Linkage Disequilibrium Statistics Research Articles

GWLD: an R package for genome-wide linkage disequilibrium analysis.

Linkage disequilibrium (LD) analysis is fundamental to the investigation of the genetic architecture of complex traits (e.g. human disease, animal and plant breeding) and population structure and evolution dynamics. However, until now, studies primarily focus on LD status between genetic variants located on the same chromosome. Moreover, genome (re)sequencing produces unprecedented numbers of genetic variants, and fast LD computation becomes a challenge. Here, we have developed GWLD, a parallelized and generalized tool designed for the rapid genome-wide calculation of LD values, including conventional D/D', r2, and (reduced) mutual information (MI and RMI) measures. LD between genetic variants within and across chromosomes can be rapidly computed and visualized in either an R package or a standalone C++ software package. To evaluate the accuracy and speed of LD calculation, we conducted comparisons using 4 real datasets. Interchromosomal LD patterns observed potentially reflect levels of selection intensity across different species. Both versions of GWLD, the R package (https://github.com/Rong-Zh/GWLD/GWLD-R) and the standalone C++ software (https://github.com/Rong-Zh/GWLD/GWLD-C++), are freely available on GitHub.

Linkage disequilibrium between rare mutations.

The statistical associations between mutations, collectively known as linkage disequilibrium, encode important information about the evolutionary forces acting within a population. Yet in contrast to single-site analogues like the site frequency spectrum, our theoretical understanding of linkage disequilibrium remains limited. In particular, little is currently known about how mutations with different ages and fitness costs contribute to expected patterns of linkage disequilibrium, even in simple settings where recombination and genetic drift are the major evolutionary forces. Here, I introduce a forward-time framework for predicting linkage disequilibrium between pairs of neutral and deleterious mutations as a function of their present-day frequencies. I show that the dynamics of linkage disequilibrium become much simpler in the limit that mutations are rare, where they admit a simple heuristic picture based on the trajectories of the underlying lineages. I use this approach to derive analytical expressions for a family of frequency-weighted linkage disequilibrium statistics as a function of the recombination rate, the frequency scale, and the additive and epistatic fitness costs of the mutations. I find that the frequency scale can have a dramatic impact on the shapes of the resulting linkage disequilibrium curves, reflecting the broad range of time scales over which these correlations arise. I also show that the differences between neutral and deleterious linkage disequilibrium are not purely driven by differences in their mutation frequencies and can instead display qualitative features that are reminiscent of epistasis. I conclude by discussing the implications of these results for recent linkage disequilibrium measurements in bacteria. This forward-time approach may provide a useful framework for predicting linkage disequilibrium across a range of evolutionary scenarios.

Evolutionary dynamics of the human pseudoautosomal regions.

Recombination between the X and Y human sex chromosomes is limited to the two pseudoautosomal regions (PARs) that present quite distinct evolutionary origins. Despite the crucial importance for male meiosis, genetic diversity patterns and evolutionary dynamics of these regions are poorly understood. In the present study, we analyzed and compared the genetic diversity of the PAR regions using publicly available genomic sequences encompassing both PAR1 and PAR2. Comparisons were performed through allele diversities, linkage disequilibrium status and recombination frequencies within and between X and Y chromosomes. In agreement with previous studies, we confirmed the role of PAR1 as a male-specific recombination hotspot, but also observed similar characteristic patterns of diversity in both regions although male recombination occurs at PAR2 to a much lower extent (at least one recombination event at PAR1 and in ≈1% in normal male meioses at PAR2). Furthermore, we demonstrate that both PARs harbor significantly different allele frequencies between X and Y chromosomes, which could support that recombination is not sufficient to homogenize the pseudoautosomal gene pool or is counterbalanced by other evolutionary forces. Nevertheless, the observed patterns of diversity are not entirely explainable by sexually antagonistic selection. A better understanding of such processes requires new data from intergenerational transmission studies of PARs, which would be decisive on the elucidation of PARs evolution and their role in male-driven heterosomal aneuploidies.

HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 allele and haplotype frequencies defined by next generation sequencing in a population of East Croatia blood donors

Next-generation sequencing (NGS) is increasingly used in transplantation settings, but also as a method of choice for in-depth analysis of population-specific HLA genetic architecture and its linkage to various diseases. With respect to complex ethnic admixture characteristic for East Croatian population, we aimed to investigate class-I (HLA-A, -B, -C) and class-II (HLA-DRB1, -DQA1, -DQB1) HLA diversity at the highest, 4-field resolution level in 120 healthy, unrelated, blood donor volunteers. Genomic DNA was extracted and HLA genotypes of class I and DQA1 genes were defined in full-length, -DQB1 from intron 1 to 3′ UTR, and -DRB1 from intron 1 to intron 4 (Illumina MiSeq platform, Omixon Twin algorithms, IMGT/HLA release 3.30.0_5). Linkage disequilibrium statistics, Hardy-Weinberg departures, and haplotype frequencies were inferred by exact tests and iterative Expectation-Maximization algorithm using PyPop 0.7.0 and Arlequin v3.5.2.2 software. Our data provide first description of 4-field allele and haplotype frequencies in Croatian population, revealing 192 class-I and class-II alleles and extended haplotypic combinations not apparent from the existing 2-field HLA reports from Croatia. This established reference database complements current knowledge of HLA diversity and should prove useful in future population studies, transplantation settings, and disease-associated HLA screening.

LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations.

Genomic research involving human genetics and evolutionary biology relies heavily on linkage disequilibrium (LD) to investigate population-specific genetic structure, functionally map regions of disease susceptibility and uncover evolutionary history. Interactive and powerful tools are needed to calculate population-specific LD estimates for integrative genomics research. LDlink is an interactive suite of web-based tools developed to query germline variants in 1000 Genomes Project population groups of interest and generate interactive tables and plots of LD estimates. As an expansion to this resource, we have developed an R package, LDlinkR, designed to rapidly calculate statistics for large lists of variants and LD attributes that eliminates the time needed to perform repetitive requests from the web-based LDlink tool. LDlinkR accelerates genomic research by providing efficient and user-friendly functions to programmatically interrogate and download pairwise LD estimates from expansive lists of genetic variants. LDlinkR is a free and publicly available R package that can be installed from the Comprehensive R Archive Network (CRAN) or downloaded from https://github.com/CBIIT/LDlinkR.

LDpop: an interactive online tool to calculate and visualize geographic LD patterns

BackgroundLinkage disequilibrium (LD)—the non-random association of alleles at different loci—defines population-specific haplotypes which vary by genomic ancestry. Assessment of allelic frequencies and LD patterns from a variety of ancestral populations enables researchers to better understand population histories as well as improve genetic understanding of diseases in which risk varies by ethnicity.ResultsWe created an interactive web module which allows for quick geographic visualization of linkage disequilibrium (LD) patterns between two user-specified germline variants across geographic populations included in the 1000 Genomes Project. Interactive maps and a downloadable, sortable summary table allow researchers to easily compute and compare allele frequencies and LD statistics of dbSNP catalogued variants. The geographic mapping of each SNP’s allele frequencies by population as well as visualization of LD statistics allows the user to easily trace geographic allelic correlation patterns and examine population-specific differences.ConclusionsLDpop is a free and publicly available cross-platform web tool which can be accessed online at https://ldlink.nci.nih.gov/?tab=ldpop

A Single-Couple Human Origin is Possible

The problem of inferring history from genetic data is complex and underdetermined; there are many possible scenarios that would explain the same data. It can be made more tractable by making reasonable simplifications to the model, but it is continually important to remember what has been demonstrated and what is merely a parsimonious working assumption. In this paper we have chosen to model the demographic ancestry of humanity using the simplest of assumptions, with a homogeneous population whose size can vary over time. All other assumptions such as the mutation rates were standard, and no natural selection was in operation. Using a previously published backwards simulation method and some newly developed and faster algorithms, we run our single-couple origin model of humanity and compare the results to allele frequency spectra and linkage disequilibrium statistics from current genetic data. We show that a single-couple origin of humanity as recent as 500kya is consistent with data. With only minor modifications of our parsimonious model assumptions, we suggest that a single-couple origin 100kya, or more recently, is possible.

