Extent and consistency across generations of linkage disequilibrium in commercial layer chicken breeding populations

Recent studies report a surprisingly high degree of marker-to-marker linkage disequilibrium (LD) in ruminant livestock populations. This has important implications for QTL mapping and marker-assisted selection. This study evaluated LD between microsatellite markers in a number of breeding populations of layer chickens using the standardized chi-square (chi(2')) measure. The results show appreciable LD among markers separated by up to 5 cM, decreasing rapidly with increased separation between markers. The LD within 5 cM was strongly conserved across generations and differed among chromosomal regions. Using marker-to-marker LD as an indication for marker-QTL LD, a genome scan of markers spaced 2 cM apart at moderate power would have good chances of uncovering most QTL segregating in these populations. However, of markers showing significant trait associations, only 57% are expected to be within 5 cM of the responsible QTL, and the remainder will be up to 20 cM away. Thus, high-resolution LD mapping of QTL will require dense marker genotyping across the region of interest to allow for interval mapping of the QTL.     

Markers informative for ancestry demonstrate consistent megabase-length linkage disequilibrium in the African American population

Admixture mapping is a potentially powerful tool for mapping complex genetic diseases. For application of this method, admixed individuals must have genomes composed of large segments derived intact from each founding population. Such segments are thought to be present in African Americans (AA) and should be demonstrable by examination of linkage disequilibrium (LD). Previous studies using a variety of polymorphic markers have variably reported long-range LD or rapid decay of LD. To further define the extent and characteristics of LD caused by admixture in the AA population, the current study utilized a set of 52 diallelic markers that were selected for large standard variances between putative representatives of the founder populations. LD was examined in over 250 marker-pairs, including linked markers from four different chromosomal regions and an equal number of matched unlinked comparisons. In the representative founder populations, strong LD was not observed for markers separated by more than 10 kb. In contrast, results indicated significant LD ( P<0.001, D'>0.3) in AA over large genomic segments exceeding 10 centiMorgans (cM) and 15 megabases (Mb). Only marginally significant LD was present between unlinked markers in this population, suggesting that choosing appropriate levels of significance for admixture mapping can minimize false positive results. The ability to detect LD for extended chromosomal segments in AA decayed not only as a function of the distance between markers, but also as a function of the standard variance of the markers. This examination of several genomic segments provides strong evidence that appropriate selection of informative markers is a crucial prerequisite for the application of admixture mapping to the AA population.     

Analysis of genomic admixture in Uyghur and its implication in mapping strategy

The Uyghur (UIG) population, settled in Xinjiang, China, is a population presenting a typical admixture of Eastern and Western anthropometric traits. We dissected its genomic structure at population level, individual level, and chromosome level by using 20,177 SNPs spanning nearly the entire chromosome 21. Our results showed that UIG was formed by two-way admixture, with 60% European ancestry and 40% East Asian ancestry. Overall linkage disequilibrium (LD) in UIG was similar to that in its parental populations represented in East Asia and Europe with regard to common alleles, and UIG manifested elevation of LD only within 500 kb and at a level of 0.1 相似文献   

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.     

Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.     

Methods for high-density admixture mapping of disease genes

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) has been proposed as an efficient approach to localizing disease-causing variants that differ in frequency (because of either drift or selection) between two historically separated populations. Near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease-susceptibility alleles. The central attraction of admixture mapping is that, since gene flow has occurred recently in modern populations (e.g., in African and Hispanic Americans in the past 20 generations), it is expected that admixture-generated linkage disequilibrium should extend for many centimorgans. High-resolution marker sets are now becoming available to test this approach, but progress will require (a). computational methods to infer ancestral origin at each point in the genome and (b). empirical characterization of the general properties of linkage disequilibrium due to admixture. Here we describe statistical methods to estimate the ancestral origin of a locus on the basis of the composite genotypes of linked markers, and we show that this approach accurately estimates states of ancestral origin along the genome. We apply this approach to show that strong admixture linkage disequilibrium extends, on average, for 17 cM in African Americans. Finally, we present power calculations under varying models of disease risk, sample size, and proportions of ancestry. Studying approximately 2500 markers in approximately 2500 patients should provide power to detect many regions contributing to common disease. A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations.     

