scholarly journals The impact of identity by descent on fitness and disease in dogs

2021 ◽  
Vol 118 (16) ◽  
pp. e2019116118
Author(s):  
Jazlyn A. Mooney ◽  
Abigail Yohannes ◽  
Kirk E. Lohmueller
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Mendelian Inheritance ◽  
Population Bottlenecks ◽  
Runs Of Homozygosity ◽  
Recent Past ◽  
Identity By Descent ◽  
Causal Variants ◽  
Future Work ◽  
The Impact

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves, and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in the Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs and that future work on understudied breeds may reveal new disease-causing variation.

scholarly journals The impact of identity-by-descent on fitness and disease in natural and domesticated Canid populations

2020 ◽  
Author(s):  
Jazlyn A. Mooney ◽  
Abigail Yohannes ◽  
Kirk E. Lohmueller
Keyword(s):  
Inbreeding Depression ◽  
Artificial Selection ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Mendelian Inheritance ◽  
New Disease ◽  
Identity By Descent ◽  
Victorian Era ◽  
Causal Variants ◽  
The Impact

AbstractDomestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and phenotype data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs, and that there remains an excess of understudied breeds that can reveal new disease-causing variation.Significance StatementDogs and humans have coexisted together for thousands of years, but it was not until the Victorian Era that humans practiced selective breeding to produce the modern standards we see today. Strong artificial selection during the breed formation period has simplified the genetic architecture of complex traits and caused an enrichment of identity-by-descent (IBD) segments in the dog genome. This study demonstrates the value of IBD segments and utilizes them to infer the recent demography of canids, predict case-control status for complex traits, locate regions of the genome potentially linked to inbreeding depression, and to identify understudied breeds where there is potential to discover new disease-associated variants.

scholarly journals High-resolution population structure and runs of homozygosity reveal the genetic architecture of complex traits in the Lipizzan horse

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Gertrud Grilz-Seger ◽  
Thomas Druml ◽  
Markus Neuditschko ◽  
Max Dobretsberger ◽  
Michaela Horna ◽  
...  
Keyword(s):  
Population Structure ◽  
High Resolution ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Runs Of Homozygosity

scholarly journals Detection and quantification of inbreeding depression for complex traits from SNP data

2017 ◽  
Vol 114 (32) ◽  
pp. 8602-8607 ◽  
Author(s):  
Loic Yengo ◽  
Zhihong Zhu ◽  
Naomi R. Wray ◽  
Bruce S. Weir ◽  
Jian Yang ◽  
...  
Keyword(s):  
Inbreeding Depression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Handgrip Strength ◽  
Uk Biobank ◽  
Snp Data ◽  
Causal Variants ◽  
Auditory Acuity ◽  
The Uk ◽  
Detection And Quantification

Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between −2.3 and −5.2 phenotypic SDs for complete inbreeding; P<0.001). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data.

scholarly journals SparsePro: an efficient genome-wide fine-mapping method integrating summary statistics and functional annotations

2021 ◽  
Author(s):  
Wenmin Zhang ◽  
Hamed S Najafabadi ◽  
Yue Li
Keyword(s):  
Fine Mapping ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Association Studies ◽  
Computational Cost ◽  
Mapping Method ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Genome Wide ◽  
Causal Variants

