were used in the analyses. Reliabilities of Interbull values were equivalent to an average of 8.53 effective records, which were used in a weighted analysis. A total of 1,341 bulls were genotyped using the Illumina BovineSNP50 BeadChip V2 (Illumina Inc., San Diego, CA). Among the genotyped bulls were 332 young bulls with no daughters in the first data set but more than 50 daughters (88.41, on average) with performance records in the second data set. For young bulls, correlations of EBV and genomic enhanced breeding value before and after progeny testing, corresponding average expected reliabilities, and effective daughter contributions (EDC) were calculated. The reliability of prediction pedigree EBV of young bulls was 0.41, corresponding to EDC=10.6. Including Interbull deregressed proofs improved the reliability of prediction by EDC=13.4 and including genotyping improved prediction reliability by EDC=6.2. Total average expected reliability of prediction reached 0.67, corresponding to EDC=30.2. The combination of domestic and Interbull sources for both genotyped and nongenotyped animals is valuable for improving the accuracy of genetic prediction in small populations of dairy cattle. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Juvenile myoclonic epilepsy locus in chromosome 6p21.2-p11: Linkage to convulsions and electroencephalography trait

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

Liu, A.W.; Delgado-Escueta, A.V.; Serratosa, J.M.

1995-08-01

Despite affecting 4 million Americans and 100-200 million persons worldwide, the precise molecular mechanisms of human epilepsies remain unknown. Juvenile myoclonic epilepsy (JME) is the most frequent and, hence, most important form of hereditary grand mal epilepsy. In this epilepsy, electroencephalographic (EEG) 15-30 Hz multispikes produce myoclonic and tonic-clonic convulsions beginning at 8-20 years of age. Moreover, EEG 3.5-6 Hz multispike wave complexes appear in clinically asymptomatic family members. We first studied 38 members of a four-generation LA-Belize family with classical JME but with no pyknoleptic absences. Five living members had JME; four clinically asymptomatic members had EEG multispike wavemore » complexes. Pairwise analysis tightly linked microsatellites centromeric to HLA, namely D6S272 (peak lod score [Z{sub max}]=3.564-3.560 at male-female recombination [{theta}{sub m=f}]=0-0.001) and D6S257 (Z{sub max}=3.672-3.6667 at {theta}{sub m=f}=0-0.001), spanning 7 cM, to convulsive seizures and EEG multispike wave complexes. A recombination between D6S276 and D6S273 in one affected member placed the JME locus within or below HLA. Pairwise, multipoint, and recombination analyses in this large family independently proved that a JME gene is located in chromsome 6p, centromeric to HLA. We next screened, with the same chromosome 6p21.2-p11 short tandem-repeat polymorphic markers, seven multiplex pedigrees with classic JME. When lod scores for small multiplex families are added to lod scores of the LA-Belize pedigree, Z{sub max} values for D6S294 and D6S257 are >7 ({theta}{sub m=f}=0.000). Our results prove that in chromosome 6p21.2-p11 an epilepsy locus exists whose phenotype consists of classic JME with convulsions and/or EEG rapid multispike wave complexes. 31 refs., 6 figs., 4 tabs.« less

Familial atrophia maculosa varioliformis cutis: case report and pedigree analysis.

PubMed

Qu, T; Wang, B; Fang, K

2005-10-01

Atrophia maculosa varioliformis cutis (AVMC) was first described in 1918, as a rarely reported form of idiopathic macular atrophy on the cheeks. Nineteen patients have been reported in the past 86 years. Recently we diagnosed a 25-year-old woman as AMVC and investigated her family history. We collected the clinical data of the pedigree and presumed that AVMV is in a autosomal dominant inheritance.

Huntington's Disease Research Roster Support with a Microcomputer Database Management System

PubMed Central

Gersting, J. M.; Conneally, P. M.; Beidelman, K.

1983-01-01

This paper chronicles the MEGADATS (Medical Genetics Acquisition and DAta Transfer System) database development effort in collecting, storing, retrieving, and plotting human family pedigrees. The newest system, MEGADATS-3M, is detailed. Emphasis is on the microcomputer version of MEGADATS-3M and its use to support the Huntington's Disease research roster project. Examples of data input and pedigree plotting are included.

Global population variability in Qiagen Investigator HDplex STRs.

PubMed

Phillips, C; Fernandez-Formoso, L; Gelabert-Besada, M; García-Magariños, M; Amigo, J; Carracedo, A; Lareu, M V

2014-01-01

Supplementary short tandem repeats (STRs) can be added to forensic analyses if the 15-24 core STRs in routine use fail to give sufficient discrimination power in complex identification or relationship testing scenarios. In this study, 10 of 12 supplementary STRs in the Qiagen Investigator HDplex kit (SE33, D2S1360, D3S1744, D4S2366, D5S2500, D6S474, D7S1517, D8S1132, D10S2325, D21S2055) were genotyped in 941 individuals from the 51 populations of the CEPH Human Genome Diversity Panel (HGDP-CEPH). The other two components of the 12-STR HDplex kit are established STRs D12S391 and D18S51 that we previously genotyped for the HGDP-CEPH panel. We describe the rare alleles identified and outline allele frequency distributions in the seven population groups of the HGDP-CEPH panel. The HDplex STRs novel to forensic application were found to be both highly informative and comparable in their power across all populations studied: at least six of the nine loci showing above average forensic discrimination power in each population group. In some rare instances certain low frequency alleles in D2S1360 were found to overlap in mobility with the neighbouring allele size ranges of D12S391, as well as those of D7S1517 with neighbouring D3S1744 and D10S2325 with neighbouring SE33. Lastly, since expanded five-dye multiplex kits of 20 STRs (Promega Powerplex 21) and 22 STRs (Promega Powerplex Fusion) have recently been introduced, we assess through simulations the increased power to analyse pairwise relationships in deficient pedigrees that can be expected from an optimum kit pair: combining HDplex with either of the above sets to provide 30 or 32 unique STRs and just two overlapping loci. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Validation of a Cost-Efficient Multi-Purpose SNP Panel for Disease Based Research

PubMed Central

Hou, Liping; Phillips, Christopher; Azaro, Marco; Brzustowicz, Linda M.; Bartlett, Christopher W.

2011-01-01

Background Here we present convergent methodologies using theoretical calculations, empirical assessment on in-house and publicly available datasets as well as in silico simulations, that validate a panel of SNPs for a variety of necessary tasks in human genetics disease research before resources are committed to larger-scale genotyping studies on those samples. While large-scale well-funded human genetic studies routinely have up to a million SNP genotypes, samples in a human genetics laboratory that are not yet part of such studies may be productively utilized in pilot projects or as part of targeted follow-up work though such smaller scale applications require at least some genome-wide genotype data for quality control purposes such as DNA “barcoding” to detect swaps or contamination issues, determining familial relationships between samples and correcting biases due to population effects such as population stratification in pilot studies. Principal Findings Empirical performance in classification of relative types for any two given DNA samples (e.g., full siblings, parental, etc) indicated that for outbred populations the panel performs sufficiently to classify relationship in extended families and therefore also for smaller structures such as trios and for twin zygosity testing. Additionally, familial relationships do not significantly diminish the (mean match) probability of sharing SNP genotypes in pedigrees, further indicating the uniqueness of the “barcode.” Simulation using these SNPs for an African American case-control disease association study demonstrated that population stratification, even in complex admixed samples, can be adequately corrected under a range of disease models using the SNP panel. Conclusion The panel has been validated for use in a variety of human disease genetics research tasks including sample barcoding, relationship verification, population substructure detection and statistical correction. Given the ease of genotyping our specific assay contained herein, this panel represents a useful and economical panel for human geneticists. PMID:21611176

Estimating variance components and breeding values for number of oocytes and number of embryos in dairy cattle using a single-step genomic evaluation.

PubMed

Cornelissen, M A M C; Mullaart, E; Van der Linde, C; Mulder, H A

2017-06-01

Reproductive technologies such as multiple ovulation and embryo transfer (MOET) and ovum pick-up (OPU) accelerate genetic improvement in dairy breeding schemes. To enhance the efficiency of embryo production, breeding values for traits such as number of oocytes (NoO) and number of MOET embryos (NoM) can help in selection of donors with high MOET or OPU efficiency. The aim of this study was therefore to estimate variance components and (genomic) breeding values for NoO and NoM based on Dutch Holstein data. Furthermore, a 10-fold cross-validation was carried out to assess the accuracy of pedigree and genomic breeding values for NoO and NoM. For NoO, 40,734 OPU sessions between 1993 and 2015 were analyzed. These OPU sessions originated from 2,543 donors, from which 1,144 were genotyped. For NoM, 35,695 sessions between 1994 and 2015 were analyzed. These MOET sessions originated from 13,868 donors, from which 3,716 were genotyped. Analyses were done using only pedigree information and using a single-step genomic BLUP (ssGBLUP) approach combining genomic information and pedigree information. Heritabilities were very similar based on pedigree information or based on ssGBLUP [i.e., 0.32 (standard error = 0.03) for NoO and 0.21 (standard error = 0.01) for NoM with pedigree, 0.31 (standard error = 0.03) for NoO, and 0.22 (standard error = 0.01) for NoM with ssGBLUP]. For animals without their own information as mimicked in the cross-validation, the accuracy of pedigree-based breeding values was 0.46 for NoO and NoM. The accuracies of genomic breeding values from ssGBLUP were 0.54 for NoO and 0.52 for NoM. These results show that including genomic information increases the accuracies. These moderate accuracies in combination with a large genetic variance show good opportunities for selection of potential bull dams. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A suite of microsatellite markers optimized for amplification of DNA from Addax (Addax nasomaculatus) blood preserved on FTA cards.

PubMed

Heim, Brett C; Ivy, Jamie A; Latch, Emily K

2012-01-01

The addax (Addax nasomaculatus) is a critically endangered antelope that is currently maintained in zoos through regional, conservation breeding programs. As for many captive species, incomplete pedigree data currently impedes the ability of addax breeding programs to confidently manage the genetics of captive populations and to select appropriate animals for reintroduction. Molecular markers are often used to improve pedigree resolution, thereby improving the long-term effectiveness of genetic management. When developing a suite of molecular markers, it is important to consider the source of DNA, as the utility of markers may vary across DNA sources. In this study, we optimized a suite of microsatellite markers for use in genotyping captive addax blood samples collected on FTA cards. We amplified 66 microsatellite loci previously described in other Artiodactyls. Sixteen markers amplified a single product in addax, but only 5 of these were found to be polymorphic in a sample of 37 addax sampled from a captive herd at Fossil Rim Wildlife Center in the US. The suite of microsatellite markers developed in this study provides a new tool for the genetic management of captive addax, and demonstrates that FTA cards can be a useful means of sample storage, provided appropriate loci are used in downstream analyses. © 2011 Wiley Periodicals, Inc.

A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China.

PubMed

Lin, Yu-Ying; Wei, Ai-Hua; Zhou, Zhi-Yong; Zhu, Wei; He, Xin; Lian, Shi

2011-10-01

The mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. A novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. This study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.

Genetic Contribution to Non-Squamous, Non-Small Cell Lung Cancer in Non-Smokers.

PubMed

Carr, Shamus R; Akerley, Wallace; Cannon-Albright, Lisa

2018-04-04

Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologies is unknown. A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (n=5408) was analyzed to evaluate the heritable contribution to lung cancer histology in smoking (n=1751) and non-smoking cases (n=818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. Significant excess distant relatedness was observed for all lung cancer histology subgroups analyzed except the small cell lung cancer subset (p=0.213). When smoking and non-smoking histologic subsets of lung cancer were considered, excess relatedness was observed only in non-smoking NSCLC (n=653; p=0.026) and, particularly, in those non-smokers with non-squamous histology (n=561; p=0.036). Sixty one pedigrees were identified which demonstrated a significant excess risk of non-smoking, non-squamous lung cancer cases; and an excess of female cases was observed among the cases in these high-risk pedigrees. This analysis supports a genetic predisposition to lung cancer carcinogenesis in non-smoking, non-squamous NSCLC cases. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Correlation between Relatives given Complete Genotypes: from Identity by Descent to Identity by Function

PubMed Central

Sverdlov, Serge; Thompson, Elizabeth A.

2013-01-01

In classical quantitative genetics, the correlation between the phenotypes of individuals with unknown genotypes and a known pedigree relationship is expressed in terms of probabilities of IBD states. In existing approaches to the inverse problem where genotypes are observed but pedigree relationships are not, dependence between phenotypes is either modeled as Bayesian uncertainty or mapped to an IBD model via inferred relatedness parameters. Neither approach yields a relationship between genotypic similarity and phenotypic similarity with a probabilistic interpretation corresponding to a generative model. We introduce a generative model for diploid allele effect based on the classic infinite allele mutation process. This approach motivates the concept of IBF (Identity by Function). The phenotypic covariance between two individuals given their diploid genotypes is expressed in terms of functional identity states. The IBF parameters define a genetic architecture for a trait without reference to specific alleles or population. Given full genome sequences, we treat a gene-scale functional region, rather than a SNP, as a QTL, modeling patterns of dominance for multiple alleles. Applications demonstrated by simulation include phenotype and effect prediction and association, and estimation of heritability and classical variance components. A simulation case study of the Missing Heritability problem illustrates a decomposition of heritability under the IBF framework into Explained and Unexplained components. PMID:23851163

Spontaneous occurrence of a potentially night blinding disorder in guinea pigs.

PubMed

Racine, Julie; Behn, Darren; Simard, Eric; Lachapelle, Pierre

2003-07-01

Several hereditary retinal disorders such as retinitis pigmentosa and congenital stationary night blindness compromise, sometimes exclusively, the activity of the rod pathway. Unfortunately, there are few animal models of these disorders that could help us better understand the pathophysiological processes involved. The purpose of this report is to present a pedigree of guinea pigs where, as a result of a consanguineous mating and subsequent selective breeding, we developed a new and naturally occurring animal model of a rod disorder. Analysis of the retinal function with the electroretinogram reveals that the threshold for rod-mediated electroretinograms (ERGs) is significantly increased by more than 2 log-units compared to that of normal guinea pigs. Furthermore, in response to a suprathreshold stimulus, also delivered under scotopic condition, which yield a mixed cone-rod response in normal guinea pigs, the ERG waveform in our mutant guinea pigs is almost identical (amplitude and timing of a- and b-waves) to that evoked in photopic condition. The above would thus suggest either a structural (abnormal development or absence) or a functional deficiency of the rod photoreceptors. We believe that our pedigree possibly represents a new animal model of a night blinding disorder, and that this condition is inherited as anautosomal recessive trait in the guinea pig population.

[Identification of a HPGD mutation in three families affected with primary hypertrophic osteoarthropathy].

PubMed

Zhang, Wanying; Wang, Tao; Huang, Shuaiwu; Zhao, Xiuli

2018-04-10

To detect mutation of HPGD gene among three pedigrees affected with primary hypertrophic osteoarthropathy (PHO) by DNA sequencing and high-resolution melting (HRM) analysis. Genomic DNA was extracted from peripheral blood samples collected from the pedigrees. PCR and direct sequencing were carried out to identify potential mutations of the HPGD gene. Amplicons containing the mutation spot were generated by nested PCR. The products were then subjected to HRM analysis using the HR-1 instrument. Direct sequencing was carried out in family members and healthy individuals to confirm the result of HRM analysis. A homozygous mutation c.310_311delCT was detected in 2 affected probands, while a heterozygous mutation c.310_311delCT was detected in the third proband. HRM analysis of the fragments encompassing HPGD exon 3 showed 3 curve patterns representing three different genotypes, i.e., the wild type, the c.310_311delCT homozygote, and the c.310_311delCT heterozygote. Result of DNA sequencing was consistent with that of the HRM analysis and phenotype of the subjects. The c.310_311delCT mutation may be the most prevalent mutation among Chinese population. HRM analysis has provided an optimized method for genetic testing of HPGD mutation for its simplicity, rapid turnover and high sensitivity.

A predictive assessment of genetic correlations between traits in chickens using markers.

PubMed

Momen, Mehdi; Mehrgardi, Ahmad Ayatollahi; Sheikhy, Ayoub; Esmailizadeh, Ali; Fozi, Masood Asadi; Kranis, Andreas; Valente, Bruno D; Rosa, Guilherme J M; Gianola, Daniel

2017-02-01

Genomic selection has been successfully implemented in plant and animal breeding programs to shorten generation intervals and accelerate genetic progress per unit of time. In practice, genomic selection can be used to improve several correlated traits simultaneously via multiple-trait prediction, which exploits correlations between traits. However, few studies have explored multiple-trait genomic selection. Our aim was to infer genetic correlations between three traits measured in broiler chickens by exploring kinship matrices based on a linear combination of measures of pedigree and marker-based relatedness. A predictive assessment was used to gauge genetic correlations. A multivariate genomic best linear unbiased prediction model was designed to combine information from pedigree and genome-wide markers in order to assess genetic correlations between three complex traits in chickens, i.e. body weight at 35 days of age (BW), ultrasound area of breast meat (BM) and hen-house egg production (HHP). A dataset with 1351 birds that were genotyped with the 600 K Affymetrix platform was used. A kinship kernel (K) was constructed as K = λ G + (1 - λ)A, where A is the numerator relationship matrix, measuring pedigree-based relatedness, and G is a genomic relationship matrix. The weight (λ) assigned to each source of information varied over the grid λ = (0, 0.2, 0.4, 0.6, 0.8, 1). Maximum likelihood estimates of heritability and genetic correlations were obtained at each λ, and the "optimum" λ was determined using cross-validation. Estimates of genetic correlations were affected by the weight placed on the source of information used to build K. For example, the genetic correlation between BW-HHP and BM-HHP changed markedly when λ varied from 0 (only A used for measuring relatedness) to 1 (only genomic information used). As λ increased, predictive correlations (correlation between observed phenotypes and predicted breeding values) increased and mean-squared predictive error decreased. However, the improvement in predictive ability was not monotonic, with an optimum found at some 0 < λ < 1, i.e., when both sources of information were used together. Our findings indicate that multiple-trait prediction may benefit from combining pedigree and marker information. Also, it appeared that expected correlated responses to selection computed from standard theory may differ from realized responses. The predictive assessment provided a metric for performance evaluation as well as a means for expressing uncertainty of outcomes of multiple-trait selection.

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

PubMed Central

van den Ende, Tom; Sharifi, Sarvi; van der Salm, Sandra M. A.; van Rootselaar, Anne-Fleur

2018-01-01

Background Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings. Methods We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria. Results Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A “benign” phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity. Discussion Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes. PMID:29416935

A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy

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

Zhang, Juanjuan; Yuan, Yimin; Lin, Bing

2012-03-23

Highlights: Black-Right-Pointing-Pointer We report the characterization of a four-generation large Chinese family with ADOA. Black-Right-Pointing-Pointer We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. Black-Right-Pointing-Pointer We do not find any mitochondrial DNA mutations associated with optic atrophy. Black-Right-Pointing-Pointer Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressivemore » visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.« less

Whole genome sequencing of one complex pedigree illustrates challenges with genomic medicine.

PubMed

Fang, Han; Wu, Yiyang; Yang, Hui; Yoon, Margaret; Jiménez-Barrón, Laura T; Mittelman, David; Robison, Reid; Wang, Kai; Lyon, Gholson J

2017-02-23

Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; however, there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants. We illustrate an integrative analysis of WGS and HPO using an extended pedigree, which involves Prader-Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. A comprehensive WGS pipeline was used to ensure reliable detection of genomic variants. Beyond variant filtering, we pursued phenotypic prioritization of candidate genes using Phenolyzer. Regarding PWS, WGS confirmed a 5.5 Mb de novo deletion of the parental allele at 15q11.2 to 15q13.1. Phenolyzer successfully returned the diagnosis of PWS, and pinpointed clinically relevant genes in the deletion. Further, Phenolyzer revealed how each of the genes is linked with the phenotypes represented by HPO terms. For HH, WGS identified a known disease variant (p.C282Y) in HFE of an affected female. Analysis of HPO terms alone fails to provide a correct diagnosis, but Phenolyzer successfully revealed the phenotype-genotype relationship using a disease-centric approach. Finally, Phenolyzer also revealed the complexity behind dysautonomia-like symptoms, and seven variants that might be associated with the phenotypes were identified by manual filtering based on a dominant inheritance model. The integration of WGS and HPO can inform comprehensive molecular diagnosis for patients, eliminate false positives and reveal novel insights into undiagnosed diseases. Due to extreme heterogeneity and insufficient knowledge of human diseases, it is also important that phenotypic and genomic data are standardized and shared simultaneously.