Patterns of diversity and linkage disequilibrium within the cosmopolitan inversion In(3R)Payne in Drosophila melanogaster are indicative of coadaptation

The cosmopolitan inversion In(3R)Payne in Drosophila melanogaster decreases in frequency with increasing distance from the equator on three continents, indicating it is subject to strong natural selection. We investigated patterns of genetic variation and linkage disequilibrium (LD) in 24 molecular markers located within and near In(3R)Payne to determine if different parts of the inversion responded to selection the same way. We found reduced variation in the markers we used compared to others distributed throughout the genome, consistent with the inversion having a relatively recent origin (相似文献   

Refining the genetic portrait of Portuguese Roma through X-chromosomal markers

Due to differences in transmission between X-chromosomal and autosomal DNA, the comparison of data derived from both markers allows deeper insight into the forces that shape the patterns of genetic diversity in populations. In this study, we applied this comparative approach to a sample of Portuguese Roma (Gypsies) by analyzing 43 X-chromosomal markers and 53 autosomal markers. Portuguese individuals of non-Gypsy ancestry were also studied. Compared with the host population, reduced levels of diversity on the X chromosome and autosomes were detected in Gypsies; this result was in line with known patterns of genetic diversity typical of Roma groups. As a consequence of the complex demographic past of the Roma, during which admixture and genetic drift played major roles, the amount of linkage disequilibrium (LD) on the X chromosome in Gypsies was considerably higher than that observed in non-Gypsies. When the pattern of differentiation on the X chromosome was compared with that of autosomes, there was evidence for asymmetries in female and male effective population sizes during the admixture between Roma and non-Roma. This result supplements previous data provided by mtDNA and the Y chromosome, underlining the importance of using combined information from the X chromosome and autosomes to dissect patterns of genetic diversity. Following the out-of-India dispersion, the Roma acquired a complex genetic pattern that was influenced by drift and introgression with surrounding populations, with important contributions from both males and females. We provide evidence that a sex-biased admixture with Europeans is probably associated with the founding of the Portuguese Gypsies.     

Temporal dynamics of linkage disequilibrium in two populations of bighorn sheep

Linkage disequilibrium (LD) is the nonrandom association of alleles at two markers. Patterns of LD have biological implications as well as practical ones when designing association studies or conservation programs aimed at identifying the genetic basis of fitness differences within and among populations. However, the temporal dynamics of LD in wild populations has received little empirical attention. In this study, we examined the overall extent of LD, the effect of sample size on the accuracy and precision of LD estimates, and the temporal dynamics of LD in two populations of bighorn sheep (Ovis canadensis) with different demographic histories. Using over 200 microsatellite loci, we assessed two metrics of multi‐allelic LD, D′, and χ^′2. We found that both populations exhibited high levels of LD, although the extent was much shorter in a native population than one that was founded via translocation, experienced a prolonged bottleneck post founding, followed by recent admixture. In addition, we observed significant variation in LD in relation to the sample size used, with small sample sizes leading to depressed estimates of the extent of LD but inflated estimates of background levels of LD. In contrast, there was not much variation in LD among yearly cross‐sections within either population once sample size was accounted for. Lack of pronounced interannual variability suggests that researchers may not have to worry about interannual variation when estimating LD in a population and can instead focus on obtaining the largest sample size possible.     

Detecting population structure using STRUCTURE software: effect of background linkage disequilibrium

STRUCTURE is the most widely used clustering software to detect population genetic structure. The last version of this software (STRUCTURE 2.1) has been enhanced recently to take into account the occurrence of linkage disequilibrium (LD) caused by admixture between populations. This last version, however, still does not consider the effects of strong background LD caused by genetic drift, and which may cause spurious results. STRUCTURE authors have, therefore, suggested a rough threshold value of the distance (1.0 cM) between two loci below which the pair of loci should not be used. Because of the sensitiveness of LD to demographic events, the distance between loci is not always a good indicator of the strength of LD. In this study, we examine the link between genomic distance and the strength of the correlation between loci (r(LD)) in a free-ranging population of mouflon (Ovis aries), and we present an empirical test of effect of r(LD) on the clustering results provided by the linkage model in STRUCTURE. We showed that a high r(LD) value increases the probability of detecting spurious clustering. We propose to use r(LD) as an index to base a decision on whether or not to use a pair of loci in a clustering analysis.     