Association of TSR1 Variants and Spontaneous Coronary Artery Dissection

BackgroundSpontaneous coronary artery dissection (SCAD) is defined as a splitting of the coronary artery wall exclusive of iatrogenesis or trauma. Since the last decades, our knowledge of the diagnosis and prognosis and therapy for SCAD has advanced; however, its causes remain unknown. ObjectivesThis study sought to identify genes associated with SCAD development in the Chinese Han population. MethodsBetween November 2011 and January 2018, the authors enrolled 85 SCAD cases and 296 non-SCAD controls from the Chinese Han population. All 381 subjects enrolled underwent detection with whole exome sequencing, followed by Sanger sequencing for confirmation. Principle component analysis was used to evaluate the structure of the population. Haploview was used to analyze the linkage disequilibrium statistics of the variants. The author used 2 gene-based association tests, optimal sequence kernel association test and mixed effects score test, to identify the causal genes or variants of SCAD. Immunohistochemistry was used to detect the expression of TSR1 in coronary artery tissues. ResultsFour genes with a suggestive association with SCAD (p < 5.41 × 10−5 in both the optimal sequence kernel association and mixed effects score tests) were identified, and TSR1 was the top hit. All TSR1 germline variants were either highly conserved across distinct species or lead to premature termination of protein syntheses. Furthermore, the expression of TSR1 was detectable in human coronary artery tissues. ConclusionsThis study describes the clinical characteristics of the Chinese Han population with SCAD and identified TSR1 as a potential causal gene, which might bring about a further progress in diagnosis and treatment of the disorder.

PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.

SummaryPhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates ‘phenome scans’, where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner (‘PhenoScanner V2’), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants.Availability and implementationPhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.

Mathematical Properties of Linkage Disequilibrium Statistics Defined by Normalization of the Coefficient D = pAB – pApB

Background: Many statistics for measuring linkage disequilibrium (LD) take the form of a normalization of the LD coefficient D. Different normalizations produce statistics with different ranges, interpretations, and arguments favoring their use. Methods: Here, to compare the mathematical properties of these normalizations, we consider 5 of these normalized statistics, describing their upper bounds, the mean values of their maxima over the set of possible allele frequency pairs, and the size of the allele frequency regions accessible given specified values of the statistics. Results: We produce detailed characterizations of these properties for the statistics d and ρ, analogous to computations previously performed for r². We examine the relationships among the statistics, uncovering conditions under which some of them have close connections. Conclusion: The results contribute insight into LD measurement, particularly the understanding of differences in the features of different LD measures when computed on the same data.

Evolution of genomic variation in the burrowing owl in response to recent colonization of urban areas.

When a species successfully colonizes an urban habitat it can be expected that its population rapidly adapts to the new environment but also experiences demographic perturbations. It is, therefore, essential to gain an understanding of the population structure and the demographic history of the urban and neighbouring rural populations before studying adaptation at the genome level. Here, we investigate populations of the burrowing owl (Athene cunicularia), a species that colonized South American cities just a few decades ago. We assembled a high-quality genome of the burrowing owl and re-sequenced 137 owls from three urban–rural population pairs at 17-fold median sequencing coverage per individual. Our data indicate that each city was independently colonized by a limited number of founders and that restricted gene flow occurred between neighbouring urban and rural populations, but not between urban populations of different cities. Using long-range linkage disequilibrium statistics in an approximate Bayesian computation approach, we estimated consistently lower population sizes in the recent past for the urban populations in comparison to the rural ones. The current urban populations all show reduced standing variation in rare single nucleotide polymorphisms (SNPs), but with different subsets of rare SNPs in different cities. This lowers the potential for local adaptation based on rare variants and makes it harder to detect consistent signals of selection in the genome.

A Pathway-Centered Analysis of Pig Domestication and Breeding in Eurasia.

Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9000 yr ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated and shared a variable percentage of genes. There were 12 genes present in >10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), a similarly important target trait during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably, in the case of pig, behavior played an important role, among other physiological and developmental processes.

PopFly: the Drosophila population genomics browser.

The recent compilation of over 1100 worldwide wild-derived Drosophila melanogaster genome sequences reassembled using a standardized pipeline provides a unique resource for population genomic studies (Drosophila Genome Nexus, DGN). A visual display of the estimated metrics describing genome-wide variation and selection patterns would allow gaining a global view and understanding of the evolutionary forces shaping genome variation. Here, we present PopFly, a population genomics-oriented genome browser, based on JBrowse software, that contains a complete inventory of population genomic parameters estimated from DGN data. This browser is designed for the automatic analysis and display of genetic variation data within and between populations along the D. melanogaster genome. PopFly allows the visualization and retrieval of functional annotations, estimates of nucleotide diversity metrics, linkage disequilibrium statistics, recombination rates, a battery of neutrality tests, and population differentiation parameters at different window sizes through the euchromatic chromosomes. PopFly is open and freely available at site http://popfly.uab.cat . sergi.hervas@uab.cat or antonio.barbadilla@uab.cat.

Elevated Linkage Disequilibrium and Signatures of Soft Sweeps Are Common in Drosophila melanogaster.