Trait variation and genetic diversity in a banana genomic selection training population

PubMed Central

Nyine, Moses; Uwimana, Brigitte; Swennen, Rony; Batte, Michael; Brown, Allan; Christelová, Pavla; Hřibová, Eva; Lorenzen, Jim

2017-01-01

Banana (Musa spp.) is an important crop in the African Great Lakes region in terms of income and food security, with the highest per capita consumption worldwide. Pests, diseases and climate change hamper sustainable production of bananas. New breeding tools with increased crossbreeding efficiency are being investigated to breed for resistant, high yielding hybrids of East African Highland banana (EAHB). These include genomic selection (GS), which will benefit breeding through increased genetic gain per unit time. Understanding trait variation and the correlation among economically important traits is an essential first step in the development and selection of suitable GS models for banana. In this study, we tested the hypothesis that trait variations in bananas are not affected by cross combination, cycle, field management and their interaction with genotype. A training population created using EAHB breeding material and its progeny was phenotyped in two contrasting conditions. A high level of correlation among vegetative and yield related traits was observed. Therefore, genomic selection models could be developed for traits that are easily measured. It is likely that the predictive ability of traits that are difficult to phenotype will be similar to less difficult traits they are highly correlated with. Genotype response to cycle and field management practices varied greatly with respect to traits. Yield related traits accounted for 31–35% of principal component variation under low and high input field management conditions. Resistance to Black Sigatoka was stable across cycles but varied under different field management depending on the genotype. The best cross combination was 1201K-1xSH3217 based on selection response (R) of hybrids. Genotyping using simple sequence repeat (SSR) markers revealed that the training population was genetically diverse, reflecting a complex pedigree background, which was mostly influenced by the male parents. PMID:28586365

Trait variation and genetic diversity in a banana genomic selection training population.

PubMed

Nyine, Moses; Uwimana, Brigitte; Swennen, Rony; Batte, Michael; Brown, Allan; Christelová, Pavla; Hřibová, Eva; Lorenzen, Jim; Doležel, Jaroslav

2017-01-01

Banana (Musa spp.) is an important crop in the African Great Lakes region in terms of income and food security, with the highest per capita consumption worldwide. Pests, diseases and climate change hamper sustainable production of bananas. New breeding tools with increased crossbreeding efficiency are being investigated to breed for resistant, high yielding hybrids of East African Highland banana (EAHB). These include genomic selection (GS), which will benefit breeding through increased genetic gain per unit time. Understanding trait variation and the correlation among economically important traits is an essential first step in the development and selection of suitable GS models for banana. In this study, we tested the hypothesis that trait variations in bananas are not affected by cross combination, cycle, field management and their interaction with genotype. A training population created using EAHB breeding material and its progeny was phenotyped in two contrasting conditions. A high level of correlation among vegetative and yield related traits was observed. Therefore, genomic selection models could be developed for traits that are easily measured. It is likely that the predictive ability of traits that are difficult to phenotype will be similar to less difficult traits they are highly correlated with. Genotype response to cycle and field management practices varied greatly with respect to traits. Yield related traits accounted for 31-35% of principal component variation under low and high input field management conditions. Resistance to Black Sigatoka was stable across cycles but varied under different field management depending on the genotype. The best cross combination was 1201K-1xSH3217 based on selection response (R) of hybrids. Genotyping using simple sequence repeat (SSR) markers revealed that the training population was genetically diverse, reflecting a complex pedigree background, which was mostly influenced by the male parents.

Enabling the use of hereditary information from pedigree tools in medical knowledge-based systems.

PubMed

Gay, Pablo; López, Beatriz; Plà, Albert; Saperas, Jordi; Pous, Carles

2013-08-01

The use of family information is a key issue to deal with inheritance illnesses. This kind of information use to come in the form of pedigree files, which contain structured information as tree or graphs, which explains the family relationships. Knowledge-based systems should incorporate the information gathered by pedigree tools to assess medical decision making. In this paper, we propose a method to achieve such a goal, which consists on the definition of new indicators, and methods and rules to compute them from family trees. The method is illustrated with several case studies. We provide information about its implementation and integration on a case-based reasoning tool. The method has been experimentally tested with breast cancer diagnosis data. The results show the feasibility of our methodology. Copyright © 2013 Elsevier Inc. All rights reserved.

Epilogue: Systems Approaches and Systems Practice

NASA Astrophysics Data System (ADS)

Reynolds, Martin; Holwell, Sue

Each of the five systems approaches discussed in this volume: system dynamics (SD), the viable systems model (VSM), strategic options development and analysis (SODA), soft systems methodology (SSM) and critical systems heuristics (CSH) has a pedigree. Not in the sense of the sometimes absurd spectacle of animals paraded at dog shows. Rather, their pedigree derives from their systems foundations, their capacity to evolve and their flexibility in use. None of the five approaches has developed out of use in restricted and controlled contexts of either low or high levels of complicatedness. Neither has any one of them evolved as a consequence of being applied only to situations with either presumed stakeholder agreement on purpose, or courteous disagreement amongst stakeholders, or stakeholder coercion. The compilation is not a celebration of abstract ‘methodologies', but of theoretically robust approaches that have a genuine pedigree in practice.

Common founder effects of hereditary hemochromatosis, Wilson´s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes.

PubMed

Olsson, K Sigvard; Wålinder, Olof; Jansson, Ulf; Wilbe, Maria; Bondeson, Marie-Louise; Stattin, Eva-Lena; Raha-Chowdhury, Ruma; Williams, Roger

2017-01-01

Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p. C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation ( KCNQ1 /p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16 th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1 (NM_138691),c.1814T>C,(p.L605P) mutation, possibly of Finnish origin. Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson´s disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN /p.S660Afs*30 and TMC1/ p.L605P were identified,none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1 st cousin unions and only 2 (2.0 %) was born out of wedlock.

26 CFR 1.1291-1 - Taxation of U.S. persons that are shareholders of PFICs that are not pedigreed QEFs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Taxation of U.S. persons that are shareholders of PFICs that are not pedigreed QEFs. 1.1291-1 Section 1.1291-1 Internal Revenue INTERNAL REVENUE... Determining Capital Gains and Losses § 1.1291-1 Taxation of U.S. persons that are shareholders of PFICs that...

26 CFR 1.1291-1 - Taxation of U.S. persons that are shareholders of PFICs that are not pedigreed QEFs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 11 2011-04-01 2011-04-01 false Taxation of U.S. persons that are shareholders of PFICs that are not pedigreed QEFs. 1.1291-1 Section 1.1291-1 Internal Revenue INTERNAL REVENUE... Rules for Determining Capital Gains and Losses § 1.1291-1 Taxation of U.S. persons that are shareholders...

Validation of DNA-based identification software by computation of pedigree likelihood ratios.

PubMed

Slooten, K

2011-08-01

Disaster victim identification (DVI) can be aided by DNA-evidence, by comparing the DNA-profiles of unidentified individuals with those of surviving relatives. The DNA-evidence is used optimally when such a comparison is done by calculating the appropriate likelihood ratios. Though conceptually simple, the calculations can be quite involved, especially with large pedigrees, precise mutation models etc. In this article we describe a series of test cases designed to check if software designed to calculate such likelihood ratios computes them correctly. The cases include both simple and more complicated pedigrees, among which inbred ones. We show how to calculate the likelihood ratio numerically and algebraically, including a general mutation model and possibility of allelic dropout. In Appendix A we show how to derive such algebraic expressions mathematically. We have set up these cases to validate new software, called Bonaparte, which performs pedigree likelihood ratio calculations in a DVI context. Bonaparte has been developed by SNN Nijmegen (The Netherlands) for the Netherlands Forensic Institute (NFI). It is available free of charge for non-commercial purposes (see www.dnadvi.nl for details). Commercial licenses can also be obtained. The software uses Bayesian networks and the junction tree algorithm to perform its calculations. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Genetic diversity and structure of elite cotton germplasm (Gossypium hirsutum L.) using genome-wide SNP data.

PubMed

Ai, XianTao; Liang, YaJun; Wang, JunDuo; Zheng, JuYun; Gong, ZhaoLong; Guo, JiangPing; Li, XueYuan; Qu, YanYing

2017-10-01

Cotton (Gossypium spp.) is the most important natural textile fiber crop, and Gossypium hirsutum L. is responsible for 90% of the annual cotton crop in the world. Information on cotton genetic diversity and population structure is essential for new breeding lines. In this study, we analyzed population structure and genetic diversity of 288 elite Gossypium hirsutum cultivar accessions collected from around the world, and especially from China, using genome-wide single nucleotide polymorphisms (SNP) markers. The average polymorphsim information content (PIC) was 0.25, indicating a relatively low degree of genetic diversity. Population structure analysis revealed extensive admixture and identified three subgroups. Phylogenetic analysis supported the subgroups identified by STRUCTURE. The results from both population structure and phylogenetic analysis were, for the most part, in agreement with pedigree information. Analysis of molecular variance revealed a larger amount of variation was due to diversity within the groups. Establishment of genetic diversity and population structure from this study could be useful for genetic and genomic analysis and systematic utilization of the standing genetic variation in upland cotton.

Clarifying sub-genomic positions of QTLs for flowering habit and fruit quality in U.S. strawberry (Fragaria×ananassa) breeding populations using pedigree-based QTL analysis

PubMed Central

Verma, Sujeet; Zurn, Jason D; Salinas, Natalia; Mathey, Megan M; Denoyes, Beatrice; Hancock, James F; Finn, Chad E; Bassil, Nahla V; Whitaker, Vance M

2017-01-01

The cultivated strawberry (Fragaria×ananassa) is consumed worldwide for its flavor and nutritional benefits. Genetic analysis of commercially important traits in strawberry are important for the development of breeding methods and tools for this species. Although several quantitative trait loci (QTL) have been previously detected for fruit quality and flowering traits using low-density genetic maps, clarity on the sub-genomic locations of these QTLs was missing. Recent discoveries in allo-octoploid strawberry genomics led to the development of the IStraw90 single-nucleotide polymorphism (SNP) array, enabling high-density genetic maps and finer resolution QTL analysis. In this study, breeder-specified traits were evaluated in the Eastern (Michigan) and Western (Oregon) United States for a common set of breeding populations during 2 years. Several QTLs were validated for soluble solids content (SSC), fruit weight (FWT), pH and titratable acidity (TA) using a pedigree-based QTL analysis approach. For fruit quality, a QTL for SSC on linkage group (LG) 6A, a QTL for FWT on LG 2BII, a QTL for pH on LG 4CII and two QTLs for TA on LGs 2A and 5B were detected. In addition, a large-effect QTL for flowering was detected at the distal end of LG 4A, coinciding with the FaPFRU locus. Marker haplotype analysis in the FaPFRU region indicated that the homozygous recessive genotype was highly predictive of seasonal flowering. SNP probes in the FaPFRU region may help facilitate marker-assisted selection for this trait. PMID:29138689

Genomic prediction in a nuclear population of layers using single-step models.

PubMed

Yan, Yiyuan; Wu, Guiqin; Liu, Aiqiao; Sun, Congjiao; Han, Wenpeng; Li, Guangqi; Yang, Ning

2018-02-01

Single-step genomic prediction method has been proposed to improve the accuracy of genomic prediction by incorporating information of both genotyped and ungenotyped animals. The objective of this study is to compare the prediction performance of single-step model with a 2-step models and the pedigree-based models in a nuclear population of layers. A total of 1,344 chickens across 4 generations were genotyped by a 600 K SNP chip. Four traits were analyzed, i.e., body weight at 28 wk (BW28), egg weight at 28 wk (EW28), laying rate at 38 wk (LR38), and Haugh unit at 36 wk (HU36). In predicting offsprings, individuals from generation 1 to 3 were used as training data and females from generation 4 were used as validation set. The accuracies of predicted breeding values by pedigree BLUP (PBLUP), genomic BLUP (GBLUP), SSGBLUP and single-step blending (SSBlending) were compared for both genotyped and ungenotyped individuals. For genotyped females, GBLUP performed no better than PBLUP because of the small size of training data, while the 2 single-step models predicted more accurately than the PBLUP model. The average predictive ability of SSGBLUP and SSBlending were 16.0% and 10.8% higher than the PBLUP model across traits, respectively. Furthermore, the predictive abilities for ungenotyped individuals were also enhanced. The average improvements of prediction abilities were 5.9% and 1.5% for SSGBLUP and SSBlending model, respectively. It was concluded that single-step models, especially the SSGBLUP model, can yield more accurate prediction of genetic merits and are preferable for practical implementation of genomic selection in layers. © 2017 Poultry Science Association Inc.

Clarifying sub-genomic positions of QTLs for flowering habit and fruit quality in U.S. strawberry (Fragaria×ananassa) breeding populations using pedigree-based QTL analysis.

PubMed

Verma, Sujeet; Zurn, Jason D; Salinas, Natalia; Mathey, Megan M; Denoyes, Beatrice; Hancock, James F; Finn, Chad E; Bassil, Nahla V; Whitaker, Vance M

2017-01-01

The cultivated strawberry ( Fragaria × ananassa ) is consumed worldwide for its flavor and nutritional benefits. Genetic analysis of commercially important traits in strawberry are important for the development of breeding methods and tools for this species. Although several quantitative trait loci (QTL) have been previously detected for fruit quality and flowering traits using low-density genetic maps, clarity on the sub-genomic locations of these QTLs was missing. Recent discoveries in allo-octoploid strawberry genomics led to the development of the IStraw90 single-nucleotide polymorphism (SNP) array, enabling high-density genetic maps and finer resolution QTL analysis. In this study, breeder-specified traits were evaluated in the Eastern (Michigan) and Western (Oregon) United States for a common set of breeding populations during 2 years. Several QTLs were validated for soluble solids content (SSC), fruit weight (FWT), pH and titratable acidity (TA) using a pedigree-based QTL analysis approach. For fruit quality, a QTL for SSC on linkage group (LG) 6A, a QTL for FWT on LG 2BII, a QTL for pH on LG 4CII and two QTLs for TA on LGs 2A and 5B were detected. In addition, a large-effect QTL for flowering was detected at the distal end of LG 4A, coinciding with the FaPFRU locus. Marker haplotype analysis in the FaPFRU region indicated that the homozygous recessive genotype was highly predictive of seasonal flowering. SNP probes in the FaPFRU region may help facilitate marker-assisted selection for this trait.

Inbreeding avoidance in an isolated indigenous Zapotec community in the valley of Oaxaca, southern Mexico.

PubMed

Little, Bertis B; Malina, Robert M

2005-06-01

We analyzed inbreeding using surname isonymy in an indigenous genetic isolate. The subjects were residents of a rural Zapotec-speaking community in the valley of Oaxaca, southern Mexico. The community can be classified as a genetic isolate with an average gene flow of < or = 3% per generation. Surnames were collected for individuals in each household in pedigree form using the culturally traditional patronym-matronym naming. Estimation of inbreeding from surname isonymy is facilitated by the traditional patronym-matronym name assignment among indigenous Mexican populations. A total of 2,149 individuals had valid surname patronym-matronym pairings, including 484 deceased ancestors. Surname isonymy analysis methods were used to estimate total inbreeding and to segregate it into random and nonrandom components. The surname isonymy coefficient computed from 119 isonymous surname pairings (119/2,149) was 0.0554. The estimated inbreeding coefficient from surname isonymy was 0.0138 (0.0554/4). The random and nonrandom components of inbreeding were F(r) = 0.0221 and F(n) = -0.0091, respectively. The results suggest that consanguinity is culturally avoided. Nonrandom inbreeding decreased total inbreeding by about 41%. Total estimated inbreeding by surname isonymy was 0.0138, which is similar to inbreeding estimated from a sample of pedigrees, 0.01. Socially prescribed inbreeding avoidance substantially lowered total F through negative nonrandom inbreeding. Even in the situation of genetic isolation and small effective population size (N(e)), estimated inbreeding is lower than may have otherwise occurred if inbreeding were only random. However, among the poorest individuals, socially prescribed jural rules for inbreeding avoidance failed to operate. Thus the preponderance of inbreeding appears to occur among the poor, economically disadvantaged in the community.

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

PubMed

Tuijnenburg, Paul; Lango Allen, Hana; Burns, Siobhan O; Greene, Daniel; Jansen, Machiel H; Staples, Emily; Stephens, Jonathan; Carss, Keren J; Biasci, Daniele; Baxendale, Helen; Thomas, Moira; Chandra, Anita; Kiani-Alikhan, Sorena; Longhurst, Hilary J; Seneviratne, Suranjith L; Oksenhendler, Eric; Simeoni, Ilenia; de Bree, Godelieve J; Tool, Anton T J; van Leeuwen, Ester M M; Ebberink, Eduard H T M; Meijer, Alexander B; Tuna, Salih; Whitehorn, Deborah; Brown, Matthew; Turro, Ernest; Thrasher, Adrian J; Smith, Kenneth G C; Thaventhiran, James E; Kuijpers, Taco W

2018-03-02

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.

PubMed

Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Alimadadi, Hossein; Noori-Daloii, Mohammad Reza

2017-05-01

Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

PubMed

Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

2005-12-30

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

[The progress and prospect of application of genetic testing technology-based gene detection technology in the diagnosis and treatment of hereditary cancer].

PubMed

He, J X; Jiang, Y F

2017-08-06

Hereditary cancer is caused by specific pathogenic gene mutations. Early detection and early intervention are the most effective ways to prevent and control hereditary cancer. High-throughput sequencing based genetic testing technology (NGS) breaks through the restrictions of pedigree analysis, provide a convenient and efficient method to detect and diagnose hereditary cancer. Here, we introduce the mechanism of hereditary cancer, summarize, discuss and prospect the application of NGS and other genetic tests in the diagnosis of hereditary retinoblastoma, hereditary breast and ovarian cancer syndrome, hereditary colorectal cancer and other complex and rare hereditary tumors.

KinLinks: Software Toolkit for Kinship Analysis and Pedigree Generation from NGS Datasets

DTIC Science & Technology

2015-04-21

Retinitis pigmentosa families 2110 and 2111 of 52 individuals across 6 generations (Figure 5a), and 54 geographically diverse samples (Supplementary Table...relationships within the Retinitis pigmentosa family. Machine Learning Classifier for pairwise kinship prediction Ten features were identified for training...family (Figure 4b), and the Retinitis pigmentosa family (Figure 5b). The auto-generated pedigrees were graphed as well as in family-tree format using

Utilising family-based designs for detecting rare variant disease associations.

PubMed

Preston, Mark D; Dudbridge, Frank

2014-03-01

Rare genetic variants are thought to be important components in the causality of many diseases but discovering these associations is challenging. We demonstrate how best to use family-based designs to improve the power to detect rare variant disease associations. We show that using genetic data from enriched families (those pedigrees with greater than one affected member) increases the power and sensitivity of existing case-control rare variant tests. However, we show that transmission- (or within-family-) based tests do not benefit from this enrichment. This means that, in studies where a limited amount of genotyping is available, choosing a single case from each of many pedigrees has greater power than selecting multiple cases from fewer pedigrees. Finally, we show how a pseudo-case-control design allows a greater range of statistical tests to be applied to family data. © 2014 The Authors. Annals of Human Genetics published by John Wiley & Sons Ltd/University College London.

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden.

PubMed

Melin, M; Entesarian, M; Carlsson, G; Garwicz, D; Klein, C; Fadeel, B; Nordenskjöld, M; Palmblad, J; Henter, J I; Dahl, N

2007-02-16

Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.

Lessons learned from family history in ocular genetics.

PubMed

Marino, Meghan J

2015-07-01

Given the vast genetic and phenotypic heterogeneity seen in ocular genetic disorders, considering a patient's clinical phenotype in the context of the family history is essential. Clinicians can improve patient care by appropriately incorporating a patient's family history into their evaluation. Obtaining, reviewing, and accurately interpreting the pedigree are skills geneticists and genetic counselors possess. However, with the field of ophthalmic genetics vastly growing, it is becoming essential for ophthalmologists to understand the utility of the pedigree and develop their abilities in eliciting this information. By not considering a patient's clinical history in the context of the family history, diagnoses can be missed or inaccurate. The purpose of this review is to inform ophthalmologists on the importance of the family history and highlight how the pedigree can aid in establishing an accurate genetic diagnosis. This review also provides to ophthalmologists helpful tips on eliciting and interpreting a patient's family history.

Efficiency of multi-breed genomic selection for dairy cattle breeds with different sizes of reference population.