Identifying causal variants from genome-wide association studies (GWASs) is challenging due to widespread linkage disequilibrium (LD). Functional annotations of the genome may help prioritize variants that are biologically relevant and thus improve fine-mapping of GWAS results. However, classical fine-mapping methods have a high computational cost, particularly when the underlying genetic architecture and LD patterns are complex. Here, we propose a novel approach, SparsePro, to efficiently conduct functionally informed statistical fine-mapping. Our method enjoys two major innovations: First, by creating a sparse low-dimensional projection of the high-dimensional genotype, we enable a linear search of causal variants instead of an exponential search of causal configurations used in existing methods; Second, we adopt a probabilistic framework with a highly efficient variational expectation-maximization algorithm to integrate statistical associations and functional priors. We evaluate SparsePro through extensive simulations using resources from the UK Biobank. Compared to state-of-the-art methods, SparsePro achieved more accurate and well-calibrated posterior inference with greatly reduced computation time. We demonstrate the utility of SparsePro by investigating the genetic architecture of five functional biomarkers of vital organs. We identify potential causal variants contributing to the genetically encoded coordination mechanisms between vital organs and pinpoint target genes with potential pleiotropic effects. In summary, we have developed an efficient genome-wide fine-mapping method with the ability to integrate functional annotations. Our method may have wide utility in understanding the genetics of complex traits as well as in increasing the yield of functional follow-up studies of GWASs.

scholarly journals De novo mutation in ancestral generations evolves haplotypes contributing to disease

2020 ◽  
Author(s):  
Zeynep Coban-Akdemir ◽  
Xiaofei Song ◽  
Davut Pehlivan ◽  
Ender Karaca ◽  
Yavuz Bayram ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Architecture ◽  
Rare Variants ◽  
De Novo ◽  
Middle Eastern ◽  
Inbreeding Coefficient ◽  
De Novo Mutation ◽  
Runs Of Homozygosity ◽  
Identity By Descent ◽  
Disease Phenotypes

SummaryWe investigated the influences of admixture and consanguinity on the genetic architecture of disease by generating a database of variants derived from exome sequencing (ES) of 853 unrelated Turkish (TK) individuals with different disease phenotypes. We observed that TK genomes are more similar to Europeans with 69.3% of the unique variants (N = 356,613) not present in the Greater Middle Eastern variome. We found higher inbreeding coefficient values in the TK cohort correlating with a larger median span of long-sized (>1.606 Mb) runs of homozygosity (ROH). We show that long-sized ROHs arose from recently configured haplotypes and are enriched for rare homozygous deleterious variants. Such haplotypes, and the combinatorial effect of their embedded ultra-rare variants, provide the most explanatory molecular diagnoses for the TK individuals’ observed disease traits. Such haplotype evolution results in homozygosity of disease associated haplotypes due to identity-by-descent in a family or extended clan.

scholarly journals SparsePro: an efficient genome-wide fine-mapping method integrating summary statistics and functional annotations

2022 ◽  
Author(s):  
Wenmin Zhang ◽  
Hamed Najafabadi ◽  
Yue Li
Keyword(s):  
Fine Mapping ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Association Studies ◽  
Computational Cost ◽  
Mapping Method ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Genome Wide ◽  
Causal Variants

Abstract Identifying causal variants from genome-wide association studies (GWASs) is challenging due to widespread linkage disequilibrium (LD). Functional annotations of the genome may help prioritize variants that are biologically relevant and thus improve fine-mapping of GWAS results. However, classical fine-mapping methods have a high computational cost, particularly when the underlying genetic architecture and LD patterns are complex. Here, we propose a novel approach, SparsePro, to efficiently conduct genome-wide fine-mapping. Our method enjoys two major innovations: First, by creating a sparse low-dimensional projection of the high-dimensional genotype data, we enable a linear search of causal variants instead of a combinatorial search of causal configurations used in most existing methods; Second, we adopt a probabilistic framework with a highly efficient variational expectation-maximization algorithm to integrate statistical associations and functional priors. We evaluate SparsePro through extensive simulations using resources from the UK Biobank. Compared to state-of-the-art methods, SparsePro achieved more accurate and well-calibrated posterior inference with greatly reduced computation time. We demonstrate the utility of SparsePro by investigating the genetic architecture of five functional biomarkers of vital organs. We show that, compared to other methods, the causal variants identified by SparsePro are highly enriched for expression quantitative trait loci and explain a larger proportion of trait heritability. We also identify potential causal variants contributing to the genetically encoded coordination mechanisms between vital organs, and pinpoint target genes with potential pleiotropic effects. In summary, we have developed an efficient genome-wide fine-mapping method with the ability to integrate functional annotations. Our method may have wide utility in understanding the genetics of complex traits as well as in increasing the yield of functional follow-up studies of GWASs. SparsePro software is available on GitHub at https://github.com/zhwm/SparsePro.

