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Journal of Dairy Science Mar 2019The objective of this study was to model differences in pedigree accuracy caused by selective genotyping. As genotypes are used to correct pedigree errors, some pedigree...
The objective of this study was to model differences in pedigree accuracy caused by selective genotyping. As genotypes are used to correct pedigree errors, some pedigree relationships are more accurate than others. These accuracy differences can be modeled with uncertain parentage models that distribute the paternal (maternal) contribution across multiple sires (dams). In our case, the parents were the parent on record and an unknown parent group to account for pedigree relationships that were not confirmed through genotypes. Pedigree accuracy was addressed through simulation and through North American Holstein data. Data were simulated to be representative of the dairy industry with heterogeneous pedigree depth, pedigree accuracy, and genotyping. Holstein data were obtained from the official evaluation for milk, fat, and protein. Two models were compared: the traditional approach, assuming accurate pedigrees, and uncertain parentage, assuming variable pedigree accuracy. The uncertain parentage model was used to add pedigree relationships for alternative parents when pedigree relationships were not certain. The uncertain parentage model included 2 possible sires (dams) when the sire (dam) could not be confirmed with genotypes. The 2 sires (dams) were the sire (dam) on record with probability 0.90 (0.95) and the unknown parent group for the birth year of the sire (dam) with probability 0.10 (0.05). An additional set of assumptions was tested in simulation to mimic an extensive dairy production system by using a sire probability of 0.75, a dam probability of 0.85, and the remainder attributed to the unknown parent groups. In the simulation, small bias differences occurred between models based on pedigree accuracy and genotype status. Rank correlations were strong between traditional and uncertain parentage models in simulation (≥0.99) and in Holstein (≥0.99). For Holsteins, the estimated breeding value differences between models were small for most animals. Thus, traditional models can continue to be used for dairy genomic prediction despite using genotypes to improve pedigree accuracy. Those genotypes can also be used to discover maternal parentage, specifically maternal grandsires and great grandsires when the dam is not known. More research is needed to understand how to use discovered maternal pedigrees in genetic prediction.
Topics: Animals; Breeding; Cattle; Dairying; Genome; Genomics; Models, Genetic; Pedigree; United States
PubMed: 30639024
DOI: 10.3168/jds.2018-15419 -
Bioinformatics (Oxford, England) Feb 2016PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data....
UNLABELLED
PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree.
AVAILABILITY AND IMPLEMENTATION
We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu.
Topics: Algorithms; Chromosomes, Human, Y; Computer Simulation; DNA, Mitochondrial; Genetics, Population; Haplotypes; Humans; Linkage Disequilibrium; Pedigree; Software
PubMed: 26515822
DOI: 10.1093/bioinformatics/btv618 -
Hereditas May 2020R is a multi-platform statistical software and an object oriented programming language. The package archive network for R provides CRAN repository that features over...
BACKGROUND
R is a multi-platform statistical software and an object oriented programming language. The package archive network for R provides CRAN repository that features over 15,000 free open source packages, at the time of writing this article (https://cran.r-project.org/web/packages, accessed in October 2019). The package ggroups is introduced in this article. The purpose of this package is providing functions for checking and processing the pedigree, calculation of the additive genetic relationship matrix and its inverse, which are used to study the population structure and predicting the genetic merit of animals. Calculation of the dominance relationship matrix and its inverse are also covered. A concept in animal breeding is genetic groups, which is about the inequality of the average genetic merits for groups of unknown parents. The package provides functions for the calculation of the matrix of genetic group contributions (Q). Calculating Q is computationally demanding, and depending on the size of the pedigree and the number of genetic groups, it might not be feasible using personal computers. Therefore, a computationally optimised function and its parallel processing alternative are provided in the package.
RESULTS
Using sample data, outputs from different functions of the package were presented to illustrate a real experience of working with the package.
CONCLUSIONS
The presented R package is a free and open source tool mainly for quantitative geneticists and ecologists, who deal with pedigree data. It provides numerous functions for handling pedigree data, and calculating various pedigree-based matrices. Some of the functions are computationally optimised for large-scale data.
Topics: Animals; Genetics, Population; Pedigree; Software
PubMed: 32366304
DOI: 10.1186/s41065-020-00124-2 -
BMC Biology Feb 2021The genealogical histories of individuals within populations are of interest to studies aiming both to uncover detailed pedigree information and overall quantitative...
BACKGROUND
The genealogical histories of individuals within populations are of interest to studies aiming both to uncover detailed pedigree information and overall quantitative population demographic histories. However, the analysis of quantitative details of individual genealogical histories has faced challenges from incomplete available pedigree records and an absence of objective and quantitative details in pedigree information. Although complete pedigree information for most individuals is difficult to track beyond a few generations, it is possible to describe a person's genealogical history using their genetic relatives revealed by identity by descent (IBD) segments-long genomic segments shared by two individuals within a population, which are identical due to inheritance from common ancestors. When modern biobanks collect genotype information for a significant fraction of a population, dense genetic connections of a person can be traced using such IBD segments, offering opportunities to characterize individuals in the context of the underlying populations. Here, we conducted an individual-centric analysis of IBD segments among the UK Biobank participants that represent 0.7% of the UK population.