PubMed

Hozé, C; Fritz, S; Phocas, F; Boichard, D; Ducrocq, V; Croiseau, P

2014-01-01

Single-breed genomic selection (GS) based on medium single nucleotide polymorphism (SNP) density (~50,000; 50K) is now routinely implemented in several large cattle breeds. However, building large enough reference populations remains a challenge for many medium or small breeds. The high-density BovineHD BeadChip (HD chip; Illumina Inc., San Diego, CA) containing 777,609 SNP developed in 2010 is characterized by short-distance linkage disequilibrium expected to be maintained across breeds. Therefore, combining reference populations can be envisioned. A population of 1,869 influential ancestors from 3 dairy breeds (Holstein, Montbéliarde, and Normande) was genotyped with the HD chip. Using this sample, 50K genotypes were imputed within breed to high-density genotypes, leading to a large HD reference population. This population was used to develop a multi-breed genomic evaluation. The goal of this paper was to investigate the gain of multi-breed genomic evaluation for a small breed. The advantage of using a large breed (Normande in the present study) to mimic a small breed is the large potential validation population to compare alternative genomic selection approaches more reliably. In the Normande breed, 3 training sets were defined with 1,597, 404, and 198 bulls, and a unique validation set included the 394 youngest bulls. For each training set, estimated breeding values (EBV) were computed using pedigree-based BLUP, single-breed BayesC, or multi-breed BayesC for which the reference population was formed by any of the Normande training data sets and 4,989 Holstein and 1,788 Montbéliarde bulls. Phenotypes were standardized by within-breed genetic standard deviation, the proportion of polygenic variance was set to 30%, and the estimated number of SNP with a nonzero effect was about 7,000. The 2 genomic selection (GS) approaches were performed using either the 50K or HD genotypes. The correlations between EBV and observed daughter yield deviations (DYD) were computed for 6 traits and using the different prediction approaches. Compared with pedigree-based BLUP, the average gain in accuracy with GS in small populations was 0.057 for the single-breed and 0.086 for multi-breed approach. This gain was up to 0.193 and 0.209, respectively, with the large reference population. Improvement of EBV prediction due to the multi-breed evaluation was higher for animals not closely related to the reference population. In the case of a breed with a small reference population size, the increase in correlation due to multi-breed GS was 0.141 for bulls without their sire in reference population compared with 0.016 for bulls with their sire in reference population. These results demonstrate that multi-breed GS can contribute to increase genomic evaluation accuracy in small breeds. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Genomic selection models double the accuracy of predicted breeding values for bacterial cold water disease resistance compared to a traditional pedigree-based model in rainbow trout aquaculture.

PubMed

Vallejo, Roger L; Leeds, Timothy D; Gao, Guangtu; Parsons, James E; Martin, Kyle E; Evenhuis, Jason P; Fragomeni, Breno O; Wiens, Gregory D; Palti, Yniv

2017-02-01

Previously, we have shown that bacterial cold water disease (BCWD) resistance in rainbow trout can be improved using traditional family-based selection, but progress has been limited to exploiting only between-family genetic variation. Genomic selection (GS) is a new alternative that enables exploitation of within-family genetic variation. We compared three GS models [single-step genomic best linear unbiased prediction (ssGBLUP), weighted ssGBLUP (wssGBLUP), and BayesB] to predict genomic-enabled breeding values (GEBV) for BCWD resistance in a commercial rainbow trout population, and compared the accuracy of GEBV to traditional estimates of breeding values (EBV) from a pedigree-based BLUP (P-BLUP) model. We also assessed the impact of sampling design on the accuracy of GEBV predictions. For these comparisons, we used BCWD survival phenotypes recorded on 7893 fish from 102 families, of which 1473 fish from 50 families had genotypes [57 K single nucleotide polymorphism (SNP) array]. Naïve siblings of the training fish (n = 930 testing fish) were genotyped to predict their GEBV and mated to produce 138 progeny testing families. In the following generation, 9968 progeny were phenotyped to empirically assess the accuracy of GEBV predictions made on their non-phenotyped parents. The accuracy of GEBV from all tested GS models were substantially higher than the P-BLUP model EBV. The highest increase in accuracy relative to the P-BLUP model was achieved with BayesB (97.2 to 108.8%), followed by wssGBLUP at iteration 2 (94.4 to 97.1%) and 3 (88.9 to 91.2%) and ssGBLUP (83.3 to 85.3%). Reducing the training sample size to n = ~1000 had no negative impact on the accuracy (0.67 to 0.72), but with n = ~500 the accuracy dropped to 0.53 to 0.61 if the training and testing fish were full-sibs, and even substantially lower, to 0.22 to 0.25, when they were not full-sibs. Using progeny performance data, we showed that the accuracy of genomic predictions is substantially higher than estimates obtained from the traditional pedigree-based BLUP model for BCWD resistance. Overall, we found that using a much smaller training sample size compared to similar studies in livestock, GS can substantially improve the selection accuracy and genetic gains for this trait in a commercial rainbow trout breeding population.

Quality of family history collection with use of a patient facing family history assessment tool.

PubMed

Wu, R Ryanne; Himmel, Tiffany L; Buchanan, Adam H; Powell, Karen P; Hauser, Elizabeth R; Ginsburg, Geoffrey S; Henrich, Vincent C; Orlando, Lori A

2014-02-13

Studies have shown that the quality of family health history (FHH) collection in primary care is inadequate to assess disease risk. To use FHH for risk assessment, collected data must have adequate detail. To address this issue, we developed a patient facing FHH assessment tool, MeTree. In this paper we report the content and quality of the FHH collected using MeTree. A hybrid implementation-effectiveness study. Patients were recruited from 2009 to 2012. Two community primary care clinics in Greensboro, NC. All non-adopted adult English speaking patients with upcoming appointments were invited to participate. Education about and collection of FHH with entry into MeTree. We report the proportion of pedigrees that were high-quality. High-quality pedigrees are defined as having all the following criteria: (1) three generations of relatives, (2) relatives' lineage, (3) relatives' gender, (4) an up-to-date FHH, (5) pertinent negatives noted, (6) age of disease onset in affected relatives, and for deceased relatives, (7) the age and (8) cause of death (Prim Care31:479-495, 2004.). Enrollment: 1,184. Participant demographics: age range 18-92 (mean 58.8, SD 11.79), 56% male, and 75% white. The median pedigree size was 21 (range 8-71) and the FHH entered into MeTree resulted in a database of 27,406 individuals. FHHs collected by MeTree were found to be high quality in 99.8% (N = 1,182/1,184) as compared to <4% at baseline. An average of 1.9 relatives per pedigree (range 0-50, SD 4.14) had no data reported. For pedigrees where at least one relative has no data (N = 497/1,184), 4.97 relatives per pedigree (range 1-50, SD 5.44) had no data. Talking with family members before using MeTree significantly decreased the proportion of relatives with no data reported (4.98% if you talked to your relative vs. 10.85% if you did not, p-value < 0.001.). Using MeTree improves the quantity and quality of the FHH data that is collected and talking with relatives prior to the collection of FHH significantly improves the quantity and quality of the data provided. This allows more patients to be accurately risk stratified and offered appropriate preventive care guided by their risk level. NCT01372553.

Li-Fraumeni syndrome: Discovery and future challenges - Joseph Fraumeni Symposium

Cancer.gov

In May 2014, NCI’s Division of Cancer Epidemiology and Genetics (DCEG) hosted Cancer Epidemiology: From Pedigrees to Populations, a scientific symposium honoring 50 years of visionary leadership by Dr. Joseph F. Fraumeni, Jr., the founding Director of DCEG. In this video, Dr. Stephen Chanock of NCI provides opening remarks. Dr. David Schottenfeld of the University of Michigan moderates a session on the search for cancer susceptibility genes. Dr. Louise Strong of University of Texas MD Anderson Cancer Center speaks about the discovery and future challenges of Li-Fraumeni syndrome research. For more information on this symposium, visit http://dceg.cancer.gov/news-events/Fraumeni-symposium-speakers.

Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees.

PubMed

Carelli, Valerio; Achilli, Alessandro; Valentino, Maria Lucia; Rengo, Chiara; Semino, Ornella; Pala, Maria; Olivieri, Anna; Mattiazzi, Marina; Pallotti, Francesco; Carrara, Franco; Zeviani, Massimo; Leuzzi, Vincenzo; Carducci, Carla; Valle, Giorgio; Simionati, Barbara; Mendieta, Luana; Salomao, Solange; Belfort, Rubens; Sadun, Alfredo A; Torroni, Antonio

2006-04-01

The mitochondrial DNA (mtDNA) of 87 index cases with Leber hereditary optic neuropathy (LHON) sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, was evaluated in detail. Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that two specific combinations of amino acid changes in the cytochrome b are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory-chain complexes I and III. The families with identical haplotypes were genealogically reinvestigated, which led to the reconnection into extended pedigrees of three pairs of families, including the Brazilian family with its Italian counterpart. The sequencing of entire mtDNA samples from the reconnected families confirmed the genealogical reconstruction but showed that the Brazilian family was heteroplasmic at two control-region positions. The survey of the two sites in 12 of the Brazilian subjects revealed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination.

Population structure in Japanese rice population

PubMed Central

Yamasaki, Masanori; Ideta, Osamu

2013-01-01

It is essential to elucidate genetic diversity and relationships among even related individuals and populations for plant breeding and genetic analysis. Since Japanese rice breeding has improved agronomic traits such as yield and eating quality, modern Japanese rice cultivars originated from narrow genetic resource and closely related. To resolve the population structure and genetic diversity in Japanese rice population, we used a total of 706 alleles detected by 134 simple sequence repeat markers in a total of 114 cultivars composed of 94 improved varieties and 20 landraces, which are representative and important for Japanese rice breeding. The landraces exhibit greater gene diversity than improved lines, suggesting that landraces can provide additional genetic diversity for future breeding. Model-based Bayesian clustering analysis revealed six subgroups and admixture situation in the cultivars, showing good agreement with pedigree information. This method could be superior to phylogenetic method in classifying a related population. The leading Japanese rice cultivar, Koshihikari is unique due to the specific genome constitution. We defined Japanese rice diverse sets that capture the maximum number of alleles for given sample sizes. These sets are useful for a variety of genetic application in Japanese rice cultivars. PMID:23641181

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

Families in space: relatedness in the Barents Sea population of polar bears (Ursus maritimus).

PubMed

Zeyl, E; Aars, J; Ehrich, D; Wiig, O

2009-02-01

The kin structure and dispersal pattern of polar bears (Ursus maritimus) of the Barents Sea was investigated during the spring mating season using two complementary approaches. First, individual genotypes based on the analyses of 27 microsatellite loci of 583 polar bears were related to field information gathered from 1146 bears in order to reconstruct the animals' pedigrees and to infer geographical distances between adult bears of different relatedness categories. According to the data, the median natal dispersal distance of the male animals was 52 km while that of the females was 93 km. Second, the relatedness of pairs of adult bears was estimated and correlated to the geographical distance between them. The female dyads had a much stronger kin structure than the male dyads. The 'pedigree approach' revealed a male kin structure which could not be detected using the 'relatedness approach'. This suggests that, on a broader scale, effective dispersal is slightly male biased. Despite fidelity to natal areas, male-mediated gene flow may nevertheless prevent genetic differentiation. Males might occasionally shift their home range which could therefore lead to a male-biased breeding dispersal. Our results showed that a nonterritorial species such as the polar bear that has a high dispersal potential, lives in a highly unstable environment and migrates seasonally is still able to exhibit a distinct kin structure during the mating season.

Selection against canine hip dysplasia: success or failure?

PubMed

Wilson, Bethany; Nicholas, Frank W; Thomson, Peter C

2011-08-01

Canine hip dysplasia (CHD) is a multifactorial skeletal disorder which is very common in pedigree dogs and represents a huge concern for canine welfare. Control schemes based on selective breeding have been in operation for decades. The aim of these schemes is to reduce the impact of CHD on canine welfare by selecting for reduced radiographic evidence of CHD pathology as assessed by a variety of phenotypes. There is less information regarding the genotypic correlation between these phenotypes and the impact of CHD on canine welfare. Although the phenotypes chosen as the basis for these control schemes have displayed heritable phenotypic variation in many studies, success in achieving improvement in the phenotypes has been mixed. There is significant room for improvement in the current schemes through the use of estimated breeding values (EBVs), which can combine a dog's CHD phenotype with CHD phenotypes of relatives, other phenotypes as they are proven to be genetically correlated with CHD (especially elbow dysplasia phenotypes), and information from genetic tests for population-relevant DNA markers, as such tests become available. Additionally, breed clubs should be encouraged and assisted to formulate rational, evidenced-based breeding recommendations for CHD which suit their individual circumstances and dynamically to adjust the breeding recommendations based on continuous tracking of CHD genetic trends. These improvements can assist in safely and effectively reducing the impact of CHD on pedigree dog welfare. Copyright © 2011 Elsevier Ltd. All rights reserved.

Impacts of using inbred animals in studies for detection of quantitative trait loci.

PubMed

Freyer, G; Vukasinovic, N; Cassell, B

2009-02-01

Effects of utilizing inbred and noninbred family structures in experiments for detection of quantitative trait loci (QTL) were compared in this simulation study. Simulations were based on a general pedigree design originating from 2 unrelated sires. A variance component approach of mapping QTL was applied to simulated data that reflected common family structures from dairy populations. Five different family structures were considered: FS0 without inbreeding, FS1 with an inbred sire from an aunt-nephew mating, FS2 with an inbred sire originating from a half-sib mating, FS3 and FS4 based on FS2 but containing an increased number of offspring of the inbred sire (FS3), and another extremely inbred sire with its final offspring (FS4). Sixty replicates each of the 5 family structures in 2 simulation scenarios each were analyzed to provide a praxis-like situation of QTL analysis. The largest proportion of QTL position estimates within the correct interval of 3 cM, best test statistic profiles and the smallest average bias were obtained from the pedigrees described by FS4 and FS2. The approach does not depend on the kind and number of genetic markers. Inbreeding is not a recommended practice for commercial dairy production because of possible inbreeding depression, but inbred animals and their offspring that already exist could be advantageous for QTL mapping, because of reduced genetic variance in inbred parents.

Identification of key ancestors of modern germplasm in a breeding program of maize.

PubMed

Technow, F; Schrag, T A; Schipprack, W; Melchinger, A E

2014-12-01

Probabilities of gene origin computed from the genomic kinships matrix can accurately identify key ancestors of modern germplasms Identifying the key ancestors of modern plant breeding populations can provide valuable insights into the history of a breeding program and provide reference genomes for next generation whole genome sequencing. In an animal breeding context, a method was developed that employs probabilities of gene origin, computed from the pedigree-based additive kinship matrix, for identifying key ancestors. Because reliable and complete pedigree information is often not available in plant breeding, we replaced the additive kinship matrix with the genomic kinship matrix. As a proof-of-concept, we applied this approach to simulated data sets with known ancestries. The relative contribution of the ancestral lines to later generations could be determined with high accuracy, with and without selection. Our method was subsequently used for identifying the key ancestors of the modern Dent germplasm of the public maize breeding program of the University of Hohenheim. We found that the modern germplasm can be traced back to six or seven key ancestors, with one or two of them having a disproportionately large contribution. These results largely corroborated conjectures based on early records of the breeding program. We conclude that probabilities of gene origin computed from the genomic kinships matrix can be used for identifying key ancestors in breeding programs and estimating the proportion of genes contributed by them.

Genomic-assisted haplotype analysis and the development of high-throughput SNP markers for salinity tolerance in soybean

PubMed Central

Patil, Gunvant; Do, Tuyen; Vuong, Tri D.; Valliyodan, Babu; Lee, Jeong-Dong; Chaudhary, Juhi; Shannon, J. Grover; Nguyen, Henry T.

2016-01-01

Soil salinity is a limiting factor of crop yield. The soybean is sensitive to soil salinity, and a dominant gene, Glyma03g32900 is primarily responsible for salt-tolerance. The identification of high throughput and robust markers as well as the deployment of salt-tolerant cultivars are effective approaches to minimize yield loss under saline conditions. We utilized high quality (15x) whole-genome resequencing (WGRS) on 106 diverse soybean lines and identified three major structural variants and allelic variation in the promoter and genic regions of the GmCHX1 gene. The discovery of single nucleotide polymorphisms (SNPs) associated with structural variants facilitated the design of six KASPar assays. Additionally, haplotype analysis and pedigree tracking of 93 U.S. ancestral lines were performed using publically available WGRS datasets. Identified SNP markers were validated, and a strong correlation was observed between the genotype and salt treatment phenotype (leaf scorch, chlorophyll content and Na+ accumulation) using a panel of 104 soybean lines and, an interspecific bi-parental population (F8) from PI483463 x Hutcheson. These markers precisely identified salt-tolerant/sensitive genotypes (>91%), and different structural-variants (>98%). These SNP assays, supported by accurate phenotyping, haplotype analyses and pedigree tracking information, will accelerate marker-assisted selection programs to enhance the development of salt-tolerant soybean cultivars. PMID:26781337

Parentage Reconstruction in Eucalyptus nitens Using SNPs and Microsatellite Markers: A Comparative Analysis of Marker Data Power and Robustness.

PubMed

Telfer, Emily J; Stovold, Grahame T; Li, Yongjun; Silva-Junior, Orzenil B; Grattapaglia, Dario G; Dungey, Heidi S

2015-01-01

Pedigree reconstruction using molecular markers enables efficient management of inbreeding in open-pollinated breeding strategies, replacing expensive and time-consuming controlled pollination. This is particularly useful in preferentially outcrossed, insect pollinated Eucalypts known to suffer considerable inbreeding depression from related matings. A single nucleotide polymorphism (SNP) marker panel consisting of 106 markers was selected for pedigree reconstruction from the recently developed high-density Eucalyptus Infinium SNP chip (EuCHIP60K). The performance of this SNP panel for pedigree reconstruction in open-pollinated progenies of two Eucalyptus nitens seed orchards was compared with that of two microsatellite panels with 13 and 16 markers respectively. The SNP marker panel out-performed one of the microsatellite panels in the resolution power to reconstruct pedigrees and out-performed both panels with respect to data quality. Parentage of all but one offspring in each clonal seed orchard was correctly matched to the expected seed parent using the SNP marker panel, whereas parentage assignment to less than a third of the expected seed parents were supported using the 13-microsatellite panel. The 16-microsatellite panel supported all but one of the recorded seed parents, one better than the SNP panel, although there was still a considerable level of missing and inconsistent data. SNP marker data was considerably superior to microsatellite data in accuracy, reproducibility and robustness. Although microsatellites and SNPs data provide equivalent resolution for pedigree reconstruction, microsatellite analysis requires more time and experience to deal with the uncertainties of allele calling and faces challenges for data transferability across labs and over time. While microsatellite analysis will continue to be useful for some breeding tasks due to the high information content, existing infrastructure and low operating costs, the multi-species SNP resource available with the EuCHIP60k, opens a whole new array of opportunities for high-throughput, genome-wide or targeted genotyping in species of Eucalyptus.

Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients

PubMed Central

De Summa, Simona; Graziano, Francesca; Pilato, Brunella; Pinto, Rosamaria; Danza, Katia; Lacalamita, Rosanna; Serratì, Simona; Sambiasi, Domenico; Grassi, Mario; Tommasi, Stefania

2017-01-01

Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance breast cancer 1/2, early onset genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h2) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms (SNPs), nuclear mitotic apparatus protein 1, cyclin D1, cytochrome C oxidase copper chaperone, fibroblast growth factor receptor 2, TOX high mobility group box family member 3 and solute carrier family 4 member 7. These 6 SNPs, previously identified by genome-wide association studies, were considered to evaluate the additive and common environmental components that contribute to the development of breast cancer in nuclear (pedigrees including only first degree relationships) and in extended families (with at most third degree relationships). A total of 22 extended pedigrees, subsequently split into 52 nuclear pedigrees were analyzed. An example of splitting process from extended to nuclear pedigree is shown in Fig. 1. Firstly, an underline latent continuous trait (Y*) using breast cancer status and information of 6 breast cancer-associated SNPs was calculated. This novel trait summarized the susceptibility of breast cancer in each individual. Secondly, the h2 of Y* was estimated using an additive polygenic-common environment-unique error model. h2 was evaluated in extended and immediate pedigrees, obtaining comparable results. h2 accounts for ~40% of the total phenotypic variance, indicating a fairly strong additive genetic effect of breast cancer susceptibility. The present study indicated the importance of the evaluation and consideration of these six SNPs, which can be used as instrumental variables in order to obtain improved genetic models that are useful for h2 analysis. PMID:28943953

Genetic rescue in an inbred Arctic fox (Vulpes lagopus) population.

