Genome-wide Patterns Of Linkage Disequilibrium Research Articles

Consequences of domestication in eastern oyster: Insights from whole genomic analyses.

Selective breeding for production traits has yielded relatively rapid successes with high-fecundity aquaculture species. Discovering the genetic changes associated with selection is an important goal for understanding adaptation and can also facilitate better predictions about the likely fitness of selected strains if they escape aquaculture farms. Here, we hypothesize domestication as a genetic change induced by inadvertent selection in culture. Our premise is that standardized culture protocols generate parallel domestication effects across independent strains. Using eastern oyster as a model and a newly developed 600K SNP array, this study tested for parallel domestication effects in multiple independent selection lines compared with their progenitor wild populations. A single contrast was made between pooled selected strains (1-17 generations in culture) and all wild progenitor samples combined. Population structure analysis indicated rank order levels of differentiation as [wild - wild] < [wild - cultured] < [cultured - cultured]. A genome scan for parallel adaptation to the captive environment applied two methodologically distinct outlier tests to the wild versus selected strain contrast and identified a total of 1174 candidate SNPs. Contrasting wild versus selected strains revealed the early evolutionary consequences of domestication in terms of genomic differentiation, standing genetic diversity, effective population size, relatedness, runs of homozygosity profiles, and genome-wide linkage disequilibrium patterns. Random Forest was used to identify 37 outlier SNPs that had the greatest discriminatory power between bulked wild and selected oysters. The outlier SNPs were in genes enriched for cytoskeletal functions, hinting at possible traits under inadvertent selection during larval culture or pediveliger setting at high density. This study documents rapid genomic changes stemming from hatchery-based cultivation of eastern oysters, identifies candidate loci responding to domestication in parallel among independent aquaculture strains, and provides potentially useful genomic resources for monitoring interbreeding between farm and wild oysters.

Local fitness and epistatic effects lead to distinct patterns of linkage disequilibrium in protein-coding genes.

Selected mutations interfere and interact with evolutionary processes at nearby loci, distorting allele frequency trajectories and creating correlations between pairs of mutations. Recent studies have used patterns of linkage disequilibrium between selected variants to test for selective interference and epistatic interactions, with some disagreement over interpreting observations from data. Interpretation is hindered by a lack of analytic or even numerical expectations for patterns of variation between pairs of loci under the combined effects of selection, dominance, epistasis, and demography. Here, I develop a numerical approach to compute the expected two-locus sampling distribution under diploid selection with arbitrary epistasis and dominance, recombination, and variable population size. I use this to explore how epistasis and dominance affect expected signed linkage disequilibrium, including for nonsteady-state demography relevant to human populations. Using whole-genome sequencing data from humans, I explore genome-wide patterns of linkage disequilibrium within protein-coding genes. I show that positive linkage disequilibrium between missense mutations within genes is driven by strong positive allele-frequency correlations between mutations that fall within the same annotated conserved domain, pointing to compensatory mutations or antagonistic epistasis as the prevailing mode of interaction within conserved genic elements. Linkage disequilibrium between missense mutations is reduced outside of conserved domains, as expected under Hill-Robertson interference. This variation in both mutational fitness effects and selective interactions within protein-coding genes calls for more refined inferences of the joint distribution of fitness and interactive effects, and the methods presented here should prove useful in that pursuit.

Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.

Recombination Rate Variation and Infrequent Sex Influence Genetic Diversity in Chlamydomonas reinhardtii.

Recombination confers a major evolutionary advantage by breaking up linkage disequilibrium between harmful and beneficial mutations, thereby facilitating selection. However, in species that are only periodically sexual, such as many microbial eukaryotes, the realized rate of recombination is also affected by the frequency of sex, meaning that infrequent sex can increase the effects of selection at linked sites despite high recombination rates. Despite this, the rate of sex of most facultatively sexual species is unknown. Here, we use genomewide patterns of linkage disequilibrium to infer fine-scale recombination rate variation in the genome of the facultatively sexual green alga Chlamydomonas reinhardtii. We observe recombination rate variation of up to two orders of magnitude and find evidence of recombination hotspots across the genome. Recombination rate is highest flanking genes, consistent with trends observed in other nonmammalian organisms, though intergenic recombination rates vary by intergenic tract length. We also find a positive relationship between nucleotide diversity and physical recombination rate, suggesting a widespread influence of selection at linked sites in the genome. Finally, we use estimates of the effective rate of recombination to calculate the rate of sex that occurs in natural populations, estimating a sexual cycle roughly every 840 generations. We argue that the relatively infrequent rate of sex and large effective population size creates a population genetic environment that increases the influence of selection on linked sites across the genome.

Genotyping by sequencing provides new insights into the diversity of Napier grass (Cenchrus purpureus) and reveals variation in genome-wide LD patterns between collections

Napier grass is an important tropical forage-grass and of growing potential as an energy crop. One-hundred-five Napier grass accessions, encompassing two independent collections, were subjected to genotyping by sequencing which generated a set of high-density genome-wide markers together with short sequence reads. The reads, averaging 54 nucleotides, were mapped to the pearl millet genome and the closest genes and annotation information were used to select candidate genes linked to key forage traits. 980 highly polymorphic SNP markers, distributed across the genome, were used to assess population structure and diversity with seven-subgroups identified. A few representative accessions were selected with the objective of distributing subsets of a manageable size for further evaluation. Genome-wide linkage disequilibrium (LD) analyses revealed a fast LD-decay, on average 2.54 kbp, in the combined population with a slower LD-decay in the ILRI collection compared with the EMBRAPA collection, the significance of which is discussed. This initiative generated high-density markers with a good distribution across the genome. The diversity analysis revealed the existence of a substantial amount of variation in the ILRI collection and identified some unique materials from the EMBRAPA collection, demonstrating the potential of the overall population for further genetic and marker-trait-association studies.