The extent to which selection and demography impact patterns of genetic diversity in natural populations of Drosophila melanogaster is yet to be fully understood. We previously observed that linkage disequilibrium (LD) at scales of ∼10 kb in the Drosophila Genetic Reference Panel (DGRP), consisting of 145 inbred strains from Raleigh, North Carolina, measured both between pairs of sites and as haplotype homozygosity, is elevated above neutral demographic expectations. We also demonstrated that signatures of strong and recent soft sweeps are abundant. However, the extent to which these patterns are specific to this derived and admixed population is unknown. It is also unclear whether these patterns are a consequence of the extensive inbreeding performed to generate the DGRP data. Here we analyze LD statistics in a sample of >100 fully-sequenced strains from Zambia; an ancestral population to the Raleigh population that has experienced little to no admixture and was generated by sequencing haploid embryos rather than inbred strains. We find an elevation in long-range LD and haplotype homozygosity compared to neutral expectations in the Zambian sample, thus showing the elevation in LD is not specific to the DGRP data set. This elevation in LD and haplotype structure remains even after controlling for possible confounders including genomic inversions, admixture, population substructure, close relatedness of individual strains, and recombination rate variation. Furthermore, signatures of partial soft sweeps similar to those found in the DGRP as well as partial hard sweeps are common in Zambia. These results suggest that while the selective forces and sources of adaptive mutations may differ in Zambia and Raleigh, elevated long-range LD and signatures of soft sweeps are generic in D. melanogaster.

SAMFIRE: multi-locus variant calling for time-resolved sequence data.

An increasingly common method for studying evolution is the collection of time-resolved short-read sequence data. Such datasets allow for the direct observation of rapid evolutionary processes, as might occur in natural microbial populations and in evolutionary experiments. In many circumstances, evolutionary pressure acting upon single variants can cause genomic changes at multiple nearby loci. SAMFIRE is an open-access software package for processing and analyzing sequence reads from time-resolved data, calling important single- and multi-locus variants over time, identifying alleles potentially affected by selection, calculating linkage disequilibrium statistics, performing haplotype reconstruction and exploiting time-resolved information to estimate the extent of uncertainty in reported genomic data. C ++ code may be found at https://github.com/cjri/samfire/ chris.illingworth@gen.cam.ac.uk Supplementary data are available at Bioinformatics online.

Linkage disequilibrium, SNP frequency change due to selection, and association mapping in popcorn chromosome regions containing QTLs for quality traits.

The objectives of this study were to assess linkage disequilibrium (LD) and selection-induced changes in single nucleotide polymorphism (SNP) frequency, and to perform association mapping in popcorn chromosome regions containing quantitative trait loci (QTLs) for quality traits. Seven tropical and two temperate popcorn populations were genotyped for 96 SNPs chosen in chromosome regions containing QTLs for quality traits. The populations were phenotyped for expansion volume, 100-kernel weight, kernel sphericity, and kernel density. The LD statistics were the difference between the observed and expected haplotype frequencies (D), the proportion of D relative to the expected maximum value in the population, and the square of the correlation between the values of alleles at two loci. Association mapping was based on least squares and Bayesian approaches. In the tropical populations, D-values greater than 0.10 were observed for SNPs separated by 100-150 Mb, while most of the D-values in the temperate populations were less than 0.05. Selection for expansion volume indirectly led to increase in LD values, population differentiation, and significant changes in SNP frequency. Some associations were observed for expansion volume and the other quality traits. The candidate genes are involved with starch, storage protein, lipid, and cell wall polysaccharides synthesis.

Fast Sampling-Based Whole-Genome Haplotype Block Recognition.

Scaling linkage disequilibrium (LD) based haplotype block recognition to the entire human genome has always been a challenge. The best-known algorithm has quadratic runtime complexity and, even when sophisticated search space pruning is applied, still requires several days of computations. Here, we propose a novel sampling-based algorithm, called S-MIG (++), where the main idea is to estimate the area that most likely contains all haplotype blocks by sampling a very small number of SNP pairs. A subsequent refinement step computes the exact blocks by considering only the SNP pairs within the estimated area. This approach significantly reduces the number of computed LD statistics, making the recognition of haplotype blocks very fast. We theoretically and empirically prove that the area containing all haplotype blocks can be estimated with a very high degree of certainty. Through experiments on the 243,080 SNPs on chromosome 20 from the 1,000 Genomes Project, we compared our previous algorithm MIG (++) with the new S-MIG (++) and observed a runtime reduction from 2.8 weeks to 34.8 hours. In a parallelized version of the S-MIG (++) algorithm using 32 parallel processes, the runtime was further reduced to 5.1 hours.