PubMed

Hasselgren, Malin; Angerbjörn, Anders; Eide, Nina E; Erlandsson, Rasmus; Flagstad, Øystein; Landa, Arild; Wallén, Johan; Norén, Karin

2018-03-28

Isolation of small populations can reduce fitness through inbreeding depression and impede population growth. Outcrossing with only a few unrelated individuals can increase demographic and genetic viability substantially, but few studies have documented such genetic rescue in natural mammal populations. We investigate the effects of immigration in a subpopulation of the endangered Scandinavian arctic fox ( Vulpes lagopus ), founded by six individuals and isolated for 9 years at an extremely small population size. Based on a long-term pedigree (105 litters, 543 individuals) combined with individual fitness traits, we found evidence for genetic rescue. Natural immigration and gene flow of three outbred males in 2010 resulted in a reduction in population average inbreeding coefficient ( f ), from 0.14 to 0.08 within 5 years. Genetic rescue was further supported by 1.9 times higher juvenile survival and 1.3 times higher breeding success in immigrant first-generation offspring compared with inbred offspring. Five years after immigration, the population had more than doubled in size and allelic richness increased by 41%. This is one of few studies that has documented genetic rescue in a natural mammal population suffering from inbreeding depression and contributes to a growing body of data demonstrating the vital connection between genetics and individual fitness. © 2018 The Author(s).

Genetic and life-history consequences of extreme climate events

PubMed Central

Mangel, Marc; Jesensek, Dusan; Garza, John Carlos; Crivelli, Alain J.

2017-01-01

Climate change is predicted to increase the frequency and intensity of extreme climate events. Tests on empirical data of theory-based predictions on the consequences of extreme climate events are thus necessary to understand the adaptive potential of species and the overarching risks associated with all aspects of climate change. We tested predictions on the genetic and life-history consequences of extreme climate events in two populations of marble trout Salmo marmoratus that have experienced severe demographic bottlenecks due to flash floods. We combined long-term field and genotyping data with pedigree reconstruction in a theory-based framework. Our results show that after flash floods, reproduction occurred at a younger age in one population. In both populations, we found the highest reproductive variance in the first cohort born after the floods due to a combination of fewer parents and higher early survival of offspring. A small number of parents allowed for demographic recovery after the floods, but the genetic bottleneck further reduced genetic diversity in both populations. Our results also elucidate some of the mechanisms responsible for a greater prevalence of faster life histories after the extreme event. PMID:28148745

The impact of privacy protections on recruitment in a multicenter stroke genetics study

PubMed Central

Chen, D.T.; Worrall, B.B.; Brown, R.D.; Brott, T.G.; Kissela, B.M.; Olson, T.S.; Rich, S.S.; Meschia, J.F.

2006-01-01

The authors reviewed the recruitment of stroke-affected sibling pairs using a letter-based, proband-initiated contact strategy. The authors randomly sampled 99 proband enrollment forms (Phase 1) and randomly sampled 50 sibling reply cards (Phase 2). The sibling response rate was 30.6%, for a pedigree response rate of 58%. Of the siblings who replied, 96% authorized further contact. Median time from proband enrollment to pedigree DNA banking, which required 3+ probands, was 134 days. PMID:15728301

Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees.

PubMed

Chen, Xue; Sheng, Xunlun; Liu, Yani; Li, Zili; Sun, Xiantao; Jiang, Chao; Qi, Rui; Yuan, Shiqin; Wang, Xuhui; Zhou, Ge; Zhen, Yanyan; Xie, Ping; Liu, Qinghuai; Yan, Biao; Zhao, Chen

2018-05-29

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES). Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification. All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology. Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations.

Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree.

PubMed

Bamashmus, M A; Downey, L M; Inglehearn, C F; Gupta, S R; Mansfield, D C

2000-04-01

Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR. Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13. The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q. This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.

Genetic heterogeneity of familial hemiplegic migraine

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

Ophoff, R.A.; Van Eijk, R.; Sandkuijl, L.A.

1994-07-01

Familial hemiplegic migraine (FHM) is a distinctive form of migraine with an autosomal dominant mode of inheritance. The migraine-like attacks are associated with transient hemiparesis. A locus for FHM has recently been assigned to chromosome 19 by linkage mapping. In the present study, five unrelated pedigrees with multiple members suffering from hemiplegic migraine were investigated. In two of the pedigrees additional symptoms, cerebellar ataxia and benign neonatal convulsions, respectively, were observed in affected members. Three pedigrees showed linkage to loci D19S391, D19S221, and D19S226 at chromosome 19p13. Haplotyping suggested a location of a FHM gene between D19S391 and D19S221. Inmore » the two remaining families, evidence against linkage was found. These results confirm the localization of a gene for familial hemiplegic migraine to the short arm of chromosome 19, but locus heterogeneity not corresponding to the observed clinical heterogeneity is likely to exist. 19 refs., 3 figs., 3 tabs.« less

An efficient algorithm to compute marginal posterior genotype probabilities for every member of a pedigree with loops

PubMed Central

2009-01-01

Background Marginal posterior genotype probabilities need to be computed for genetic analyses such as geneticcounseling in humans and selective breeding in animal and plant species. Methods In this paper, we describe a peeling based, deterministic, exact algorithm to compute efficiently genotype probabilities for every member of a pedigree with loops without recourse to junction-tree methods from graph theory. The efficiency in computing the likelihood by peeling comes from storing intermediate results in multidimensional tables called cutsets. Computing marginal genotype probabilities for individual i requires recomputing the likelihood for each of the possible genotypes of individual i. This can be done efficiently by storing intermediate results in two types of cutsets called anterior and posterior cutsets and reusing these intermediate results to compute the likelihood. Examples A small example is used to illustrate the theoretical concepts discussed in this paper, and marginal genotype probabilities are computed at a monogenic disease locus for every member in a real cattle pedigree. PMID:19958551

Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy.

PubMed Central

Seri, M; Cusano, R; Forabosco, P; Cinti, R; Caroli, F; Picco, P; Bini, R; Morra, V B; De Michele, G; Lerone, M; Silengo, M; Pela, I; Borrone, C; Romeo, G; Devoto, M

1999-01-01

We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition. PMID:9973297

Genetic drift. Descent, lineage, and pedigree of the Trojans in Homer's Iliad.

PubMed

Bazopoulou-Kyrkanidou, Euterpe

2007-12-15

Homer's Iliad, is an epic poem that describes the last 70 days of the Trojan War, which was waged against the city of Troy by the Achaeans. Here, the descent, lineage, and the pedigree of the Trojans are presented. In the Illiad, they are said to have originated from Zeus. Beginning with him, the Trojan pedigree comprised 17 men in 8 generations with Dardanus, founder of Dardania in the second generation; Tros, King of the Trojans in the fourth generation; and the two heroes Hector and Aeneas in the eighth generation. In the seventh generation, Priam, as King of the Trojans, had a huge family, including 50 sons: 19 children with his wife Hecabe, other sons with many different wives, and some daughters as well. Hector, the first born, became leader of the Trojans. Hector's brother, Paris, in abducting Helen of Sparta, the wife of King Menelaus, caused the Trojan War to break out. (c) 2007 Wiley-Liss, Inc.

Hereditary breast/ovarian cancer--pitfalls in genetic counseling.

PubMed

Dagan, E; Gershoni-Baruch, R

2001-10-01

Genetic counseling and risk assessment, given to women with a family history of breast/ovarian cancer, are regularly based on pedigree analysis. In the Ashkenazi Jewish population, hereditary breast/ovarian cancer is mainly attributed to three founder mutations, namely, 185delAG, 5382insC, and 6174delT, in BRCA1/2 genes. The overall frequency of these mutations, in the Jewish Ashkenazi population, is as high as 2.5%. Based on clinical and family history data, the results of BRCA molecular testing, in Ashkenazi individuals at risk, are appropriately anticipated in most cases. Here we report on five families, in which the segregation of BRCA1/2 mutations, in affected and unaffected family members, was unexpected, emphasizing the need to test, for founder mutations, every Ashkenazi individual at risk, irrespective of the genotype of affected family members. Ultimately, risk assessments and recommendations, in Ashkenazi women, should be invariably based on the results of genetic testing.

Haplotypes identified by 10 DNA restriction fragment length polymorphisms at the human low density lipoprotein receptor gene locus.

PubMed Central

Kotze, M J; Langenhoven, E; Retief, A E; Seftel, H C; Henderson, H E; Weich, H F

1989-01-01

Ten useful two allele restriction fragment length polymorphisms of the low density lipoprotein receptor gene were used for haplotype analysis in 45 unrelated familial hypercholesterolaemic (FH) patients, 60 normal controls, and 32 FH homozygotes, all of whom were white Afrikaners. Pedigree analysis in 27 informative heterozygous FH and 23 normal families has shown the segregation of at least 17 haplotypes in the normal population (111 chromosomes) compared to a predominant association of two of these haplotypes with the disease in the FH subjects. This association was further confirmed in 32 FH homozygotes, indicating at least two 'founder' members for the disease in the Afrikaner population. Recombination events were not detected in any of the families studied and we thus conclude that the haplotypes associated with FH function as specific markers for the disease and will allow presymptomatic diagnosis in affected families. PMID:2565980

Inheritance pattern of platelet membrane fluidity in Alzheimer disease.

PubMed Central

Chakravarti, A; Slaugenhaupt, S A; Zubenko, G S

1989-01-01

The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in labeled platelet membranes, an index of membrane fluidity, is a stable, familial trait that is associated with a clinically distinct subtype of Alzheimer disease. Complex segregation analysis of this continuous variable was performed on 95 members of 14 pedigrees identified through probands who had autopsy-confirmed or clinically diagnosed Alzheimer disease. The results suggest that platelet membrane fluidity is controlled by a single genetic locus, PMF, with two alleles that have additive effects. The PMF locus appears to explain approximately 80% of the total variation in platelet membrane fluidity within the families of patients with Alzheimer disease. PMID:2729275

Whole-exome sequencing for variant discovery in blepharospasm.

PubMed

Tian, Jun; Vemula, Satya R; Xiao, Jianfeng; Valente, Enza Maria; Defazio, Giovanni; Petrucci, Simona; Gigante, Angelo Fabio; Rudzińska-Bar, Monika; Wszolek, Zbigniew K; Kennelly, Kathleen D; Uitti, Ryan J; van Gerpen, Jay A; Hedera, Peter; Trimble, Elizabeth J; LeDoux, Mark S

2018-05-16

Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Inferred Paternity and Male Reproductive Success in a Killer Whale (Orcinus orca) Population.

PubMed

Ford, Michael J; Hanson, M Bradley; Hempelmann, Jennifer A; Ayres, Katherine L; Emmons, Candice K; Schorr, Gregory S; Baird, Robin W; Balcomb, Kenneth C; Wasser, Samuel K; Parsons, Kim M; Balcomb-Bartok, Kelly

2011-01-01

We used data from 78 individuals at 26 microsatellite loci to infer parental and sibling relationships within a community of fish-eating ("resident") eastern North Pacific killer whales (Orcinus orca). Paternity analysis involving 15 mother/calf pairs and 8 potential fathers and whole-pedigree analysis of the entire sample produced consistent results. The variance in male reproductive success was greater than expected by chance and similar to that of other aquatic mammals. Although the number of confirmed paternities was small, reproductive success appeared to increase with male age and size. We found no evidence that males from outside this small population sired any of the sampled individuals. In contrast to previous results in a different population, many offspring were the result of matings within the same "pod" (long-term social group). Despite this pattern of breeding within social groups, we found no evidence of offspring produced by matings between close relatives, and the average internal relatedness of individuals was significantly less than expected if mating were random. The population's estimated effective size was <30 or about 1/3 of the current census size. Patterns of allele frequency variation were consistent with a population bottleneck.

LOD score exclusion analyses for candidate genes using random population samples.

PubMed

Deng, H W; Li, J; Recker, R R

2001-05-01

While extensive analyses have been conducted to test for, no formal analyses have been conducted to test against, the importance of candidate genes with random population samples. We develop a LOD score approach for exclusion analyses of candidate genes with random population samples. Under this approach, specific genetic effects and inheritance models at candidate genes can be analysed and if a LOD score is < or = - 2.0, the locus can be excluded from having an effect larger than that specified. Computer simulations show that, with sample sizes often employed in association studies, this approach has high power to exclude a gene from having moderate genetic effects. In contrast to regular association analyses, population admixture will not affect the robustness of our analyses; in fact, it renders our analyses more conservative and thus any significant exclusion result is robust. Our exclusion analysis complements association analysis for candidate genes in random population samples and is parallel to the exclusion mapping analyses that may be conducted in linkage analyses with pedigrees or relative pairs. The usefulness of the approach is demonstrated by an application to test the importance of vitamin D receptor and estrogen receptor genes underlying the differential risk to osteoporotic fractures.

Efficient computation of kinship and identity coefficients on large pedigrees.

PubMed

Cheng, En; Elliott, Brendan; Ozsoyoglu, Z Meral

2009-06-01

With the rapidly expanding field of medical genetics and genetic counseling, genealogy information is becoming increasingly abundant. An important computation on pedigree data is the calculation of identity coefficients, which provide a complete description of the degree of relatedness of a pair of individuals. The areas of application of identity coefficients are numerous and diverse, from genetic counseling to disease tracking, and thus, the computation of identity coefficients merits special attention. However, the computation of identity coefficients is not done directly, but rather as the final step after computing a set of generalized kinship coefficients. In this paper, we first propose a novel Path-Counting Formula for calculating generalized kinship coefficients, which is motivated by Wright's path-counting method for computing inbreeding coefficient. We then present an efficient and scalable scheme for calculating generalized kinship coefficients on large pedigrees using NodeCodes, a special encoding scheme for expediting the evaluation of queries on pedigree graph structures. Furthermore, we propose an improved scheme using Family NodeCodes for the computation of generalized kinship coefficients, which is motivated by the significant improvement of using Family NodeCodes for inbreeding coefficient over the use of NodeCodes. We also perform experiments for evaluating the efficiency of our method, and compare it with the performance of the traditional recursive algorithm for three individuals. Experimental results demonstrate that the resulting scheme is more scalable and efficient than the traditional recursive methods for computing generalized kinship coefficients.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PubMed

Allen, R C; Russell, S R; Streb, L M; Alsheikheh, A; Stone, E M

2006-02-01

To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. Longitudinal cohort study. A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Impact of computer-assisted data collection, evaluation and management on the cancer genetic counselor's time providing patient care.

PubMed

Cohen, Stephanie A; McIlvried, Dawn E

2011-06-01

Cancer genetic counseling sessions traditionally encompass collecting medical and family history information, evaluating that information for the likelihood of a genetic predisposition for a hereditary cancer syndrome, conveying that information to the patient, offering genetic testing when appropriate, obtaining consent and subsequently documenting the encounter with a clinic note and pedigree. Software programs exist to collect family and medical history information electronically, intending to improve efficiency and simplicity of collecting, managing and storing this data. This study compares the genetic counselor's time spent in cancer genetic counseling tasks in a traditional model and one using computer-assisted data collection, which is then used to generate a pedigree, risk assessment and consult note. Genetic counselor time spent collecting family and medical history and providing face-to-face counseling for a new patient session decreased from an average of 85-69 min when using the computer-assisted data collection. However, there was no statistically significant change in overall genetic counselor time on all aspects of the genetic counseling process, due to an increased amount of time spent generating an electronic pedigree and consult note. Improvements in the computer program's technical design would potentially minimize data manipulation. Certain aspects of this program, such as electronic collection of family history and risk assessment, appear effective in improving cancer genetic counseling efficiency while others, such as generating an electronic pedigree and consult note, do not.

Seroprevalence study of feline coronavirus in owned and feral cats in Sydney, Australia.

PubMed

Bell, E T; Toribio, J A L M L; White, J D; Malik, R; Norris, J M

2006-03-01

i) To establish the seroprevalence of Feline Coronavirus (FCoV) infection in two defined groups of cats in Sydney: owned and feral cats; ii) to identify factors associated with an increased risk of infection with FCoV; and iii) to establish the seroprevalence and FCoV antibody titres of owned cats with immunohistochemically confirmed feline infectious peritonitis (FIP). Prospective multi-institutional cross sectional study. Procedure Serum samples from owned cats presented to three inner city veterinary clinics in Sydney and feral cats from a colony in South Western Sydney over an 11-month period were tested for FCoV antibodies using the Immunocomb test kit. The relationship between serological score and six major factors (breed, age, gender, number of cats per household, living environment and health status) in the owned cat sample population was analysed and compared to cats with FIR RESULTS: The seroprevalence of FCoV infection in the sample population of owned and feral cats was 34% and 0%, respectively. The median Immunocomb scores of DSH, Persian, Siamese and Devon Rex cats were significantly lower than that of Burmese, BSH, Abyssinian, Birman, Ragdoll and Russian Blue. The median lmmunocomb score of pedigree cats less than 2 years-of-age was significantly higher than for pedigree cats greater than 2 years-of-age. This distinction was not evident in DSH cats in these age groups. The number of cats per household at the time of blood collection had a strong positive association with Immunocomb score. The median Immunocomb score of cats with immunohistochemically confirmed FIP was significantly higher than cats in the sample population of owned cats but there was sufficient overlap between these two groups to make definitive diagnosis of FIP by serology impossible. This represents the first seroprevalence study of FCoV in Australia. The major determinants of antibody score of owned cats identified in this study were breed, age and the number of cats per household. The significant relationship between the breed of the cat and the FCoV antibody titre further supports the notion, proposed previously by the authors, that breed related differences exist in the immunological response to FCoV infection.

Genetic variation and population structure of maize inbred lines adapted to the mid-altitude sub-humid maize agro-ecology of Ethiopia using single nucleotide polymorphic (SNP) markers.

PubMed

Ertiro, Berhanu Tadesse; Semagn, Kassa; Das, Biswanath; Olsen, Michael; Labuschagne, Maryke; Worku, Mosisa; Wegary, Dagne; Azmach, Girum; Ogugo, Veronica; Keno, Tolera; Abebe, Beyene; Chibsa, Temesgen; Menkir, Abebe

2017-10-12

Molecular characterization is important for efficient utilization of germplasm and development of improved varieties. In the present study, we investigated the genetic purity, relatedness and population structure of 265 maize inbred lines from the Ethiopian Institute of Agricultural Research (EIAR), the International Maize and Wheat Improvement Centre (CIMMYT) and the International Institute of Tropical Agriculture (IITA) using 220,878 single nucleotide polymorphic (SNP) markers obtained using genotyping by sequencing (GBS). Only 22% of the inbred lines were considered pure with <5% heterogeneity, while the remaining 78% of the inbred lines had a heterogeneity ranging from 5.1 to 31.5%. Pairwise genetic distances among the 265 inbred lines varied from 0.011 to 0.345, with 89% of the pairs falling between 0.301 and 0.345. Only <1% of the pairs had a genetic distance lower than 0.200, which included 14 pairs of sister lines that were nearly identical. Relative kinship analysis showed that the kinship coefficients for 59% of the pairs of lines was close to zero, which agrees with the genetic distance estimates. Principal coordinate analysis, discriminant analysis of principal components (DAPC) and the model-based population structure analysis consistently suggested the presence of three groups, which generally agreed with pedigree information (genetic background). Although not distinct enough, the SNP markers showed some level of separation between the two CIMMYT heterotic groups A and B established based on pedigree and combining ability information. The high level of heterogeneity detected in most of the inbred lines suggested the requirement for purification or further inbreeding except those deliberately maintained at early inbreeding level. The genetic distance and relative kinship analysis clearly indicated the uniqueness of most of the inbred lines in the maize germplasm available for breeders in the mid-altitude maize breeding program of Ethiopia. Results from the present study facilitate the maize breeding work in Ethiopia and germplasm exchange among breeding programs in Africa. We suggest the incorporation of high density molecular marker information in future heterotic group assignments.

A limited number of Y chromosome lineages is present in North American Holsteins.