scholarly journals Assortative Mating Biases Marker-based Heritability Estimators

2021 ◽  
Author(s):  
Richard Border ◽  
Sean O'Rourke ◽  
Teresa de Candia ◽  
Michael E Goddard ◽  
Peter M Visscher ◽  
...  
Keyword(s):  
Assortative Mating ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Molecular Genetic ◽  
Simulation Based ◽  
Theoretical Predictions ◽  
Causal Variants ◽  
The Uk ◽  
Moments Estimators ◽  
Biased Estimates

Many complex traits are subject to assortative mating (AM), with recent molecular genetic findings confirming longstanding theoretical predictions that AM alters genetic architecture by inducing long range dependence across causal variants. However, all marker-based heritability estimators assume mating is random. We provide mathematical and simulation-based evidence demonstrating that both method-of-moments estimators and likelihood-based estimators produce biased estimates in the presence of AM and that common approaches to account for population structure fail to mitigate this bias. Then, examining height and educational attainment in the UK Biobank, we demonstrate that these biases affect real world traits. Finally, we derive corrected heritability estimators for traits under equilibrium AM.

The Impact of BRICS in Reconstructing the International Order

2020 ◽  
pp. 87
Author(s):  
Tareq Mohammed Dhannoon AL Taie
Keyword(s):  
International System ◽  
Political Influence ◽  
Active Role ◽  
International Order ◽  
First Century ◽  
International Affairs ◽  
Strategic Action ◽  
Brics Countries ◽  
Future Work ◽  
The Impact

The BRICS countries have a historical aspiration for global leadership, especially Russia and China, and other countries trying to have a position in the pyramid of international powers in the twenty-first century, especially Brazil, India and South Africa, they worked to unify their efforts, in order to achieve integration in the strategic action, activate its role in International affairs, ending American domination , and restructuring an international system that have an active role in its interactions.       The research hypothesis is based on the idea that the BRICS group, despite the nature of its economic composition and its long-term goals, but its political influence as a bloc, is greater than the proportion of its economic influence in restructuring the new international order. The BRICS group has the capabilities to reshape the international order, but disputes among some of its members represent a challenge to its future work. Its goals will not be achieved without teamwork. Third world countries, especially those that reject unipolarism, have regarded one of the pillars supporting multi-polarity, aiming of giving them freedom of movement in international relations. The ultimate goal of the BRICS is a political nature, as economic mechanisms are used to achieve political goals.

Economic Structure of Pakistan.—By Khawaja Amjad Saeed. Accountancy and Taxation Service Institute, Lahore, 1977. pp. 396.

1978 ◽  
Vol 17 (2) ◽  
pp. 264-265
Author(s):  
Moin-ud-din Moin-ud-din
Keyword(s):  
Foreign Aid ◽  
Statistical Data ◽  
International Comparisons ◽  
Balance Of Payments ◽  
Development Effort ◽  
Recent Past ◽  
World Economic ◽  
World Economic Order ◽  
The Impact ◽  
Vast Range

A number of books on Pakistan's economy have recently been published, but most of them do hot provide the latest statistical data or keep pace with events and development during the 1970's. The book under review, however, has admirably fulfilled the requirements. It covers a vast range of subjects concerning economic development in the country during the recent past The book is divided into nine parts and covers such diverse areas as development, industry, the price situation and the impact of inflation, Pakistan's planning and development effort, trade priorities and balance of payments situation, .taxation* foreign aid, and socio-economic reforms. The analysis is general, broadbased, and historical in perspective and a large amount of data have been put together. To bring out a clearer picture international comparisons are made whereever possible, especially in the last part of the book where the author reiterates on the need for a "New World Economic Order".

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