RESULTS
We made a high-quality call set of IBD segments over 5 cM among all 500,000 UK Biobank participants. On average, one UK individual shares IBD segments with 14,000 UK Biobank participants, which we refer to as "relatives." Using these segments, approximately 80% of a person's genome can be imputed. We subsequently propose genealogical descriptors based on the genetic connections of relative cohorts of individuals sharing at least one IBD segment and show that such descriptors offer important information about one's genetic makeup, personal genealogical history, and social behavior. Through analysis of relative counts sharing segments at different lengths, we identified a group, potentially British Jews, who has a distinct pattern of familial expansion history. Finally, using the enrichment of relatives in one's neighborhood, we identified regional variations of personal preference favoring living closer to one's extended families.
CONCLUSIONS
Our analysis revealed genetic makeup, personal genealogical history, and social behaviors at the population scale, opening possibilities for further studies of individual's genetic connections in biobank data.
Topics: Biological Specimen Banks; Genealogy and Heraldry; Genetic Variation; Humans; Pedigree; United Kingdom
PubMed: 33593342
DOI: 10.1186/s12915-021-00964-y -
JACC. Heart Failure Nov 2022
Topics: Humans; Heart Failure; Cardiomyopathy, Dilated; Pedigree; Mutation
PubMed: 36328646
DOI: 10.1016/j.jchf.2022.08.003 -
Journal of Neurosurgery Jul 2023Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique...
OBJECTIVE
Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique high-risk pedigree population resource and approach to identify rare candidate variants that likely predispose individuals to CM and protein structure prediction tools to identify pathogenicity mechanisms.
METHODS
By using the Utah Population Database, the authors identified pedigrees with significantly increased numbers of members with CM diagnosis. From a separate DNA biorepository of 451 samples from CM patients and families, 32 CM patients belonging to 1 or more of 24 high-risk Chiari pedigrees were identified. Two high-risk pedigrees had 3 CM-affected relatives, and 22 pedigrees had 2 CM-affected relatives. To identify rare candidate predisposition gene variants, whole-exome sequence data from these 32 CM patients belonging to 24 CM-affected related pairs from high-risk pedigrees were analyzed. The I-TASSER package for protein structure prediction was used to predict the structures of both the wild-type and mutant proteins found here.
RESULTS
Sequence analysis of the 24 affected relative pairs identified 38 rare candidate Chiari predisposition gene variants that were shared by at least 1 CM-affected pair from a high-risk pedigree. The authors found a candidate variant in HOXC4 that was shared by 2 CM-affected patients in 2 independent pedigrees. All 4 of these CM cases, 2 in each pedigree, exhibited a specific craniocervical bony phenotype defined by a clivoaxial angle less than 125°. The protein structure prediction results suggested that the mutation considered here may reduce the binding affinity of HOXC4 to DNA.
CONCLUSIONS
Analysis of unique and powerful Utah genetic resources allowed identification of 38 strong candidate CM predisposition gene variants. These variants should be pursued in independent populations. One of the candidates, a rare HOXC4 variant, was identified in 2 high-risk CM pedigrees, with this variant possibly predisposing patients to a Chiari phenotype with craniocervical kyphosis.
Topics: Humans; Genetic Predisposition to Disease; Genotype; Homeodomain Proteins; Mutation; Pedigree; Phenotype; Risk Factors; Brain
PubMed: 36433874
DOI: 10.3171/2022.10.JNS22956 -
Journal of Clinical Laboratory Analysis Nov 2022Inherited AT deficiency is an autosomal-dominant thrombophilic disorder usually caused by various SERPINC1 defects associated with a high risk of recurrent venous...
BACKGROUND
Inherited AT deficiency is an autosomal-dominant thrombophilic disorder usually caused by various SERPINC1 defects associated with a high risk of recurrent venous thromboembolism. In this article, the phenotype, gene mutation, and molecular pathogenic mechanisms were determined in three pedigrees with inherited AT deficiency.
METHODS
Coagulation indices were examined on STAGO STA-R-MAX analyzer. The AT:Ag was analyzed by ELISA. All exons and flanking sequences of SERPINC1 were amplified by PCR. AT wild type and three mutant expression plasmids were constructed and then transfected into HEK293FT cells. The expression level of AT protein was analyzed by ELISA and Western blot.