PubMed

Yue, Xiang-Peng; Dechow, Chad; Liu, Wan-Sheng

2015-04-01

Holsteins are the most numerous dairy cattle breed in North America and the breed has undergone intensive selection for improving milk production and conformation. Theoretically, this intensive selection could lead to a reduction of the effective population size and reduced genetic diversity. The objective of this study was to investigate the effective population size of the Holstein Y chromosome and the effects of limited Y chromosome lineages on male reproduction and the future of the breed. Paternal pedigree information of 62,897 Holstein bulls born between 1950 and 2013 in North America and 220,872 bulls evaluated by multiple-trait across-country genetic evaluations of Interbull (Uppsala, Sweden) were collected and analyzed. The results indicated that the number of Y chromosome lineages in Holsteins has undergone a dramatic decrease during the past 50 years because of artificial selection and the application of artificial insemination (AI) technology. All current Holstein AI bulls in North America are the descendants of only 2 ancestors (Hulleman and Neptune H) born in 1880. These 2 ancestral Y-lineages are continued through 3 dominant pedigrees from the 1960s; namely, Pawnee Farm Arlinda Chief, Round Oak Rag Apple Elevation, and Penstate Ivanhoe Star, with a contribution of 48.78, 51.06, and 0.16% to the Holstein bull population in the 2010s, respectively. The Y-lineage of Penstate Ivanhoe Star is almost eliminated from the breed. The genetic variations in the 2 ancestral Y-lineages were evaluated among 257 bulls by determining the copy number variations (CNV) of 3 Y-linked gene families: PRAMEY, HSFY, and ZNF280BY, which are spread along the majority (95%) of the bovine Y chromosome male-specific region (MSY). No significant difference was found between the 2 ancestral Y-lineages, although large CNV were observed within each lineage. This study suggests minimal genetic diversity on the Y chromosome in Holsteins and provides a starting point for investigating the effect of the extremely limited number of Y-lineages on male reproduction and other traits important for the future of the Holstein breed. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Mutational analysis of the HGO gene in Finnish alkaptonuria patients

PubMed Central

de Bernabe, D. B.-V.; Peterson, P.; Luopajarvi, K.; Matintalo, P.; Alho, A.; Konttinen, Y.; Krohn, K.; de Cordoba, S. R.; Ranki, A.

1999-01-01

Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.


Keywords: alkaptonuria; homogentisate-1,2-dioxygenase; Finland PMID:10594001

CARHTA GENE: multipopulation integrated genetic and radiation hybrid mapping.

PubMed

de Givry, Simon; Bouchez, Martin; Chabrier, Patrick; Milan, Denis; Schiex, Thomas

2005-04-15

CAR(H)(T)A GENE: is an integrated genetic and radiation hybrid (RH) mapping tool which can deal with multiple populations, including mixtures of genetic and RH data. CAR(H)(T)A GENE: performs multipoint maximum likelihood estimations with accelerated expectation-maximization algorithms for some pedigrees and has sophisticated algorithms for marker ordering. Dedicated heuristics for framework mapping are also included. CAR(H)(T)A GENE: can be used as a C++ library, through a shell command and a graphical interface. The XML output for companion tools is integrated. The program is available free of charge from www.inra.fr/bia/T/CarthaGene for Linux, Windows and Solaris machines (with Open Source). tschiex@toulouse.inra.fr.

A new method of linkage analysis using LOD scores for quantitative traits supports linkage of monoamine oxidase activity to D17S250 in the Collaborative Study on the Genetics of Alcoholism pedigrees.

PubMed

Curtis, David; Knight, Jo; Sham, Pak C

2005-09-01

Although LOD score methods have been applied to diseases with complex modes of inheritance, linkage analysis of quantitative traits has tended to rely on non-parametric methods based on regression or variance components analysis. Here, we describe a new method for LOD score analysis of quantitative traits which does not require specification of a mode of inheritance. The technique is derived from the MFLINK method for dichotomous traits. A range of plausible transmission models is constructed, constrained to yield the correct population mean and variance for the trait but differing with respect to the contribution to the variance due to the locus under consideration. Maximized LOD scores under homogeneity and admixture are calculated, as is a model-free LOD score which compares the maximized likelihoods under admixture assuming linkage and no linkage. These LOD scores have known asymptotic distributions and hence can be used to provide a statistical test for linkage. The method has been implemented in a program called QMFLINK. It was applied to data sets simulated using a variety of transmission models and to a measure of monoamine oxidase activity in 105 pedigrees from the Collaborative Study on the Genetics of Alcoholism. With the simulated data, the results showed that the new method could detect linkage well if the true allele frequency for the trait was close to that specified. However, it performed poorly on models in which the true allele frequency was much rarer. For the Collaborative Study on the Genetics of Alcoholism data set only a modest overlap was observed between the results obtained from the new method and those obtained when the same data were analysed previously using regression and variance components analysis. Of interest is that D17S250 produced a maximized LOD score under homogeneity and admixture of 2.6 but did not indicate linkage using the previous methods. However, this region did produce evidence for linkage in a separate data set, suggesting that QMFLINK may have been able to detect a true linkage which was not picked up by the other methods. The application of model-free LOD score analysis to quantitative traits is novel and deserves further evaluation of its merits and disadvantages relative to other methods.

Empirical comparison between different methods for genomic prediction of number of piglets born alive in moderate sized breeding populations.

PubMed

Fangmann, A; Sharifi, R A; Heinkel, J; Danowski, K; Schrade, H; Erbe, M; Simianer, H

2017-04-01

Currently used multi-step methods to incorporate genomic information in the prediction of breeding values (BV) implicitly involve many assumptions which, if violated, may result in loss of information, inaccuracies and bias. To overcome this, single-step genomic best linear unbiased prediction (ssGBLUP) was proposed combining pedigree, phenotype and genotype of all individuals for genetic evaluation. Our objective was to implement ssGBLUP for genomic predictions in pigs and to compare the accuracy of ssGBLUP with that of multi-step methods with empirical data of moderately sized pig breeding populations. Different predictions were performed: conventional parent average (PA), direct genomic value (DGV) calculated with genomic BLUP (GBLUP), a GEBV obtained by blending the DGV with PA, and ssGBLUP. Data comprised individuals from a German Landrace (LR) and Large White (LW) population. The trait 'number of piglets born alive' (NBA) was available for 182,054 litters of 41,090 LR sows and 15,750 litters from 4534 LW sows. The pedigree contained 174,021 animals, of which 147,461 (26,560) animals were LR (LW) animals. In total, 526 LR and 455 LW animals were genotyped with the Illumina PorcineSNP60 BeadChip. After quality control and imputation, 495 LR (424 LW) animals with 44,368 (43,678) SNP on 18 autosomes remained for the analysis. Predictive abilities, i.e., correlations between de-regressed proofs and genomic BV, were calculated with a five-fold cross validation and with a forward prediction for young genotyped validation animals born after 2011. Generally, predictive abilities for LR were rather small (0.08 for GBLUP, 0.19 for GEBV and 0.18 for ssGBLUP). For LW, ssGBLUP had the greatest predictive ability (0.45). For both breeds, assessment of reliabilities for young genotyped animals indicated that genomic prediction outperforms PA with ssGBLUP providing greater reliabilities (0.40 for LR and 0.32 for LW) than GEBV (0.35 for LR and 0.29 for LW). Grouping of animals according to information sources revealed that genomic prediction had the highest potential benefit for genotyped animals without their own phenotype. Although, ssGBLUP did not generally outperform GBLUP or GEBV, the results suggest that ssGBLUP can be a useful and conceptually convincing approach for practical genomic prediction of NBA in moderately sized LR and LW populations.

Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis.

PubMed

Feng, Yuan; Hong, Yaqiang; Zhang, Xin; Cao, Chunwei; Yang, Xichao; Lai, Shujuan; Fan, Chunmei; Cheng, Feng; Yan, Mei; Li, Chaohua; Huang, Wan; Chen, Wei; Zhu, Ping; Zeng, Changqing

2018-08-20

Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

Deciphering the genetic control of fruit texture in apple by multiple family-based analysis and genome-wide association

PubMed Central

Di Guardo, Mario; Bink, Marco C.A.M.; Guerra, Walter; Letschka, Thomas; Lozano, Lidia; Busatto, Nicola; Poles, Lara; Tadiello, Alice; Bianco, Luca; Visser, Richard G.F.; van de Weg, Eric

2017-01-01

Abstract Fruit texture is a complex feature composed of mechanical and acoustic properties relying on the modifications occurring in the cell wall throughout fruit development and ripening. Apple is characterized by a large variation in fruit texture behavior that directly impacts both the consumer’s appreciation and post-harvest performance. To decipher the genetic control of fruit texture comprehensively, two complementing quantitative trait locus (QTL) mapping approaches were employed. The first was represented by a pedigree-based analysis (PBA) carried out on six full-sib pedigreed families, while the second was a genome-wide association study (GWAS) performed on a collection of 233 apple accessions. Both plant materials were genotyped with a 20K single nucleotide polymorphism (SNP) array and phenotyped with a sophisticated high-resolution texture analyzer. The overall QTL results indicated the fundamental role of chromosome 10 in controlling the mechanical properties, while chromosomes 2 and 14 were more associated with the acoustic response. The latter QTL, moreover, showed a consistent relationship between the QTL-estimated genotypes and the acoustic performance assessed among seedlings. The in silico annotation of these intervals revealed interesting candidate genes potentially involved in fruit texture regulation, as suggested by the gene expression profile. The joint integration of these approaches sheds light on the specific control of fruit texture, enabling important genetic information to assist in the selection of valuable fruit quality apple varieties. PMID:28338805

Deciphering the genetic control of fruit texture in apple by multiple family-based analysis and genome-wide association.

PubMed

Di Guardo, Mario; Bink, Marco C A M; Guerra, Walter; Letschka, Thomas; Lozano, Lidia; Busatto, Nicola; Poles, Lara; Tadiello, Alice; Bianco, Luca; Visser, Richard G F; van de Weg, Eric; Costa, Fabrizio

2017-03-01

Fruit texture is a complex feature composed of mechanical and acoustic properties relying on the modifications occurring in the cell wall throughout fruit development and ripening. Apple is characterized by a large variation in fruit texture behavior that directly impacts both the consumer's appreciation and post-harvest performance. To decipher the genetic control of fruit texture comprehensively, two complementing quantitative trait locus (QTL) mapping approaches were employed. The first was represented by a pedigree-based analysis (PBA) carried out on six full-sib pedigreed families, while the second was a genome-wide association study (GWAS) performed on a collection of 233 apple accessions. Both plant materials were genotyped with a 20K single nucleotide polymorphism (SNP) array and phenotyped with a sophisticated high-resolution texture analyzer. The overall QTL results indicated the fundamental role of chromosome 10 in controlling the mechanical properties, while chromosomes 2 and 14 were more associated with the acoustic response. The latter QTL, moreover, showed a consistent relationship between the QTL-estimated genotypes and the acoustic performance assessed among seedlings. The in silico annotation of these intervals revealed interesting candidate genes potentially involved in fruit texture regulation, as suggested by the gene expression profile. The joint integration of these approaches sheds light on the specific control of fruit texture, enabling important genetic information to assist in the selection of valuable fruit quality apple varieties. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Optimized testing schemes using nucleus progeny, adult MOET siblings, or juvenile MOET pedigrees in dairy cattle closed populations.

PubMed

Bondoc, O L; Smith, C

1993-01-12

Selection response rates are predicted for nucleus progeny testing, adult multiple ovulation and embryo transfer (MOET) sib testing, and juvenile MOET pedigree testing in closed populations. Deterministic models are adapted to adjust predicted genetic gains for the effects of population size and structure, selection disequilibrium, sampling losses, and inbreeding depression. The improvement schemes were optimized for different numbers of sires used and first lactation females recorded per year. The number of nucleus daughters tested per sire, and of females per MOET full sibship, that maximize the predicted response to selection per year, were determined. Annual genetic gains and inbreeding rates were interpolated to the same planning horizon (20 years) to compare the optimized schemes for a wide range of situations. The predicted maximum genetic gain per year is higher for adult MOET than for juvenile MOET (due to the proportional extra time to collect the embryos needed) and for nucleus progeny testing. Average annual inbreeding rates are much higher for MOET schemes than for nucleus progeny testing. The advantages of adult and juvenile over nucleus progeny testing are little affected by planning horizon, but are higher with more females recorded per year, higher heritability, and higher reproductive and MOET success rates. Comparison of the schemes at the same level of inbreeding is fairer for fixed testing resources. At the same inbreeding level, the genetic advantage of adult MOET was generally maintained, but juvenile MOET then lost its advantage over progeny testing in these closed populations. ZUSAMMENFASSUNG: Optimierte Prüfpläne für Nukleusnachkommen, adulte MOET Geschwister oder juvenile MOET Pedigrees in geschlossenen Milchviehpopulationen Selektionserfolge werden für Nukleusnachkommenprüfung, adulte multiple Ovulation (MOET) und Embryotransfer, Geschwisterprüfung und juvenile MOET Pedigreeprüfung geschlossener Populationen geschätzt. Deterministische Modelle werden modifiziert zur Berücksichtigung geschätzter genetischer Fortschritte für die Wirkungen von Populationsgröße, Struktur, Selektionsungleichgewicht, Stichprobenungenauigkeit und Inzuchtdepression. Die Zuchtpläne werden für verschiedene Zahlen von Stieren und Erstlaktationskühe pro Jahr optimiert. Die Zahl der geprüften Nukleustöchter je Stier und Kühe je MOETVollgeschwistergruppe, die den geschätzten Erfolg maximieren, werden bestimmt. Um die optimierten Pläne über einen weiten Bereich zu vergleichen, werden jährlicher Zuchtfortschritt und Inzuchtzuwachs für den gleichen Planungshorizont von 20 Jahren interpoliert. Der geschätzte maximale Zuchtfortschritt pro Jahr ist für adultes MOET höher als bei juvenilem (wegen zusätzlicher Zeit zur Embryonengewinnung) und bei Nukleusnachkommenschaftsprüfung. Durchschnittliche jährliche Inzuchtraten sind viel höher für MOET Pläne als für das Nachkommenschaftsprüfsystem. Die Vorteile des adulten und juvenilen MOET über Nukleusnachkommenprüfung werden durch den Planungshorizont nur geringfügig tangiert, werden aber höher, wenn mehr weibliche Tiere je Jahr geprüft werden bei höherer Heritabilität, höherer Reproduktions- und Erfolgsrate. Der Vergleich der Pläne beim gleichen Inzuchtniveau ist für gegebene Testresourcen angemessener. 1993 Blackwell Verlag GmbH.

Determinants of male floating behaviour and floater reproduction in a threatened population of the hihi (Notiomystis cincta)

PubMed Central

Brekke, Patricia; Ewen, John G; Clucas, Gemma; Santure, Anna W

2015-01-01

Floating males are usually thought of as nonbreeders. However, some floating individuals are able to reproduce through extra-pair copulations. Floater reproductive success can impact breeders’ sex ratio, reproductive variance, multiple paternity and inbreeding, particularly in small populations. Changes in reproductive variance alter the rate of genetic drift and loss of genetic diversity. Therefore, genetic management of threatened species requires an understanding of floater reproduction and determinants of floating behaviour to effectively conserve species. Here, we used a pedigreed, free-living population of the endangered New Zealand hihi (Notiomystis cincta) to assess variance in male reproductive success and test the genetic (inbreeding and heritability) and conditional (age and size) factors that influence floater behaviour and reproduction. Floater reproduction is common in this species. However, floater individuals have lower reproductive success and variance in reproductive success than territorial males (total and extra-pair fledglings), so their relative impact on the population's reproductive performance is low. Whether an individual becomes a floater, and if so then how successful they are, is determined mainly by individual age (young and old) and to lesser extents male size (small) and inbreeding level (inbred). Floating males have a small, but important role in population reproduction and persistence of threatened populations. PMID:26366197

Genetic rescue of an insular population of large mammals

PubMed Central

Hogg, John T; Forbes, Stephen H; Steele, Brian M; Luikart, Gordon

2006-01-01

Natural populations worldwide are increasingly fragmented by habitat loss. Isolation at small population size is thought to reduce individual and population fitness via inbreeding depression. However, little is known about the time-scale over which adverse genetic effects may develop in natural populations or the number and types of traits likely to be affected. The benefits of restoring gene flow to isolates are therefore also largely unknown. In contrast, the potential costs of migration (e.g. disease spread) are readily apparent. Management for ecological connectivity has therefore been controversial and sometimes avoided. Using pedigree and life-history data collected during 25 years of study, we evaluated genetic decline and rescue in a population of bighorn sheep founded by 12 individuals in 1922 and isolated at an average size of 42 animals for 10–12 generations. Immigration was restored experimentally, beginning in 1985. We detected marked improvements in reproduction, survival and five fitness-related traits among descendants of the 15 recent migrants. Trait values were increased by 23–257% in maximally outbred individuals. This is the first demonstration, to our knowledge, of increased male and female fitness attributable to outbreeding realized in a fully competitive natural setting. Our findings suggest that genetic principles deserve broader recognition as practical management tools with near-term consequences for large-mammal conservation. PMID:16777743

Combined variants in factor VIII and prostaglandin synthase-1 amplify hemorrhage severity across three generations of descendants.

PubMed

Nance, D; Campbell, R A; Rowley, J W; Downie, J M; Jorde, L B; Kahr, W H; Mereby, S A; Tolley, N D; Zimmerman, G A; Weyrich, A S; Rondina, M T

2016-11-01

Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway. Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G 2 assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B 2 release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G 2 , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage. © 2016 International Society on Thrombosis and Haemostasis.

Evaluation of allocation methods for calculation of carbon footprint of grass-based dairy production.

PubMed

Rice, P; O'Brien, D; Shalloo, L; Holden, N M

2017-11-01

A major methodological issue for life cycle assessment, commonly used to quantify greenhouse gas emissions from livestock systems, is allocation from multifunctional processes. When a process produces more than one output, the environmental burden has to be assigned between the outputs, such as milk and meat from a dairy cow. In the absence of an objective function for choosing an allocation method, a decision must be made considering a range of factors, one of which is the availability and quality of necessary data. The objective of this study was to evaluate allocation methods to calculate the climate change impact of the economically average (€/ha) dairy farm in Ireland considering both milk and meat outputs, focusing specifically on the pedigree of the available data for each method. The methods were: economic, energy, protein, emergy, mass of liveweight, mass of carcass weight and physical causality. The data quality for each method was expressed using a pedigree score based on reliability of the source, completeness, temporal applicability, geographical alignment and technological appropriateness. Scenario analysis was used to compare the normalised impact per functional unit (FU) from the different allocation methods, between the best and worst third of farms (in economic terms, €/ha) in the national farm survey. For the average farm, the allocation factors for milk ranged from 75% (physical causality) to 89% (mass of carcass weight), which in turn resulted in an impact per FU, from 1.04 to 1.22 kg CO 2 -eq/kg (fat and protein corrected milk). Pedigree scores ranged from 6.0 to 17.1 with protein and economic allocation having the best pedigree. It was concluded that when making the choice of allocation method, the quality of the data available (pedigree) should be given greater emphasis during the decision making process because the effect of allocation on the results. A range of allocation methods could be deployed to understand the uncertainty associated with the decision. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparing population structure as inferred from genealogical versus genetic information.

PubMed

Colonna, Vincenza; Nutile, Teresa; Ferrucci, Ronald R; Fardella, Giulio; Aversano, Mario; Barbujani, Guido; Ciullo, Marina

2009-12-01

Algorithms for inferring population structure from genetic data (ie, population assignment methods) have shown to effectively recognize genetic clusters in human populations. However, their performance in identifying groups of genealogically related individuals, especially in scanty-differentiated populations, has not been tested empirically thus far. For this study, we had access to both genealogical and genetic data from two closely related, isolated villages in southern Italy. We found that nearly all living individuals were included in a single pedigree, with multiple inbreeding loops. Despite F(st) between villages being a low 0.008, genetic clustering analysis identified two clusters roughly corresponding to the two villages. Average kinship between individuals (estimated from genealogies) increased at increasing values of group membership (estimated from the genetic data), showing that the observed genetic clusters represent individuals who are more closely related to each other than to random members of the population. Further, average kinship within clusters and F(st) between clusters increases with increasingly stringent membership threshold requirements. We conclude that a limited number of genetic markers is sufficient to detect structuring, and that the results of genetic analyses faithfully mirror the structuring inferred from detailed analyses of population genealogies, even when F(st) values are low, as in the case of the two villages. We then estimate the impact of observed levels of population structure on association studies using simulated data.