Genomic signatures of selection in cattle through variation of allele frequencies and linkage disequilibrium

The aim of this study was to evaluate the impact of artificial selection on Slovak Spotted and Slovak Pinzgau genomes through identification of selection signatures and to characterize most important genomic regions reflecting the selective breeding for traits of interest during the formation of those breeds. The genotyping data for in total of 236 animals were included in this study. Two approaches were used to identify genomic footprints of selection: Wright's FST statistic and variation in genome-wide linkage disequilibrium patterns between selected populations. Based on applied methods, in total of 18 genomic regions under strong selection pressure were detected across 10 autosomes (BTA 4, MTA5, BTA6, BTA7, BTA11, BTA12, BTA20, BTA22, and BTA23). The longest region was identified on BTA6 close to genes affecting milk production and coat colour pattern, while the shortest one was found on BTA11. In addition, inside the identified regions some of the other genes affecting the milk production traits (casein family, HAL, IGF1, ABCG2, SPP1), carcass traits and body composition (MYBPC1, MYH9, PACRGL), reproduction (AMDHD1), temperament (SNRPF), and coat colour (KIT, KDR) were found. Because of this, all of the detected regions can be attributed mostly to improvement of milk production and muscle development, thus selection for dual-purpose performance.

Fast Ordered Sampling of DNA Sequence Variants.

Explosive growth in the amount of genomic data is matched by increasing power of consumer-grade computers. Even applications that require powerful servers can be quickly tested on desktop or laptop machines if we can generate representative samples from large data sets. I describe a fast and memory-efficient implementation of an on-line sampling method developed for tape drives 30 years ago. Focusing on genotype files, I test the performance of this technique on modern solid-state and spinning hard drives, and show that it performs well compared to a simple sampling scheme. I illustrate its utility by developing a method to quickly estimate genome-wide patterns of linkage disequilibrium (LD) decay with distance. I provide open-source software that samples loci from several variant format files, a separate program that performs LD decay estimates, and a C++ library that lets developers incorporate these methods into their own projects.

Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies

Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.

A comprehensive linkage map of the dog genome.

We have leveraged the reference sequence of a boxer to construct the first complete linkage map for the domestic dog. The new map improves access to the dog's unique biology, from human disease counterparts to fascinating evolutionary adaptations. The map was constructed with approximately 3000 microsatellite markers developed from the reference sequence. Familial resources afforded 450 mostly phase-known meioses for map assembly. The genotype data supported a framework map with approximately 1500 loci. An additional approximately 1500 markers served as map validators, contributing modestly to estimates of recombination rate but supporting the framework content. Data from approximately 22,000 SNPs informing on a subset of meioses supported map integrity. The sex-averaged map extended 21 M and revealed marked region- and sex-specific differences in recombination rate. The map will enable empiric coverage estimates and multipoint linkage analysis. Knowledge of the variation in recombination rate will also inform on genomewide patterns of linkage disequilibrium (LD), and thus benefit association, selective sweep, and phylogenetic mapping approaches. The computational and wet-bench strategies can be applied to the reference genome of any nonmodel organism to assemble a de novo linkage map.

Molecular diversity and genome-wide linkage disequilibrium patterns in a worldwide collection of Oryza sativa and its wild relatives

Genetic diversity analysis within a species is vital for understanding evolutionary processes at the population and genomic levels. We report a detailed study of molecular diversity, polymorphism and linkage disequilibrium in three groups of rice (Oryza) germplasm accessions based on 176 SSR markers. The first group included 65 rice (O. sativa L.) accessions introduced from seven countries, including five regions of China. The second group included 58 US rice varieties released in the past 25 years. The third group consisted of 54 accessions of rice wild relatives represented by ten different species. The number of alleles per SSR marker ranged from 4 to 32 with a mean of 16 alleles and the polymorphism information content values ranged from 0.43 to 0.91 with a mean of 0.70. The variation in SSR alleles was a significant contribution to the genetic discrimination of the 177 accessions within the three Oryza groups. Analysis of molecular variance identified deviation from Hardy–Weinberg equilibrium. Principal coordinates analysis clearly separated the accessions into their respective three groups. Neighbor-joining phylogenetic cluster reflects the ordination of each accession. Linkage disequilibrium (D′) averaged 0.75 in wild Oryza spp., and about 0.5 in both US and international O. sativa accessions. Our results showed that LD among adjacent loci in both O. sativa and Oryza spp. accessions is strong enough to be detecting marker-trait association via genome-wide scans.

Extent and Distribution of Linkage Disequilibrium in Three Genomic Regions

The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.

Consistent Long-Range Linkage Disequilibrium Generated by Admixture in a Bantu-Semitic Hybrid Population

Both the optimal marker density for genome scans in case-control association studies and the appropriate study design for the testing of candidate genes depend on the genomic pattern of linkage disequilibrium (LD). In this study, we provide the first conclusive demonstration that the diverse demographic histories of human populations have produced dramatic differences in genomewide patterns of LD. Using a panel of 66 markers spanning the X chromosome, we show that, in the Lemba, a Bantu-Semitic hybrid population, markers </= approximately 21 cM apart have a significantly greater tendency to show LD than do unlinked markers. In three populations with less evidence of admixture, however, excess LD disappears >2 cM. Moreover, analysis of Bantu and Ashkenazi populations as putative parental populations of the Lemba shows a significant relationship between allele-frequency differentials and the LD observed in the Lemba, which demonstrates that much of the excess LD is due to admixture. Our results suggest that demographic history has such a profound effect on LD that it will not be possible to predict patterns a priori but that it will be necessary to empirically evaluate the patterns in all populations of interest.