Demography,recombination hotspot intensity,and the block structure of linkage disequilibrium

BACKGROUND: Effective gene mapping based on genetic association data will require detailed knowledge of patterns of linkage disequilibrium (LD) in human populations. It has been recently suggested that linkage disequilibrium in humans may be organized in a block-like structure, with islands of high LD separated by regions of rapid breakdown of LD due to recombination hotspots. The experimental data to date, however, are limited, and fundamental questions remain about the implications of recombination rate heterogeneity. Here, we use computer simulations to evaluate how such heterogeneity influences patterns of LD, and we develop formal criteria to assess whether the patterns are functionally block like in the context of association mapping.RESULTS: Our analyses suggest that, even in models of extreme recombination rate heterogeneity, some human populations will have a functionally block-like structure to the pattern of LD, but others will not, depending on their precise demographic histories. In fact, for many models, we find that, following an LD-generating event, populations may move through discrete phases that can be functionally described as pre-block, block, and post-block. An analysis of observed and expected patterns of LD surrounding hotspots within the MHC Class II region confirms these theoretical expectations.CONCLUSIONS: Even if highly punctuated patterns of recombination are the rule, patterns of LD are still likely to show differences among populations and among genomic regions that are of practical importance in the design of genetic association studies. The notion that the average extent of LD is a useful concept for the design of association studies must be abandoned in light of the experimental and theoretical evidence.     

Divergence between Human Populations Estimated from Linkage Disequilibrium

Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to ~0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or ~25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time.     

The distribution of long range admixture linkage disequilibrium in an African-American population

OBJECTIVES: To better understand the effect of admixture on long range linkage disequilibrium (LD), we characterized extended LD in gene-rich regions of an African-American population. METHODS: Approximately 290 cM of chromosomes 1, 3, 6, 11-17, 20 and 22 were scanned using 109 polymorphic microsatellite markers spaced an average of 3 cM apart. Disequilibrium between loci (D') was based on maximum-likelihood estimates of haplotype frequencies computed for 200 unrelated African Americans. RESULTS: Mean D' values were highest on chromosomes 6p23-p21.3 (D' = 0.33) and 15p22.2-p25.3 (D' = 0.34), and lowest on chromosome 12p11.2-q14 (D' = 0.21). Overall, the variance in LD among chromosomes accounted for approximately two-thirds of the total LD variance. Of the 434 locus pairs spaced between 0.3 and 38.7 cM apart, there was no detectable correlation between LD and recombination distance and a weak negative correlation between LD and physical distance (r(s) = -0.12; p = 0.031). For the 192 intrachromosomal locus pairs where allele frequency data were available from the Centre d'Etude du Polymorphisme humain (CEPH), we found a statistically significant positive correlation between LD and the allelic frequency differences (delta) between the African-American study population and Caucasian reference CEPH population (r(s) = 0.53; p < 0.0001). The correlation between LD and both recombination and physical distance was markedly increased for locus pairs with high delta levels. CONCLUSIONS: Our results suggest that recent Caucasian admixture maintains a high level of long range LD in African Americans on a genomic scale, and selected markers with large African American/Caucasian delta levels may be useful in association studies.     

Signatures of demographic history and natural selection in the human major histocompatibility complex Loci

Many lines of evidence show that several HLA loci have experienced balancing selection. However, distinguishing among demographic and selective explanations for patterns of variation observed with HLA genes remains a challenge. In this study we address this issue using data from a diverse set of human populations at six classical HLA loci and, employing a comparative genomics approach, contrast results for HLA loci to those for non-HLA markers. Using a variety of analytic methods, we confirm and extend evidence for selection acting on several HLA loci. We find that allele frequency distributions for four of the six HLA loci deviate from neutral expectations and show that this is unlikely to be explained solely by demographic factors. Other features of HLA variation are explained in part by demographic history, including decreased heterozygosity and increased LD for populations at greater distances from Africa and a similar apportionment of genetic variation for HLA loci compared to putatively neutral non-HLA loci. On the basis of contrasts among different HLA loci and between HLA and non-HLA loci, we conclude that HLA loci bear detectable signatures of both natural selection and demographic history.     

Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica

We report a comparative genetic characterization of two population isolates with parallel demographic histories: the Central Valley of Costa Rica (CVCR) and Antioquia (in northwest Colombia). The analysis of mtDNA, Y-chromosome and autosomal polymorphisms shows that Antioquia and the CVCR are genetically very similar, indicating that closely related parental populations founded these two isolates. In both populations, the male ancestry is predominantly European, whereas the female ancestry is mostly Amerind. In agreement with their isolation, the Amerindian mtDNA diversity of Antioquia and the CVCR is typical of ethnically-defined native populations and is markedly lower than in other Latin American populations. A comparison of linkage disequilibrium (LD) at 18 marker pairs in Antioquia and the CVCR shows that markers in LD in both populations are located at short genetic distances (相似文献   

Y chromosomes traveling south: the cohen modal haplotype and the origins of the Lemba--the "Black Jews of Southern Africa"

The Lemba are a traditionally endogamous group speaking a variety of Bantu languages who live in a number of locations in southern Africa. They claim descent from Jews who came to Africa from "Sena." "Sena" is variously identified by them as Sanaa in Yemen, Judea, Egypt, or Ethiopia. A previous study using Y-chromosome markers suggested both a Bantu and a Semitic contribution to the Lemba gene pool, a suggestion that is not inconsistent with Lemba oral tradition. To provide a more detailed picture of the Lemba paternal genetic heritage, we analyzed 399 Y chromosomes for six microsatellites and six biallelic markers in six populations (Lemba, Bantu, Yemeni-Hadramaut, Yemeni-Sena, Sephardic Jews, and Ashkenazic Jews). The high resolution afforded by the markers shows that Lemba Y chromosomes are clearly divided into Semitic and Bantu clades. Interestingly, one of the Lemba clans carries, at a very high frequency, a particular Y-chromosome type termed the "Cohen modal haplotype," which is known to be characteristic of the paternally inherited Jewish priesthood and is thought, more generally, to be a potential signature haplotype of Judaic origin. The Bantu Y-chromosome samples are predominantly (>80%) YAP+ and include a modal haplotype at high frequency. Assuming a rapid expansion of the eastern Bantu, we used variation in microsatellite alleles in YAP+ sY81-G Bantu Y chromosomes to calculate a rough date, 3,000-5,000 years before the present, for the start of their expansion.     

Linkage analysis of a complex disease through use of admixed populations

Linkage disequilibrium arising from the recent admixture of genetically distinct populations can be potentially useful in mapping genes for complex diseases. McKeigue has proposed a method that conditions on parental admixture to detect linkage. We show that this method tests for linkage only under specific assumptions, such as equal admixture in the parental generation and admixture that occurs in a single generation. In practice, these assumptions are unlikely to hold for natural populations, resulting in an inflation of the type I error rate when testing for linkage by this method. In this article, we generalize McKeigue's approach of testing for linkage to allow two different admixture models: (1) intermixture admixture and (2) continuous gene flow. We calculate the sample size required for a genomewide search by this method under different disease models: multiplicative, additive, recessive, and dominant. Our results show that the sample size required to obtain 90% power to detect a putative mutant allele at a genomewide significance level of 5% can usually be achieved in practice if informative markers are available at a density of 2 cM.     

Design and analysis of admixture mapping studies

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.     

Population divergence with or without admixture: selecting models using an ABC approach

Genetic data have been widely used to reconstruct the demographic history of populations, including the estimation of migration rates, divergence times and relative admixture contribution from different populations. Recently, increasing interest has been given to the ability of genetic data to distinguish alternative models. One of the issues that has plagued this kind of inference is that ancestral shared polymorphism is often difficult to separate from admixture or gene flow. Here, we applied an approximate Bayesian computation (ABC) approach to select the model that best fits microsatellite data among alternative splitting and admixture models. We performed a simulation study and showed that with reasonably large data sets (20 loci) it is possible to identify with a high level of accuracy the model that generated the data. This suggests that it is possible to distinguish genetic patterns due to past admixture events from those due to shared polymorphism (population split without admixture). We then apply this approach to microsatellite data from an endangered and endemic Iberian freshwater fish species, in which a clustering analysis suggested that one of the populations could be admixed. In contrast, our results suggest that the observed genetic patterns are better explained by a population split model without admixture.