Comparing population structure as inferred from genealogical versus genetic information

PubMed Central

Colonna, Vincenza; Nutile, Teresa; Ferrucci, Ronald R; Fardella, Giulio; Aversano, Mario; Barbujani, Guido; Ciullo, Marina

2009-01-01

Algorithms for inferring population structure from genetic data (ie, population assignment methods) have shown to effectively recognize genetic clusters in human populations. However, their performance in identifying groups of genealogically related individuals, especially in scanty-differentiated populations, has not been tested empirically thus far. For this study, we had access to both genealogical and genetic data from two closely related, isolated villages in southern Italy. We found that nearly all living individuals were included in a single pedigree, with multiple inbreeding loops. Despite Fst between villages being a low 0.008, genetic clustering analysis identified two clusters roughly corresponding to the two villages. Average kinship between individuals (estimated from genealogies) increased at increasing values of group membership (estimated from the genetic data), showing that the observed genetic clusters represent individuals who are more closely related to each other than to random members of the population. Further, average kinship within clusters and Fst between clusters increases with increasingly stringent membership threshold requirements. We conclude that a limited number of genetic markers is sufficient to detect structuring, and that the results of genetic analyses faithfully mirror the structuring inferred from detailed analyses of population genealogies, even when Fst values are low, as in the case of the two villages. We then estimate the impact of observed levels of population structure on association studies using simulated data. PMID:19550436

Familial epilepsy in Algeria: Clinical features and inheritance profiles.

PubMed

Chentouf, Amina; Dahdouh, Aïcha; Guipponi, Michel; Oubaiche, Mohand Laïd; Chaouch, Malika; Hamamy, Hanan; Antonarakis, Stylianos E

2015-09-01

To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5 ± 6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in Mexican Americans.

PubMed

Arya, Rector; Duggirala, Ravindranath; Jenkinson, Christopher P; Almasy, Laura; Blangero, John; O'Connell, Peter; Stern, Michael P

2004-02-01

Although several genomewide scans have identified quantitative-trait loci influencing several obesity-related traits in humans, genes influencing normal variation in obesity phenotypes have not yet been identified. We therefore performed a genome scan of body mass index (BMI) on Mexican Americans, a population prone to obesity and diabetes, using a variance-components linkage analysis to identify loci that influence BMI. We used phenotypic data from 430 individuals (26% diabetics, 59% females, mean age +/- SD = 43 +/- 17 years, mean BMI +/- SD = 30.0 +/- 6.7, mean leptin (ng/ml) +/- SD = 22.1 +/- 17.1) distributed across 27 low-income Mexican American pedigrees who participated in the San Antonio Family Diabetes Study (SAFDS) for whom a 10-15-cM map is available. In this genomewide search, after accounting for the covariate effects of age, sex, diabetes, and leptin, we identified a genetic region exhibiting the most highly significant evidence for linkage (LOD 4.5) with BMI on chromosome 4p (4p15.1) at 42 cM, near marker D4S2912. This linkage result has been confirmed in an independent linkage study of severe obesity in Utah pedigrees. Two strong positional candidates, the human peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGC1) and cholecystokinin A receptor (CCKAR) with major roles in the development of obesity, are located in this region. In conclusion, we identified a major genetic locus influencing BMI on chromosome 4p in Mexican Americans.

Tempo and mode of genomic mutations unveil human evolutionary history.

PubMed

Hara, Yuichiro

2015-01-01

Mutations that have occurred in human genomes provide insight into various aspects of evolutionary history such as speciation events and degrees of natural selection. Comparing genome sequences between human and great apes or among humans is a feasible approach for inferring human evolutionary history. Recent advances in high-throughput or so-called 'next-generation' DNA sequencing technologies have enabled the sequencing of thousands of individual human genomes, as well as a variety of reference genomes of hominids, many of which are publicly available. These sequence data can help to unveil the detailed demographic history of the lineage leading to humans as well as the explosion of modern human population size in the last several thousand years. In addition, high-throughput sequencing illustrates the tempo and mode of de novo mutations, which are producing human genetic variation at this moment. Pedigree-based human genome sequencing has shown that mutation rates vary significantly across the human genome. These studies have also provided an improved timescale of human evolution, because the mutation rate estimated from pedigree analysis is half that estimated from traditional analyses based on molecular phylogeny. Because of the dramatic reduction in sequencing cost, sequencing on-demand samples designed for specific studies is now also becoming popular. To produce data of sufficient quality to meet the requirements of the study, it is necessary to set an explicit sequencing plan that includes the choice of sample collection methods, sequencing platforms, and number of sequence reads.

Ascertainment correction for Markov chain Monte Carlo segregation and linkage analysis of a quantitative trait.

PubMed

Ma, Jianzhong; Amos, Christopher I; Warwick Daw, E

2007-09-01

Although extended pedigrees are often sampled through probands with extreme levels of a quantitative trait, Markov chain Monte Carlo (MCMC) methods for segregation and linkage analysis have not been able to perform ascertainment corrections. Further, the extent to which ascertainment of pedigrees leads to biases in the estimation of segregation and linkage parameters has not been previously studied for MCMC procedures. In this paper, we studied these issues with a Bayesian MCMC approach for joint segregation and linkage analysis, as implemented in the package Loki. We first simulated pedigrees ascertained through individuals with extreme values of a quantitative trait in spirit of the sequential sampling theory of Cannings and Thompson [Cannings and Thompson [1977] Clin. Genet. 12:208-212]. Using our simulated data, we detected no bias in estimates of the trait locus location. However, in addition to allele frequencies, when the ascertainment threshold was higher than or close to the true value of the highest genotypic mean, bias was also found in the estimation of this parameter. When there were multiple trait loci, this bias destroyed the additivity of the effects of the trait loci, and caused biases in the estimation all genotypic means when a purely additive model was used for analyzing the data. To account for pedigree ascertainment with sequential sampling, we developed a Bayesian ascertainment approach and implemented Metropolis-Hastings updates in the MCMC samplers used in Loki. Ascertainment correction greatly reduced biases in parameter estimates. Our method is designed for multiple, but a fixed number of trait loci. Copyright (c) 2007 Wiley-Liss, Inc.

Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree

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

Dunne, P.W.; Doody, R.S.; Epstein, H.F.

Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female tomore » male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.« less

Ultra-low-density genotype panels for breed assignment of Angus and Hereford cattle.

PubMed

Judge, M M; Kelleher, M M; Kearney, J F; Sleator, R D; Berry, D P

2017-06-01

Angus and Hereford beef is marketed internationally for apparent superior meat quality attributes; DNA-based breed authenticity could be a useful instrument to ensure consumer confidence on premium meat products. The objective of this study was to develop an ultra-low-density genotype panel to accurately quantify the Angus and Hereford breed proportion in biological samples. Medium-density genotypes (13 306 single nucleotide polymorphisms (SNPs)) were available on 54 703 commercial and 4042 purebred animals. The breed proportion of the commercial animals was generated from the medium-density genotypes and this estimate was regarded as the gold-standard breed composition. Ten genotype panels (100 to 1000 SNPs) were developed from the medium-density genotypes; five methods were used to identify the most informative SNPs and these included the Delta statistic, the fixation (F st) statistic and an index of both. Breed assignment analyses were undertaken for each breed, panel density and SNP selection method separately with a programme to infer population structure using the entire 13 306 SNP panel (representing the gold-standard measure). Breed assignment was undertaken for all commercial animals (n=54 703), animals deemed to contain some proportion of Angus based on pedigree (n=5740) and animals deemed to contain some proportion of Hereford based on pedigree (n=5187). The predicted breed proportion of all animals from the lower density panels was then compared with the gold-standard breed prediction. Panel density, SNP selection method and breed all had a significant effect on the correlation of predicted and actual breed proportion. Regardless of breed, the Index method of SNP selection numerically (but not significantly) outperformed all other selection methods in accuracy (i.e. correlation and root mean square of prediction) when panel density was ⩾300 SNPs. The correlation between actual and predicted breed proportion increased as panel density increased. Using 300 SNPs (selected using the global index method), the correlation between predicted and actual breed proportion was 0.993 and 0.995 in the Angus and Hereford validation populations, respectively. When SNP panels optimised for breed prediction in one population were used to predict the breed proportion of a separate population, the correlation between predicted and actual breed proportion was 0.034 and 0.044 weaker in the Hereford and Angus populations, respectively (using the 300 SNP panel). It is necessary to include at least 300 to 400 SNPs (per breed) on genotype panels to accurately predict breed proportion from biological samples.

Quantifying intrinsic and extrinsic control of single-cell fates in cancer and stem/progenitor cell pedigrees with competing risks analysis

PubMed Central

Cornwell, J. A.; Hallett, R. M.; der Mauer, S. Auf; Motazedian, A.; Schroeder, T.; Draper, J. S.; Harvey, R. P.; Nordon, R. E.

2016-01-01

The molecular control of cell fate and behaviour is a central theme in biology. Inherent heterogeneity within cell populations requires that control of cell fate is studied at the single-cell level. Time-lapse imaging and single-cell tracking are powerful technologies for acquiring cell lifetime data, allowing quantification of how cell-intrinsic and extrinsic factors control single-cell fates over time. However, cell lifetime data contain complex features. Competing cell fates, censoring, and the possible inter-dependence of competing fates, currently present challenges to modelling cell lifetime data. Thus far such features are largely ignored, resulting in loss of data and introducing a source of bias. Here we show that competing risks and concordance statistics, previously applied to clinical data and the study of genetic influences on life events in twins, respectively, can be used to quantify intrinsic and extrinsic control of single-cell fates. Using these statistics we demonstrate that 1) breast cancer cell fate after chemotherapy is dependent on p53 genotype; 2) granulocyte macrophage progenitors and their differentiated progeny have concordant fates; and 3) cytokines promote self-renewal of cardiac mesenchymal stem cells by symmetric divisions. Therefore, competing risks and concordance statistics provide a robust and unbiased approach for evaluating hypotheses at the single-cell level. PMID:27250534

Phenotypic expression of the HLA-linked iron-loading gene in the Afrikaner population of the western Cape.

PubMed

Meyer, T E; Baynes, R D; Bothwell, T H; Jenkins, T; Ballot, D; Jooste, P L; Green, A; Du Toit, E; Jacobs, P

1988-03-05

A previous study conducted on a group of Afrikaans-speaking subjects in the south-western Cape indicated a high frequency (0.115) of the HLA-linked iron-loading gene which causes idiopathic haemochromatosis. The results of phenotypic and genotypic studies on the first degree relatives of identified homozygotes and heterozygotes are now reported. There was considerable heterogeneity of phenotypic expression in the group of heterozygotes, with overlap between the homozygous and heterozygous subjects. The heterozygous relatives of heterozygous index cases, who had been identified on the basis of a serum ferritin concentration greater than 400 micrograms/l, appeared to have more frequent and more marked abnormalities of iron measurements than the heterozygote relatives of homozygous index cases (serum ferritin value greater than 400 micrograms/l, percentage transferrin saturation greater than 60). This suggests that the screening test was identifying a group of more significantly affected heterozygotes, with biochemical abnormalities that overlapped with the identified homozygotes. The index cases were followed up over a period of 5 years and during this time the 7 subjects diagnosed as heterozygotes showed a progressive increase in serum ferritin concentrations, which suggests some iron accumulation. Individual pedigrees included instances of gene recombination within the major histocompatibility complex, and of probable false-positive genotype assignment. The overall results confirm a high frequency of the gene in this particular community.

Predicting Flowering Behavior and Exploring Its Genetic Determinism in an Apple Multi-family Population Based on Statistical Indices and Simplified Phenotyping.

PubMed

Durand, Jean-Baptiste; Allard, Alix; Guitton, Baptiste; van de Weg, Eric; Bink, Marco C A M; Costes, Evelyne

2017-01-01

Irregular flowering over years is commonly observed in fruit trees. The early prediction of tree behavior is highly desirable in breeding programmes. This study aims at performing such predictions, combining simplified phenotyping and statistics methods. Sequences of vegetative vs. floral annual shoots (AS) were observed along axes in trees belonging to five apple related full-sib families. Sequences were analyzed using Markovian and linear mixed models including year and site effects. Indices of flowering irregularity, periodicity and synchronicity were estimated, at tree and axis scales. They were used to predict tree behavior and detect QTL with a Bayesian pedigree-based analysis, using an integrated genetic map containing 6,849 SNPs. The combination of a Biennial Bearing Index (BBI) with an autoregressive coefficient (γ g ) efficiently predicted and classified the genotype behaviors, despite few misclassifications. Four QTLs common to BBIs and γ g and one for synchronicity were highlighted and revealed the complex genetic architecture of the traits. Irregularity resulted from high AS synchronism, whereas regularity resulted from either asynchronous locally alternating or continual regular AS flowering. A relevant and time-saving method, based on a posteriori sampling of axes and statistical indices is proposed, which is efficient to evaluate the tree breeding values for flowering regularity and could be transferred to other species.

Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

PubMed

Suleiman, Suleiman H; Koko, Mahmoud E; Nasir, Wafaa H; Elfateh, Ommnyiah; Elgizouli, Ubai K; Abdallah, Mohammed O E; Alfarouk, Khalid O; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M A; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M; Mohamed, Hiba S; Ibrahim, Muntaser E

2015-01-01

The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

Winning the genetic lottery: biasing birth sex ratio results in more grandchildren.

PubMed

Thogerson, Collette M; Brady, Colleen M; Howard, Richard D; Mason, Georgia J; Pajor, Edmond A; Vicino, Greg A; Garner, Joseph P

2013-01-01

Population dynamics predicts that on average parents should invest equally in male and female offspring; similarly, the physiology of mammalian sex determination is supposedly stochastic, producing equal numbers of sons and daughters. However, a high quality parent can maximize fitness by biasing their birth sex ratio (SR) to the sex with the greatest potential to disproportionately outperform peers. All SR manipulation theories share a fundamental prediction: grandparents who bias birth SR should produce more grandoffspring via the favored sex. The celebrated examples of biased birth SRs in nature consistent with SR manipulation theories provide compelling circumstantial evidence. However, this prediction has never been directly tested in mammals, primarily because the complete three-generation pedigrees needed to test whether individual favored offspring produce more grandoffspring for the biasing grandparent are essentially impossible to obtain in nature. Three-generation pedigrees were constructed using 90 years of captive breeding records from 198 mammalian species. Male and female grandparents consistently biased their birth SR toward the sex that maximized second-generation success. The most strongly male-biased granddams and grandsires produced respectively 29% and 25% more grandoffspring than non-skewing conspecifics. The sons of the most male-biasing granddams were 2.7 times as fecund as those of granddams with a 50∶50 bias (similar results are seen in grandsires). Daughters of the strongest female-biasing granddams were 1.2 times as fecund as those of non-biasing females (this effect is not seen in grandsires). To our knowledge, these results are the first formal test of the hypothesis that birth SR manipulation is adaptive in mammals in terms of grandchildren produced, showing that SR manipulation can explain biased birth SR in general across mammalian species. These findings also have practical implications: parental control of birth SR has the potential to accelerate genetic loss and risk of extinction within captive populations of endangered species.

Cancer Incidence in First- and Second-Degree Relatives of BRCA1 and BRCA2 Mutation Carriers.

PubMed

Streff, Haley; Profato, Jessica; Ye, Yuanqing; Nebgen, Denise; Peterson, Susan K; Singletary, Claire; Arun, Banu K; Litton, Jennifer K

2016-07-01

Mutations in the BRCA1 and BRCA2 genes are associated with increased risk of breast, ovarian, and several other cancers. The purpose of the present study was to evaluate the incidence of cancer in first- and second-degree relatives of BRCA mutation carriers compared with the general population. A total of 1,086 pedigrees of BRCA mutation carriers was obtained from a prospectively maintained, internal review board-approved study of persons referred for clinical genetic counseling at the University of Texas MD Anderson Cancer Center. We identified 9,032 first- and second-degree relatives from 784 pedigrees that had demonstrated a clear indication of parental origin of mutation. Standardized incidence ratios (SIRs) were used to compare the observed incidence of 20 primary cancer sites to the expected incidence of each cancer based on the calculated risk estimates according to each subject's age, sex, and ethnicity. BRCA1 families had increased SIRs for breast and ovarian cancer (p < .001) and decreased SIRs for kidney, lung, prostate, and thyroid cancer and non-Hodgkin's lymphoma (p < .001). BRCA2 families had increased SIRs for breast, ovarian, and pancreatic cancer (p < .001) and decreased SIRs for kidney, lung, thyroid, and uterine cancer and non-Hodgkin's lymphoma (p < .0025). Analysis of only first-degree relatives (n = 4,099) identified no decreased SIRs and agreed with the increased SIRs observed in the overall study population. We have confirmed previous reports of an association between breast, ovarian, and pancreatic cancers with BRCA mutations. Additional research to quantify the relative risks of these cancers for BRCA mutation carriers can help tailor recommendations for risk reduction and enhance genetic counseling. BRCA gene mutations have been well described to carry an increased risk of both breast and ovarian cancer. However, the implications and risks of other cancers continues to be investigated. Evaluating the risks for other cancers further is key in identifying and managing risk reduction strategies. ©AlphaMed Press.

Assessing effective population size, coancestry and inbreeding effects on litter size using the pedigree and SNP data in closed lines of the Iberian pig breed.

PubMed

Silió, L; Barragán, C; Fernández, A I; García-Casco, J; Rodríguez, M C

2016-04-01

The complete pedigree of two closed Iberian pig lines (Gamito and Torbiscal), with 798 and 4077 reproducers, has been used to measure the evolution of coancestry (f) and inbreeding (F) for autosomal and X-linked genes along 16 and 28 respective equivalent discrete generations. At the last generation, the mean values of each line were f = 0.41 and 0.22, F = 0.35 and 0.18, fX  = 0.46 and 0.22 and FX  = 0.47 and 0.19, respectively. Other calculated parameters were the effective number of founders (final values, 6.8 and 35.2) and non-founders (1.5 and 2.4), founder genome equivalents (1.2 and 2.3) and effective population size (16.0 and 57.7). Measures of Torbiscal effective size based on rates of coancestry (66.1), inbreeding (65.0) and linkage disequilibrium (71.0) were estimated from whole-genome SNP genotyping data. Values of new and old inbreeding and their respective rates by generation were computed to detect purging effects of natural selection. The analysis of 6854 Torbiscal litters showed significant negative impacts of new and fast inbreeding on litter size, as expected from the purging hypothesis: -0.20 born piglets per litter by a 10% of new inbreeding, and -0.03 and -0.02 piglets by 1% of total and new inbreeding rates, respectively. The analysis performed on 1274 litters of the Gamito line failed to show purging effects. The only significant results were reductions in -0.91 and -0.17 piglets by a 10% of old and X-linked genes inbreeding, respectively. These results may be useful for some practical issues in conservation programs of farm or captive wild animals. © 2015 Blackwell Verlag GmbH.

Multigenerational pedigree with STAR syndrome: A novel FAM58A variant and expansion of the phenotype.

PubMed

Boczek, Nicole J; Kruisselbrink, Teresa; Cousin, Margot A; Blackburn, Patrick R; Klee, Eric W; Gavrilova, Ralitza H; Lanpher, Brendan C

2017-05-01

STAR syndrome is a rare X-linked dominant disorder characterized by toe Syndactyly, Telecanthus, Anogenital malformations, and Renal malformations, and is caused by loss-of-function variants in FAM58A. Our proband presented with the hallmark features of STAR syndrome, as well as some additional less typical features including tethered cord and hearing loss. The proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity. Clinical whole exome sequencing revealed a novel pathogenic nonsense variant, c.651G>A (p.Trp217X; NM_152274), in FAM58A in the proband, mother, and maternal half-sister. This pedigree represents the 11-13th patients described with STAR syndrome and the third instance of familial inheritance. To our knowledge, this is the first occurrence of a nonsense variant in FAM58A described in individuals with STAR syndrome and the phenotype in this pedigree suggests that tethered cord and hearing loss are features of STAR syndrome. © 2017 Wiley Periodicals, Inc.

Central obesity, hypertension and coronary artery disease: The seed and soil hypothesis

PubMed Central

Dwivedi, Shridhar; Aggarwal, Amitesh

2011-01-01

Coronary artery disease (CAD) is a multifactorial disease wherein hereditary and environmental factors play a major role. Our hypothesis is that an individual’s genetic profile functions as soil while various environmental factors such as physical inactivity, smoking, stress, etc. act as seeds in the etiopathogenesis of CAD. Much of the information regarding genetic and environmental factors can be determined in a pedigree chart by taking a history of the index patient, including details of major risk factors such as age, sex, smoking, hypertension, diabetes, coronary artery disease and stroke in the family. Preparing such a chart is a cost-effective way of initiating primary preventive measures in patients in a developing economy. The advantage of a detailed pedigree chart is to provide a snapshot view of the evident and underlying risk factors in the family as a whole, and not to merely study conventional risk factors. It elucidates the hidden stressors and hereditary factors responsible for cardiovascular disease in the family. We report herein an illustrative pedigree chart which exemplifies our above hypothesis. PMID:21286217

Design and implementation of a twin-family database for behavior genetics and genomics studies.