Genome-wide association study revealed a promising region and candidate genes for eggshell quality in an F2 resource population.

BackgroundEggshell is subject to quality loss with aging process of laying hens, and damaged eggshells result in economic losses of eggs. However, the genetic architecture underlying the dynamic eggshell quality remains elusive. Here, we measured eggshell quality traits, including eggshell weight (ESW), eggshell thickness (EST) and eggshell strength (ESS) at 11 time points from onset of laying to 72 weeks of age and conducted comprehensive genome-wide association studies (GWAS) in 1534 F2 hens derived from reciprocal crosses between White Leghorn (WL) and Dongxiang chickens (DX).ResultsESWs at all ages exhibited moderate SNP-based heritability estimates (0.30 ~ 0.46), while the estimates for EST (0.21 ~ 0.31) and ESS (0.20 ~ 0.27) were relatively low. Eleven independent univariate genome-wide screens for each trait totally identified 1059, 1026 and 1356 significant associations with ESW, EST and ESS, respectively. Most significant loci were in a region spanning from 57.3 to 71.4 Mb of chromosome 1 (GGA1), which together account for 8.4 ~ 16.5 % of the phenotypic variance for ESW from 32 to 72 weeks of age, 4.1 ~ 6.9 % and 2.95 ~ 16.1 % for EST and ESS from 40 to 72 weeks of age. According to linkage disequilibrium (LD) and conditional analysis, the significant SNPs in this region were in extremely strong linkage disequilibrium status. Ultimately, two missense SNPs in GGA1 and one in GGA4 were considered as promising loci on three independent genes including ITPR2, PIK3C2G, and NCAPG. The homozygotes of advantageously effective alleles on PIK3C2G and ITPR2 possessed the best eggshell quality and could partly counteract the negative effect of aging process. NCAPG had certain effect on eggshell quality for young hens.ConclusionsIdentification of the promising region as well as potential candidate genes will greatly advance our understanding of the genetic basis underlying dynamic eggshell quality and has the practical significance in breeding program for the improvement of eggshell quality, especially at the later part of laying cycle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1795-7) contains supplementary material, which is available to authorized users.

How Population Growth Affects Linkage Disequilibrium

The "LD curve" relates the linkage disequilibrium (LD) between pairs of nucleotide sites to the distance that separates them along the chromosome. The shape of this curve reflects natural selection, admixture between populations, and the history of population size. This article derives new results about the last of these effects. When a population expands in size, the LD curve grows steeper, and this effect is especially pronounced following a bottleneck in population size. When a population shrinks, the LD curve rises but remains relatively flat. As LD converges toward a new equilibrium, its time path may not be monotonic. Following an episode of growth, for example, it declines to a low value before rising toward the new equilibrium. These changes happen at different rates for different LD statistics. They are especially slow for estimates of [Formula: see text], which therefore allow inferences about ancient population history. For the human population of Europe, these results suggest a history of population growth.

LRRC4 haplotypes are associated with pituitary adenoma in a Chinese population

Pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations such as GNAS, MEN1, CNC, and FIPA. LRRC4 is relatively tissue-specific expressed gene in the normal brain and downregulated expression in glioma (87.5%), meningioma (80.9%), and pituitary adenoma (85.5%). It has been suggested that the aberrant expression of LRRC4 contributes to tumorigenesis in glioma. However, little is known yet about association between LRRC4 and risk of pituitary adenoma. In this study, we genotyped three LRRC4 haplotype-tagging SNPs (htSNP) by direct sequencing in case-control studies, which included 183 Han Chinese patients diagnosed with pituitary adenoma and 183 age-, gender-matched, and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNP. We observed statistically significant differences regarding the genotype TT + CT of rs6944446 in the NCA. Haplotype AC of rs3823994-rs6944446 is suggested to have a protective effect in the development of pituitary adenoma (OR 0.339; 95% CI 0.123-0.934). However, haplotype GT of rs3808058-rs6944446 (OR 1.575; 95% CI 1.048-2.368) and AGT of rs3823994-rs6944446-rs3808058 (OR 1.673; 95% CI 1.056-2.651) might be a risk factor for pituitary adenoma development. In a brief, the results support the hypothesis that polymorphisms or haplotypes in the LRRC4 may have important research significance and could be used to predict the risk of pituitary adenoma.