RESULTS
The AT:A and AT:Ag of probands 1 and 3 were decreased to 49% and 52 mg/dL, 38% and 44 mg/dL, respectively. The AT:A of proband 2 was decreased to 32%. The SERPINC1 gene analysis indicated that there was a p.Ile421Thr in proband 1, a p.Leu417Gln in proband 2, and a p.Met252Thr in proband 3, respectively. The AT mRNA expression level of the three mutants was not significantly different from AT-WT by qRT-PCR. The results of ELISA and Western blot tests showed that the AT-M252T and AT-I421T mutants had a higher AT expression than the AT wild type (AT-WT), and the AT protein expression of AT-L417Q mutants had no significant difference compared with AT-WT in the cell lysate. The AT expression levels of AT-M252T and AT-I421T mutants were lower than that of AT-WT, and there was no significant difference between AT-L417Q mutant and AT-WT in the supernatant.
CONCLUSION
The p.I421T and p.M252T mutations affected the secretion of AT protein leading to type I AT deficiency of probands 1 and 3. The p.Leu417Gln mutation was responsible for the impaired or ineffective activity AT protein in proband 2 and caused type II AT deficiency.
Topics: Humans; Pedigree; Antithrombin III Deficiency; Phenotype; Mutation; Antithrombins
PubMed: 36268972
DOI: 10.1002/jcla.24732 -
Molecular Ecology Resources May 2021A primary challenge in the analysis of free-ranging animal populations is the accurate estimation of relatedness among individuals. Many aspects of population analysis...
A primary challenge in the analysis of free-ranging animal populations is the accurate estimation of relatedness among individuals. Many aspects of population analysis rely on knowledge of relatedness patterns, including socioecology, demography, heritability and gene mapping analyses, wildlife conservation and the management of breeding colonies. Methods for determining relatedness using genome-wide data have improved our ability to determine kinship and reconstruct pedigrees in humans. However, methods for reconstructing complex pedigree structures and estimating distant relatedness (beyond third-degree) have not been widely applied to other species. We sequenced the genomes of 150 male rhesus macaques from the Tulane National Primate Research Center colony to estimate pairwise relatedness, reconstruct closely related pedigrees, estimate more distant relationships and augment colony records. Methods for determining relatedness developed for human genetic data were applied and evaluated in the analysis of nonhuman primates, including identity-by-descent-based methods for pedigree reconstruction and shared segment-based inference of more distant relatedness. We compared the genotype-based pedigrees and estimated relationships to available colony pedigree records and found high concordance (95.5% agreement) between expected and identified relationships for close relatives. In addition, we detected distant relationships not captured in colony records, including some as distant as twelfth-degree. Furthermore, while deep sequence coverage is preferable, we show that this approach can also provide valuable information when only low-coverage (5×) sequence data is available. Our findings demonstrate the value of these methods for determination of relatedness in various animal populations, with diverse applications to conservation biology, evolutionary and ecological research and biomedical studies.
Topics: Animals; Breeding; Chromosome Mapping; Genetics, Population; Genome; Genotype; Macaca mulatta; Male; Pedigree; Polymorphism, Single Nucleotide
PubMed: 33386679
DOI: 10.1111/1755-0998.13317 -
Genetic Epidemiology Apr 2019The transmission disequilibrium test (TDT) is the gold standard for testing the association between a genetic variant and disease in samples consisting of affected... (Comparative Study)
Comparative Study
The transmission disequilibrium test (TDT) is the gold standard for testing the association between a genetic variant and disease in samples consisting of affected individuals and their parents. In practice, more complex pedigree structures, that is siblings with no parents, or three-generational pedigrees with possibly missing genotypes, are common. There are several generalizations of the TDT that are suitable for use with arbitrary pedigree structures. We consider three such frequently used generalizations, family-based association test, pedigree disequilibrium test, and generalized disequilibrium test, that have accompanying software and compare them regarding validity and power in the single variant setting. We use simulations to study the effects of population admixture, populations whose genotypes are not in Hardy-Weinberg equilibrium (HWE), different pedigree structures, and the presence of linkage. Whereas our results show that some TDT generalizations can have a substantially increased Type 1 error, these tests are often used in substantive research without caveats about the validity of their Type 1 error. For the association analysis of rare variants in sequencing studies, region-based extensions of the TDT generalizations, that rely on the postulated robustness of the single variant tests, have been proposed. We discuss the implications of our results for these region-based extensions.
Topics: Computer Simulation; Family; Female; Gene Frequency; Genetic Association Studies; Genetic Linkage; Humans; Linkage Disequilibrium; Male; Models, Genetic; Parents; Pedigree; Software
PubMed: 30609057
DOI: 10.1002/gepi.22181 -
G3 (Bethesda, Md.) Mar 2017Maximization of genetic gain in forest tree breeding programs is contingent on the accuracy of the predicted breeding values and precision of the estimated genetic...
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 () 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.
Topics: Breeding; Genetic Markers; Genotyping Techniques; Pedigree; Picea; Pollination
PubMed: 28122953
DOI: 10.1534/g3.116.037895