PubMed

Boomsma, Dorret I; Willemsen, Gonneke; Vink, Jacqueline M; Bartels, Meike; Groot, Paul; Hottenga, Jouke Jan; van Beijsterveldt, C E M Toos; Stroet, Therese; van Dijk, Rob; Wertheim, Rien; Visser, Marco; van der Kleij, Frank

2008-06-01

In this article we describe the design and implementation of a database for extended twin families. The database does not focus on probands or on index twins, as this approach becomes problematic when larger multigenerational families are included, when more than one set of multiples is present within a family, or when families turn out to be part of a larger pedigree. Instead, we present an alternative approach that uses a highly flexible notion of persons and relations. The relations among the subjects in the database have a one-to-many structure, are user-definable and extendible and support arbitrarily complicated pedigrees. Some additional characteristics of the database are highlighted, such as the storage of historical data, predefined expressions for advanced queries, output facilities for individuals and relations among individuals and an easy-to-use multi-step wizard for contacting participants. This solution presents a flexible approach to accommodate pedigrees of arbitrary size, multiple biological and nonbiological relationships among participants and dynamic changes in these relations that occur over time, which can be implemented for any type of multigenerational family study.

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha.

PubMed

Carroll, L S; Williams, N M; Moskvina, V; Russell, E; Norton, N; Williams, H J; Peirce, T; Georgieva, L; Dwyer, S; Grozeva, D; Greene, E; Farmer, A; McGuffin, P; Morris, D W; Corvin, A; Gill, M; Rujescu, D; Sham, P; Holmans, P; Jones, I; Kirov, G; Craddock, N; O'Donovan, M C; Owen, M J

2010-11-01

We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.

Applying Quantitative Genetic Methods to Primate Social Behavior

PubMed Central

Brent, Lauren J. N.

2013-01-01

Increasingly, behavioral ecologists have applied quantitative genetic methods to investigate the evolution of behaviors in wild animal populations. The promise of quantitative genetics in unmanaged populations opens the door for simultaneous analysis of inheritance, phenotypic plasticity, and patterns of selection on behavioral phenotypes all within the same study. In this article, we describe how quantitative genetic techniques provide studies of the evolution of behavior with information that is unique and valuable. We outline technical obstacles for applying quantitative genetic techniques that are of particular relevance to studies of behavior in primates, especially those living in noncaptive populations, e.g., the need for pedigree information, non-Gaussian phenotypes, and demonstrate how many of these barriers are now surmountable. We illustrate this by applying recent quantitative genetic methods to spatial proximity data, a simple and widely collected primate social behavior, from adult rhesus macaques on Cayo Santiago. Our analysis shows that proximity measures are consistent across repeated measurements on individuals (repeatable) and that kin have similar mean measurements (heritable). Quantitative genetics may hold lessons of considerable importance for studies of primate behavior, even those without a specific genetic focus. PMID:24659839

Genetic and life-history consequences of extreme climate events.

PubMed

Vincenzi, Simone; Mangel, Marc; Jesensek, Dusan; Garza, John Carlos; Crivelli, Alain J

2017-02-08

Climate change is predicted to increase the frequency and intensity of extreme climate events. Tests on empirical data of theory-based predictions on the consequences of extreme climate events are thus necessary to understand the adaptive potential of species and the overarching risks associated with all aspects of climate change. We tested predictions on the genetic and life-history consequences of extreme climate events in two populations of marble trout Salmo marmoratus that have experienced severe demographic bottlenecks due to flash floods. We combined long-term field and genotyping data with pedigree reconstruction in a theory-based framework. Our results show that after flash floods, reproduction occurred at a younger age in one population. In both populations, we found the highest reproductive variance in the first cohort born after the floods due to a combination of fewer parents and higher early survival of offspring. A small number of parents allowed for demographic recovery after the floods, but the genetic bottleneck further reduced genetic diversity in both populations. Our results also elucidate some of the mechanisms responsible for a greater prevalence of faster life histories after the extreme event. © 2017 The Author(s).

Expression Variants of the Lipogenic AGPAT6 Gene Affect Diverse Milk Composition Phenotypes in Bos taurus

PubMed Central

Littlejohn, Mathew D.; Tiplady, Kathryn; Lopdell, Thomas; Law, Tania A.; Scott, Andrew; Harland, Chad; Sherlock, Ric; Henty, Kristen; Obolonkin, Vlad; Lehnert, Klaus; MacGibbon, Alistair; Spelman, Richard J.; Davis, Stephen R.; Snell, Russell G.

2014-01-01

Milk is composed of a complex mixture of lipids, proteins, carbohydrates and various vitamins and minerals as a source of nutrition for young mammals. The composition of milk varies between individuals, with lipid composition in particular being highly heritable. Recent reports have highlighted a region of bovine chromosome 27 harbouring variants affecting milk fat percentage and fatty acid content. We aimed to further investigate this locus in two independent cattle populations, consisting of a Holstein-Friesian x Jersey crossbreed pedigree of 711 F2 cows, and a collection of 32,530 mixed ancestry Bos taurus cows. Bayesian genome-wide association mapping using markers imputed from the Illumina BovineHD chip revealed a large quantitative trait locus (QTL) for milk fat percentage on chromosome 27, present in both populations. We also investigated a range of other milk composition phenotypes, and report additional associations at this locus for fat yield, protein percentage and yield, lactose percentage and yield, milk volume, and the proportions of numerous milk fatty acids. We then used mammary RNA sequence data from 212 lactating cows to assess the transcript abundance of genes located in the milk fat percentage QTL interval. This analysis revealed a strong eQTL for AGPAT6, demonstrating that high milk fat percentage genotype is also additively associated with increased expression of the AGPAT6 gene. Finally, we used whole genome sequence data from six F1 sires to target a panel of novel AGPAT6 locus variants for genotyping in the F2 crossbreed population. Association analysis of 58 of these variants revealed highly significant association for polymorphisms mapping to the 5′UTR exons and intron 1 of AGPAT6. Taken together, these data suggest that variants affecting the expression of AGPAT6 are causally involved in differential milk fat synthesis, with pleiotropic consequences for a diverse range of other milk components. PMID:24465687

Estimated breeding values for canine hip dysplasia radiographic traits in a cohort of Australian German Shepherd dogs.

PubMed

Wilson, Bethany J; Nicholas, Frank W; James, John W; Wade, Claire M; Thomson, Peter C

2013-01-01

Canine hip dysplasia (CHD) is a serious and common musculoskeletal disease of pedigree dogs and therefore represents both an important welfare concern and an imperative breeding priority. The typical heritability estimates for radiographic CHD traits suggest that the accuracy of breeding dog selection could be substantially improved by the use of estimated breeding values (EBVs) in place of selection based on phenotypes of individuals. The British Veterinary Association/Kennel Club scoring method is a complex measure composed of nine bilateral ordinal traits, intended to evaluate both early and late dysplastic changes. However, the ordinal nature of the traits may represent a technical challenge for calculation of EBVs using linear methods. The purpose of the current study was to calculate EBVs of British Veterinary Association/Kennel Club traits in the Australian population of German Shepherd Dogs, using linear (both as individual traits and a summed phenotype), binary and ordinal methods to determine the optimal method for EBV calculation. Ordinal EBVs correlated well with linear EBVs (r = 0.90-0.99) and somewhat well with EBVs for the sum of the individual traits (r = 0.58-0.92). Correlation of ordinal and binary EBVs varied widely (r = 0.24-0.99) depending on the trait and cut-point considered. The ordinal EBVs have increased accuracy (0.48-0.69) of selection compared with accuracies from individual phenotype-based selection (0.40-0.52). Despite the high correlations between linear and ordinal EBVs, the underlying relationship between EBVs calculated by the two methods was not always linear, leading us to suggest that ordinal models should be used wherever possible. As the population of German Shepherd Dogs which was studied was purportedly under selection for the traits studied, we examined the EBVs for evidence of a genetic trend in these traits and found substantial genetic improvement over time. This study suggests the use of ordinal EBVs could increase the rate of genetic improvement in this population.

Familial atrophia maculosa varioliformis cutis: first case report from the Indian subcontinent with pedigree analysis.

PubMed

Goyal, Tarang; Varshney, Anupam; Bakshi, S K

2012-01-01

Familial atrophia maculosa varioliformis cutis is a very rare disorder with less than 28 cases being reported in the literature worldwide and remains a mystery both as far as genetics and the virtue of its pathogenesis is concerned. We present a case of mother and son, both having this disorder with presentations unique in terms of sites involved and try to draw a five generations pedigree chart for the same. We further support its inheritance pattern as autosomal dominant. Also, we propose oral isotretinoin as an effective treatment modality for the same.

Association analysis of whole genome sequencing data accounting for longitudinal and family designs.

PubMed

Hu, Yijuan; Hui, Qin; Sun, Yan V

2014-01-01

Using the whole genome sequencing data and the simulated longitudinal phenotypes for 849 pedigree-based individuals from Genetic Analysis Workshop 18, we investigated various approaches to detecting the association of rare and common variants with blood pressure traits. We compared three strategies for longitudinal data: (a) using the baseline measurement only, (b) using the average from multiple visits, and (c) using all individual measurements. We also compared the power of using all of the pedigree-based data and the unrelated subset. The analyses were performed without knowledge of the underlying simulating model.

It's a bear market: evolutionary and ecological effects of predation on two wild sockeye salmon populations

PubMed Central

Lin, J E; Hard, J J; Naish, K A; Peterson, D; Hilborn, R; Hauser, L

2016-01-01

Predation can affect both phenotypic variation and population productivity in the wild, but quantifying evolutionary and demographic effects of predation in natural environments is challenging. The aim of this study was to estimate selection differentials and coefficients associated with brown bear (Ursus arctos) predation in wild sockeye salmon (Oncorhynchus nerka) populations spawning in pristine habitat that is often subject to intense predation pressure. Using reconstructed genetic pedigrees, individual reproductive success (RS) was estimated in two sockeye salmon populations for two consecutive brood years with very different predation intensities across brood years. Phenotypic data on individual adult body length, body depth, stream entry timing and reproductive lifespan were used to calculate selection coefficients based on RS, and genetic variance components were estimated using animal models. Bears consistently killed larger and more recently arrived adults, although selection differentials were small. In both populations, mean RS was higher in the brood year experiencing lower predation intensity. Selection coefficients were similar across brood years with different levels of predation, often indicating stabilizing selection on reproductive lifespan as well as directional selection for longer reproductive lifespan. Despite these selection pressures, genetic covariation of morphology, phenology and lifespan appears to have maintained variation in spawner body size and stream entry timing in both populations. Our results therefore suggest considerable demographic but limited evolutionary effects of bear predation in the two study populations. PMID:26860201

[Analysis of the population structure of the Black Forest Draught Horse].

PubMed

Aberle, Kerstin; Wrede, Jörn; Distl, Ottmar

2003-01-01

Gene contributions of foreign populations as well as coefficients of inbreeding and relationship were evaluated in 699 Black Forest Draught horses of Baden-Württemberg actually registered in the year 2002. Based on nearly complete 5-generation-pedigrees and after taking into account the remaining incompleteness, the mean coefficient of inbreeding for the total population was 6.5%. The recently by incrossing with different breeds newly established lines of stallions showed significantly lower mean coefficients of inbreeding. High rates of inbreeding of about 1.6% in the last five generations could also be faced by incrossing stallions of foreign coldblooded populations what resulted in a decrease of inbreeding in the last generation. In the total population the mean degree of relationship was 16%. The mean degree of relationships within lines of stallions was between 18.3 and 26.8%. The coefficients of relationships between lines of stallions varied between 5.1 and 16.6%. Especially, the newly established lines of stallions showed a lower mean degree of relationships to the other different lines of stallions. The proportion of purebred Black Forest Draught horses in the total population was nearly 70%. Assuming that most animals of unknown origin were purebred, the proportion of purebred Black Forest Draught horses reached about 90%. Austrian Noric, Swiss Freiberg and South German Coldblood stallions were the most important contributors to the Black Forest Draught horse population.

It's a bear market: evolutionary and ecological effects of predation on two wild sockeye salmon populations.

PubMed

Lin, J E; Hard, J J; Naish, K A; Peterson, D; Hilborn, R; Hauser, L

2016-05-01

Predation can affect both phenotypic variation and population productivity in the wild, but quantifying evolutionary and demographic effects of predation in natural environments is challenging. The aim of this study was to estimate selection differentials and coefficients associated with brown bear (Ursus arctos) predation in wild sockeye salmon (Oncorhynchus nerka) populations spawning in pristine habitat that is often subject to intense predation pressure. Using reconstructed genetic pedigrees, individual reproductive success (RS) was estimated in two sockeye salmon populations for two consecutive brood years with very different predation intensities across brood years. Phenotypic data on individual adult body length, body depth, stream entry timing and reproductive lifespan were used to calculate selection coefficients based on RS, and genetic variance components were estimated using animal models. Bears consistently killed larger and more recently arrived adults, although selection differentials were small. In both populations, mean RS was higher in the brood year experiencing lower predation intensity. Selection coefficients were similar across brood years with different levels of predation, often indicating stabilizing selection on reproductive lifespan as well as directional selection for longer reproductive lifespan. Despite these selection pressures, genetic covariation of morphology, phenology and lifespan appears to have maintained variation in spawner body size and stream entry timing in both populations. Our results therefore suggest considerable demographic but limited evolutionary effects of bear predation in the two study populations.

Alternative reproductive tactics increase effective population size and decrease inbreeding in wild Atlantic salmon

PubMed Central

Perrier, Charles; Normandeau, Éric; Dionne, Mélanie; Richard, Antoine; Bernatchez, Louis

2014-01-01

While nonanadromous males (stream-resident and/or mature male parr) contribute to reproduction in anadromous salmonids, little is known about their impacts on key population genetic parameters. Here, we evaluated the contribution of Atlantic salmon mature male parr to the effective number of breeders (Nb) using both demographic (variance in reproductive success) and genetic (linkage disequilibrium) methods, the number of alleles, and the relatedness among breeders. We used a recently published pedigree reconstruction of a wild anadromous Atlantic salmon population in which 2548 fry born in 2010 were assigned parentage to 144 anadromous female and 101 anadromous females that returned to the river to spawn in 2009 and to 462 mature male parr. Demographic and genetic methods revealed that mature male parr increased population Nb by 1.79 and 1.85 times, respectively. Moreover, mature male parr boosted the number of alleles found among progenies. Finally, mature male parr were in average less related to anadromous females than were anadromous males, likely because of asynchronous sexual maturation between mature male parr and anadromous fish of a given cohort. By increasing Nb and allelic richness, and by decreasing inbreeding, the reproductive contribution of mature male parr has important evolutionary and conservation implications for declining Atlantic salmon populations. PMID:25553070

Multiple autoimmune diseases syndrome in Italian Greyhounds: preliminary studies of genome-wide diversity and possible associations within the dog leukocyte antigen (DLA) complex.

PubMed

Pedersen, Niels C; Liu, Hongwei; Greenfield, Daniel L; Echols, Layle Griffioen

2012-01-15

A disorder manifested by multiple autoimmune disorders, and resembling autoimmune polyendocrine syndrome type 2 (APS-2) in humans, may exist in Italian Greyhounds. The incidence of this disorder is increasing and its potential impact on the health of the breed is becoming of great concern. The aims of the present study were to document the existence of this syndrome, conduct a preliminary assessment of genetic diversity across the breed and within affected and unaffected dogs, determine whether the disorder associates with the dog leukocyte antigen (DLA) complex, and demonstrate similarities to APS-2 of humans. To these ends, information on disease, pedigrees, and blood or buccal swab samples were collected from affected and healthy Italian Greyhounds and extracted DNA analyzed. Analysis of Y chromosome markers and mitochondrial DNA sequences showed that Italian Greyhounds evolved from a single patriline and two major and four minor matrilines. A panel of 24 highly polymorphic simple tandem repeat (STR) markers across 20 autosomes demonstrated that affected and unaffected dogs were not distinguishable from the population as a whole by heterozygosity, F-statistics, and principal component analysis (PCA). However, analysis of allele frequencies at each STR loci identified regions of increased or decreased disease risk on four chromosomes. A similar genetic analysis using 109 single nucleotide polymorphisms (SNPs) across the DLA region showed differences between affected and unaffected dogs. PCA and zygosity mapping of DLA SNPs from unrelated dogs demonstrated two distinct subpopulations among the affected individuals. One population was very homozygous and the other closely resembled unaffected dogs in its heterozygosity, suggesting the evolution of a disease prone bloodline as a result of non-random selection. Exon 2 sequencing of the DLA class II genes demonstrated 5-8 alleles at each locus and 14 three loci haplotypes. Two specific haplotypes containing DRB1*00203 or DRB1*02901 were associated with increased disease risk in about one-third of affected dogs. However, high density SNP association mapping across the DLA region and CFA12 did not corroborate the association. Copyright © 2011 Elsevier B.V. All rights reserved.

HaploForge: a comprehensive pedigree drawing and haplotype visualization web application.

PubMed

Tekman, Mehmet; Medlar, Alan; Mozere, Monika; Kleta, Robert; Stanescu, Horia

2017-12-15

Haplotype reconstruction is an important tool for understanding the aetiology of human disease. Haplotyping infers the most likely phase of observed genotypes conditional on constraints imposed by the genotypes of other pedigree members. The results of haplotype reconstruction, when visualized appropriately, show which alleles are identical by descent despite the presence of untyped individuals. When used in concert with linkage analysis, haplotyping can help delineate a locus of interest and provide a succinct explanation for the transmission of the trait locus. Unfortunately, the design choices made by existing haplotype visualization programs do not scale to large numbers of markers. Indeed, following haplotypes from generation to generation requires excessive scrolling back and forth. In addition, the most widely used program for haplotype visualization produces inconsistent recombination artefacts for the X chromosome. To resolve these issues, we developed HaploForge, a novel web application for haplotype visualization and pedigree drawing. HaploForge takes advantage of HTML5 to be fast, portable and avoid the need for local installation. It can accurately visualize autosomal and X-linked haplotypes from both outbred and consanguineous pedigrees. Haplotypes are coloured based on identity by descent using a novel A* search algorithm and we provide a flexible viewing mode to aid visual inspection. HaploForge can currently process haplotype reconstruction output from Allegro, GeneHunter, Merlin and Simwalk. HaploForge is licensed under GPLv3 and is hosted and maintained via GitHub. https://github.com/mtekman/haploforge. r.kleta@ucl.ac.uk. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

[The significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis].

PubMed

Zhang, J; Wang, Y N; Wang, J S; Wu, L; Wei, N; Fu, L; Gao, Z; Chen, J H; Pei, R J; Wang, Z

2016-07-01

To investigate the significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis (HLH). Four cases of primary HLH patients with PRF1, UNC13D and SH2D1A gene mutations were conducted pedigree investigation, including family genetic screening and detections of immunological parameters (NK cell activity, CD107a degranulation and expression of HLH related defective protein), to evaluate the significance of these different indicators in the diagnosis of primary HLH and explore their correlations. The DNA mutations of the four families included missense mutation c.T172C (p.S58P) and non- frameshift deletions c.1083_1094del (p.361_365del), missense mutation c.C1349T (p.T450M) and frameshift mutation c.1090_1091delCT (p.T364fsX93) in PRF1 gene, missense mutation c.G2588A (p.G863D) in UNC13D gene and hemizygous mutation c.32T>G (p.I11S) in SH2D1A gene. The patients and their family members presented decreased NK cell activities. Individuals who carried mutations of PRF1 gene and SH2D1A gene showed low expression of perforin (PRF1) and signaling lymphocytic activation molecule associated protein (SAP). And the patient with UNC13D gene mutation and his family member with identical mutation showed significant reducing cytotoxic degranulation function (expression of CD107a). Pedigree genetic screening and rapid detection of immunological parameters might play an important role in the diagnosis of primary HLH, and both of them had good consistency. As an efficient detection means, the rapid immunological detection indicators would provide reliable basis for the early diagnosis of the primary HLH.

Estimation of total genetic effects for survival time in crossbred laying hens showing cannibalism, using pedigree or genomic information.

PubMed

Brinker, T; Raymond, B; Bijma, P; Vereijken, A; Ellen, E D

2017-02-01

Mortality of laying hens due to cannibalism is a major problem in the egg-laying industry. Survival depends on two genetic effects: the direct genetic effect of the individual itself (DGE) and the indirect genetic effects of its group mates (IGE). For hens housed in sire-family groups, DGE and IGE cannot be estimated using pedigree information, but the combined effect of DGE and IGE is estimated in the total breeding value (TBV). Genomic information provides information on actual genetic relationships between individuals and might be a tool to improve TBV accuracy. We investigated whether genomic information of the sire increased TBV accuracy compared with pedigree information, and we estimated genetic parameters for survival time. A sire model with pedigree information (BLUP) and a sire model with genomic information (ssGBLUP) were used. We used survival time records of 7290 crossbred offspring with intact beaks from four crosses. Cross-validation was used to compare the models. Using ssGBLUP did not improve TBV accuracy compared with BLUP which is probably due to the limited number of sires available per cross (~50). Genetic parameter estimates were similar for BLUP and ssGBLUP. For both BLUP and ssGBLUP, total heritable variance (T 2 ), expressed as a proportion of phenotypic variance, ranged from 0.03 ± 0.04 to 0.25 ± 0.09. Further research is needed on breeding value estimation for socially affected traits measured on individuals kept in single-family groups. © 2016 The Authors. Journal of Animal Breeding and Genetics Published by Blackwell Verlag GmbH.

Molecular and pedigree analysis applied to conservation of animal genetic resources: the case of Brazilian Somali hair sheep.

PubMed

Paiva, Samuel R; Facó, Olivardo; Faria, Danielle A; Lacerda, Thaísa; Barretto, Gabriel B; Carneiro, Paulo L S; Lobo, Raimundo N B; McManus, Concepta

2011-10-01

The first registers of Somali sheep in Brazil are from the beginning of the 1900s. This breed, adapted to the dry climate and scarce food supply, is restricted in the northeast region of the country. Molecular marker technologies, especially those based on genotyping microsatellite and mtDNA loci, can be used in conjunction with breeding (pedigree analysis) and consequently the maintenance of genetic variation in herds. Animals from the Brazilian Somali Conservation Nuclei from Embrapa Sheep and Goats in Ceará State were used to validate genetic monitoring by traditional pedigree methods and molecular markers. Nineteen microsatellite markers and 404 base pairs from the control region of mtDNA were used. For total herd diversity, an average 5.32 alleles were found, with expected heterozygosity of 0.5896, observed heterozygosity of 0.6451, 0.4126 for molecular coancestrality, and coefficient of inbreeding (F (IS)) was -0.095. Comparing molecular coancestrality means over the years, there was a consistent increase in this parameter within the herd, increasing from 0.4157 to 0.4769 in 2 years (approx. 12% variation). Sixteen mtDNA haplotypes were identified. Inbreeding and other estimates from genealogical analyses confirm the results from molecular markers. From these results, it is possible to state that microsatellites are useful tools in genetic management of herds, especially when routine herd recording is not carried out, or there were gaps in recent generations. As well as pedigree control, genetic diversity can be optimized. Based on the results, and despite herd recording in the herd of Brazilian Somali of Embrapa Sheep and Goats, additional management measures need to be carried out in this herd to reduce inbreeding and optimize genetic variation.

Identity-by-Descent-Based Phasing and Imputation in Founder Populations Using Graphical Models

PubMed Central

Palin, Kimmo; Campbell, Harry; Wright, Alan F; Wilson, James F; Durbin, Richard

2011-01-01

Accurate knowledge of haplotypes, the combination of alleles co-residing on a single copy of a chromosome, enables powerful gene mapping and sequence imputation methods. Since humans are diploid, haplotypes must be derived from genotypes by a phasing process. In this study, we present a new computational model for haplotype phasing based on pairwise sharing of haplotypes inferred to be Identical-By-Descent (IBD). We apply the Bayesian network based model in a new phasing algorithm, called systematic long-range phasing (SLRP), that can capitalize on the close genetic relationships in isolated founder populations, and show with simulated and real genome-wide genotype data that SLRP substantially reduces the rate of phasing errors compared to previous phasing algorithms. Furthermore, the method accurately identifies regions of IBD, enabling linkage-like studies without pedigrees, and can be used to impute most genotypes with very low error rate. Genet. Epidemiol. 2011. © 2011 Wiley Periodicals, Inc.35:853-860, 2011 PMID:22006673

Inheritance pattern of microsatellite loci and their use for kinship analysis in the Japanese scallop Patinopecten yessoensis

NASA Astrophysics Data System (ADS)

Xu, Kefeng; Li, Qi

2009-06-01

The inheritance mode of seven microsatellite markers was investigated in Patinopecten yessoensis larvae from four controlled crosses, and the feasibility of using these markers for kinship estimation was also examined. All the seven microsatellite loci were compatible with Mendelian inheritance. Neither sex-linked barriers to transmission nor major barriers to fertilization between gametes from the parents were evident. Two of the seven loci showed the presence of null alleles in two families, suggesting the need to conduct comprehensive species-specific inheritance studies for microsatellite loci used in population genetic studies. However, even if the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from four families were all unambiguously discriminated in the neighbor-joining dendrogram. This result indicates that the microsatellite markers used may be capable of discriminating between related and unrelated scallop larvae in the absence of pedigree information, and of investigating the effective number of parents contributing to the hatchery population of the Japanese scallop.

Design considerations for genetic linkage and association studies.

PubMed

Nsengimana, Jérémie; Bishop, D Timothy

2012-01-01

This chapter describes the main issues that genetic epidemiologists usually consider in the design of linkage and association studies. For linkage, we briefly consider the situation of rare, highly penetrant alleles showing a disease pattern consistent with Mendelian inheritance investigated through parametric methods in large pedigrees or with autozygosity mapping in inbred families, and we then turn our focus to the most common design, affected sibling pairs, of more relevance for common, complex diseases. Theoretical and more practical power and sample size calculations are provided as a function of the strength of the genetic effect being investigated. We also discuss the impact of other determinants of statistical power such as disease heterogeneity, pedigree, and genotyping errors, as well as the effect of the type and density of genetic markers. Linkage studies should be as large as possible to have sufficient power in relation to the expected genetic effect size. Segregation analysis, a formal statistical technique to describe the underlying genetic susceptibility, may assist in the estimation of the relevant parameters to apply, for instance. However, segregation analyses estimate the total genetic component rather than a single-locus effect. Locus heterogeneity should be considered when power is estimated and at the analysis stage, i.e. assuming smaller locus effect than the total the genetic component from segregation studies. Disease heterogeneity should be minimised by considering subtypes if they are well defined or by otherwise collecting known sources of heterogeneity and adjusting for them as covariates; the power will depend upon the relationship between the disease subtype and the underlying genotypes. Ultimately, identifying susceptibility alleles of modest effects (e.g. RR≤1.5) requires a number of families that seem unfeasible in a single study. Meta-analysis and data pooling between different research groups can provide a sizeable study, but both approaches require even a higher level of vigilance about locus and disease heterogeneity when data come from different populations. All necessary steps should be taken to minimise pedigree and genotyping errors at the study design stage as they are, for the most part, due to human factors. A two-stage design is more cost-effective than one stage when using short tandem repeats (STRs). However, dense single-nucleotide polymorphism (SNP) arrays offer a more robust alternative, and due to their lower cost per unit, the total cost of studies using SNPs may in the future become comparable to that of studies using STRs in one or two stages. For association studies, we consider the popular case-control design for dichotomous phenotypes, and we provide power and sample size calculations for one-stage and multistage designs. For candidate genes, guidelines are given on the prioritisation of genetic variants, and for genome-wide association studies (GWAS), the issue of choosing an appropriate SNP array is discussed. A warning is issued regarding the danger of designing an underpowered replication study following an initial GWAS. The risk of finding spurious association due to population stratification, cryptic relatedness, and differential bias is underlined. GWAS have a high power to detect common variants of high or moderate effect. For weaker effects (e.g. relative risk<1.2), the power is greatly reduced, particularly for recessive loci. While sample sizes of 10,000 or 20,000 cases are not beyond reach for most common diseases, only meta-analyses and data pooling can allow attaining a study size of this magnitude for many other diseases. It is acknowledged that detecting the effects from rare alleles (i.e. frequency<5%) is not feasible in GWAS, and it is expected that novel methods and technology, such as next-generation resequencing, will fill this gap. At the current stage, the choice of which GWAS SNP array to use does not influence the power in populations of European ancestry. A multistage design reduces the study cost but has less power than the standard one-stage design. If one opts for a multistage design, the power can be improved by jointly analysing the data from different stages for the SNPs they share. The estimates of locus contribution to disease risk from genome-wide scans are often biased, and relying on them might result in an underpowered replication study. Population structure has so far caused less spurious associations than initially feared, thanks to systematic ethnicity matching and application of standard quality control measures. Differential bias could be a more serious threat and must be minimised by strictly controlling all the aspects of DNA acquisition, storage, and processing.

Sequential recruitment of study participants may inflate genetic heritability estimates.

PubMed

Noce, Damia; Gögele, Martin; Schwienbacher, Christine; Caprioli, Giulia; De Grandi, Alessandro; Foco, Luisa; Platzgummer, Stefan; Pramstaller, Peter P; Pattaro, Cristian

2017-06-01

After the success of genome-wide association studies to uncover complex trait loci, attempts to explain the remaining genetic heritability (h 2 ) are mainly focused on unraveling rare variant associations and gene-gene or gene-environment interactions. Little attention is paid to the possibility that h 2 estimates are inflated as a consequence of the epidemiological study design. We studied the time series of 54 biochemical traits in 4373 individuals from the Cooperative Health Research In South Tyrol (CHRIS) study, a pedigree-based study enrolling ten participants/day over several years, with close relatives preferentially invited within the same day. We observed distributional changes of measured traits over time. We hypothesized that the combination of such changes with the pedigree structure might generate a shared-environment component with consequent h 2 inflation. We performed variance components (VC) h 2 estimation for all traits after accounting for the enrollment period in a linear mixed model (two-stage approach). Accounting for the enrollment period caused a median h 2 reduction of 4%. For 9 traits, the reduction was of >20%. Results were confirmed by a Bayesian Markov chain Monte Carlo analysis with all VCs included at the same time (one-stage approach). The electrolytes were the traits most affected by the enrollment period. The h 2 inflation was independent of the h 2 magnitude, laboratory protocol changes, and length of the enrollment period. The enrollment process may induce shared-environment effects even under very stringent and standardized operating procedures, causing h 2 inflation. Including the day of participation as a random effect is a sensitive way to avoid overestimation.

Three Approaches to Modeling Gene-Environment Interactions in Longitudinal Family Data: Gene-Smoking Interactions in Blood Pressure.

PubMed

Basson, Jacob; Sung, Yun Ju; de Las Fuentes, Lisa; Schwander, Karen L; Vazquez, Ana; Rao, Dabeeru C

2016-01-01

Blood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene-smoking interactions have detected novel BP loci in cross-sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied. Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene-smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations (GEE), hierarchical linear modeling, and pedigree-based mixed modeling. The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single-visit analyses. The pedigree-based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene-smoking interactions. The GEE, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency <1% were included in the analysis. The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data. © 2015 WILEY PERIODICALS, INC.

SNP Data Quality Control in a National Beef and Dairy Cattle System and Highly Accurate SNP Based Parentage Verification and Identification

PubMed Central

McClure, Matthew C.; McCarthy, John; Flynn, Paul; McClure, Jennifer C.; Dair, Emma; O'Connell, D. K.; Kearney, John F.

2018-01-01

A major use of genetic data is parentage verification and identification as inaccurate pedigrees negatively affect genetic gain. Since 2012 the international standard for single nucleotide polymorphism (SNP) verification in Bos taurus cattle has been the ISAG SNP panels. While these ISAG panels provide an increased level of parentage accuracy over microsatellite markers (MS), they can validate the wrong parent at ≤1% misconcordance rate levels, indicating that more SNP are needed if a more accurate pedigree is required. With rapidly increasing numbers of cattle being genotyped in Ireland that represent 61 B. taurus breeds from a wide range of farm types: beef/dairy, AI/pedigree/commercial, purebred/crossbred, and large to small herd size the Irish Cattle Breeding Federation (ICBF) analyzed different SNP densities to determine that at a minimum ≥500 SNP are needed to consistently predict only one set of parents at a ≤1% misconcordance rate. For parentage validation and prediction ICBF uses 800 SNP (ICBF800) selected based on SNP clustering quality, ISAG200 inclusion, call rate (CR), and minor allele frequency (MAF) in the Irish cattle population. Large datasets require sample and SNP quality control (QC). Most publications only deal with SNP QC via CR, MAF, parent-progeny conflicts, and Hardy-Weinberg deviation, but not sample QC. We report here parentage, SNP QC, and a genomic sample QC pipelines to deal with the unique challenges of >1 million genotypes from a national herd such as SNP genotype errors from mis-tagging of animals, lab errors, farm errors, and multiple other issues that can arise. We divide the pipeline into two parts: a Genotype QC and an Animal QC pipeline. The Genotype QC identifies samples with low call rate, missing or mixed genotype classes (no BB genotype or ABTG alleles present), and low genotype frequencies. The Animal QC handles situations where the genotype might not belong to the listed individual by identifying: >1 non-matching genotypes per animal, SNP duplicates, sex and breed prediction mismatches, parentage and progeny validation results, and other situations. The Animal QC pipeline make use of ICBF800 SNP set where appropriate to identify errors in a computationally efficient yet still highly accurate method. PMID:29599798

Discovery of quantitative trait loci for resistance to parasitic nematode infection in sheep: I. Analysis of outcross pedigrees

PubMed Central

Crawford, Allan M; Paterson, Korena A; Dodds, Ken G; Diez Tascon, Cristina; Williamson, Penny A; Roberts Thomson, Meredith; Bisset, Stewart A; Beattie, Anne E; Greer, Gordon J; Green, Richard S; Wheeler, Roger; Shaw, Richard J; Knowler, Kevin; McEwan, John C

2006-01-01

Background Currently most pastoral farmers rely on anthelmintic drenches to control gastrointestinal parasitic nematodes in sheep. Resistance to anthelmintics is rapidly increasing in nematode populations such that on some farms none of the drench families are now completely effective. It is well established that host resistance to nematode infection is a moderately heritable trait. This study was undertaken to identify regions of the genome, quantitative trait loci (QTL) that contain genes affecting resistance to parasitic nematodes. Results Rams obtained from crossing nematode parasite resistant and susceptible selection lines were used to derive five large half-sib families comprising between 348 and 101 offspring per sire. Total offspring comprised 940 lambs. Extensive measurements for a range of parasite burden and immune function traits in all offspring allowed each lamb in each pedigree to be ranked for relative resistance to nematode parasites. Initially the 22 most resistant and 22 most susceptible progeny from each pedigree were used in a genome scan that used 203 microsatellite markers spread across all sheep autosomes. This study identified 9 chromosomes with regions showing sufficient linkage to warrant the genotyping of all offspring. After genotyping all offspring with markers covering Chromosomes 1, 3, 4, 5, 8, 12, 13, 22 and 23, the telomeric end of chromosome 8 was identified as having a significant QTL for parasite resistance as measured by the number of Trichostrongylus spp. adults in the abomasum and small intestine at the end of the second parasite challenge. Two further QTL for associated immune function traits of total serum IgE and T. colubiformis specific serum IgG, at the end of the second parasite challenge, were identified on chromosome 23. Conclusion Despite parasite resistance being a moderately heritable trait, this large study was able to identify only a single significant QTL associated with it. The QTL concerned adult parasite burdens at the end of the second parasite challenge when the lambs were approximately 6 months old. Our failure to discover more QTL suggests that most of the genes controlling this trait are of relatively small effect. The large number of suggestive QTL discovered (more than one per family per trait than would be expected by chance) also supports this conclusion. PMID:16846521

Discovery of quantitative trait loci for resistance to parasitic nematode infection in sheep: I. Analysis of outcross pedigrees.

PubMed

Crawford, Allan M; Paterson, Korena A; Dodds, Ken G; Diez Tascon, Cristina; Williamson, Penny A; Roberts Thomson, Meredith; Bisset, Stewart A; Beattie, Anne E; Greer, Gordon J; Green, Richard S; Wheeler, Roger; Shaw, Richard J; Knowler, Kevin; McEwan, John C

2006-07-18

Currently most pastoral farmers rely on anthelmintic drenches to control gastrointestinal parasitic nematodes in sheep. Resistance to anthelmintics is rapidly increasing in nematode populations such that on some farms none of the drench families are now completely effective. It is well established that host resistance to nematode infection is a moderately heritable trait. This study was undertaken to identify regions of the genome, quantitative trait loci (QTL) that contain genes affecting resistance to parasitic nematodes. Rams obtained from crossing nematode parasite resistant and susceptible selection lines were used to derive five large half-sib families comprising between 348 and 101 offspring per sire. Total offspring comprised 940 lambs. Extensive measurements for a range of parasite burden and immune function traits in all offspring allowed each lamb in each pedigree to be ranked for relative resistance to nematode parasites. Initially the 22 most resistant and 22 most susceptible progeny from each pedigree were used in a genome scan that used 203 microsatellite markers spread across all sheep autosomes. This study identified 9 chromosomes with regions showing sufficient linkage to warrant the genotyping of all offspring. After genotyping all offspring with markers covering Chromosomes 1, 3, 4, 5, 8, 12, 13, 22 and 23, the telomeric end of chromosome 8 was identified as having a significant QTL for parasite resistance as measured by the number of Trichostrongylus spp. adults in the abomasum and small intestine at the end of the second parasite challenge. Two further QTL for associated immune function traits of total serum IgE and T. colubiformis specific serum IgG, at the end of the second parasite challenge, were identified on chromosome 23. Despite parasite resistance being a moderately heritable trait, this large study was able to identify only a single significant QTL associated with it. The QTL concerned adult parasite burdens at the end of the second parasite challenge when the lambs were approximately 6 months old. Our failure to discover more QTL suggests that most of the genes controlling this trait are of relatively small effect. The large number of suggestive QTL discovered (more than one per family per trait than would be expected by chance) also supports this conclusion.

Cryptic Distant Relatives Are Common in Both Isolated and Cosmopolitan Genetic Samples

PubMed Central

Macpherson, J. Michael; Eriksson, Nick; Saxonov, Serge; Pe'er, Itsik; Mountain, Joanna L.

2012-01-01

Although a few hundred single nucleotide polymorphisms (SNPs) suffice to infer close familial relationships, high density genome-wide SNP data make possible the inference of more distant relationships such as 2nd to 9th cousinships. In order to characterize the relationship between genetic similarity and degree of kinship given a timeframe of 100–300 years, we analyzed the sharing of DNA inferred to be identical by descent (IBD) in a subset of individuals from the 23andMe customer database (n = 22,757) and from the Human Genome Diversity Panel (HGDP-CEPH, n = 952). With data from 121 populations, we show that the average amount of DNA shared IBD in most ethnolinguistically-defined populations, for example Native American groups, Finns and Ashkenazi Jews, differs from continentally-defined populations by several orders of magnitude. Via extensive pedigree-based simulations, we determined bounds for predicted degrees of relationship given the amount of genomic IBD sharing in both endogamous and ‘unrelated’ population samples. Using these bounds as a guide, we detected tens of thousands of 2nd to 9th degree cousin pairs within a heterogenous set of 5,000 Europeans. The ubiquity of distant relatives, detected via IBD segments, in both ethnolinguistic populations and in large ‘unrelated’ populations samples has important implications for genetic genealogy, forensics and genotype/phenotype mapping studies. PMID:22509285

Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations

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

Eichler, E.E.; Nelson, D.L.

1996-07-12

In an attempt to understand the allelic diversity and mutability of the human FMR1 CGG repeat, we have analyzed the AGG substructure of this locus within six genetically-closed populations (Mbuti pygmy, Baka pygmy, R. surui, Karitiana, Mayan, and Hutterite). Most alleles (61/92 or 66%) possessed two AGG interspersions occurring with a periodicity of one AGG every nine or ten CGG repeats, indicating that this pattern is highly conserved in all human populations. Significant differences in allele distribution were observed among the populations for rare variants possessing fewer or more AGG interruptions than the canonical FMR1 CGG repeat sequence. Comparisons ofmore » expected heterozygosity of the FMR1 CGG repeat locus with 30 other microsatellite loci, demonstrated remarkably similar levels of polymorphism within each population, suggesting that most FMR1 CGG repeat alleles mutate at rates indistinguishable from other microsatellite loci. A single allele (1 out of 92) was identified with a large uninterrupted tract of pure repeats (42 pure CGG triplets). Retrospective pedigree analysis indicated that this allele had been transmitted unstably. Although such alleles mutate rapidly and likely represent evolving premutations, our analysis suggests that in spite of the estimated frequency of their occurrence, these unstable alleles do not significantly alter the expected heterozygosity of the FMR1 CGG repeat in the human population. 45 refs., 1 fig., 2 tabs.« less