Admixture Linkage Disequilibrium Research Articles

Estimating the timing of multiple admixture events using 3-locus linkage disequilibrium.

Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions. However, to estimate admixture times, spatial information from admixed chromosomes of local ancestry or the decay of admixture linkage disequilibrium (ALD) is used. One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. To address this limitation, we derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we evaluate the performance of this method on a range of different admixture histories. As an example, we apply the method to the Colombian and Mexican samples from the 1000 Genomes project. The implementation of our method is available at https://github.com/Genomics-HSE/LaNeta.

Admixture Mapping in African Americans Identifies New Risk Loci for HCV-Related Cirrhosis

Cirrhosis is the main predisposing condition for hepatocellular carcinoma. Host genetic risk factors have been reported for cirrhosis; however, whether there is a genetic contribution to racial disparities in cirrhosis requires further investigation. We used an affected-only mapping by admixture linkage disequilibrium analysis to characterize the genetic risk of cirrhosis in 227 African American patients with cirrhosis genotyped at 19,804 ancestry-informative marker single nucleotide polymorphisms. We additionally performed analyses stratified by hepatitis C virus (HCV) infection status. To replicate our findings, we conducted a case-control analysis in an external study population (452 cases and 196 controls). The mean age of patients was 63.3 years and 98.2% were male. Risk factors for cirrhosis included HCV infection (83.7%) and alcohol abuse (56.4%). In the admixture mapping analysis, we found that European ancestry on chromosome 2q21.1 and African ancestry on chromosome 6p21.2 were associated with increased risk of cirrhosis in African Americans. In the fine-mapping analysis, we identified regions near POTEKP on 2q21.1 (P= .0001) and DNAH8 on 6p21.2 (P= .0017) that were associated with cirrhosis. As the admixture peaks in the HCV-positive patients were the same as those in the overall group, findings in the analysis are reflective of the HCV-positive group. In the replication analysis, the results on chromosome 2 were not significant after adjusting for multiple comparisons, and we could not replicate the results on chromosome6. We used admixture mapping to identify novel genomic regions on 2q21.1 and 6p21.2 that may be associated with HCV-related cirrhosis risk in African Americans.

Multilocus evaluation of genetic predictors of multiple sclerosis.

Genome-wide association studies identified numerous susceptibility loci for multiple sclerosis in populations of European ancestry, but the associations are not always reproducible in other populations due to admixture and different linkage disequilibrium patterns obscuring true association signals. Our aim was to identify genetic predictors of multiple sclerosis in three ethnically homogenous populations from the Volga-Ural region of Russian Federation. In the largest to date study of multiple sclerosis in Russian population, involving 2048 participants from the Republic of Bashkortostan, Russian Federation (641 patients with multiple sclerosis and 1407 unaffected individuals), we performed replication analysis of previously identified genome-wide signals for multiple sclerosis. Associations were tested using logistic regression analysis under additive genetic model adjusted for sex. Meta-analysis of the study results in three populations was performed under fixed effects and random effects models. We demonstrate the association with multiple sclerosis of the five variants (INAVA rs7522462, EOMES rs11129295, C6orf10 rs3129934, CD86 rs9282641, and GPR65 rs2119704). The strongest association (OR=2.16, CI:1.85-2.74, P=2.53x10-13) was detected for rs3129934 polymorphism in the major histocompatibility region. Multilocus analysis has revealed 322 and 27 allelic patterns associated with multiple sclerosis in women and men, respectively. In women, the highest risk of MS was conferred by C6orf10 rs3129934*T/T+STAT3 rs744166*T combination (OR=11.87), in men - by C6orf10 rs3129934*T+EOMES rs11129295*C+RPS6KB1 rs180515*C combination (OR=3.25). We confirm five associations with multiple sclerosis previously reported in genome-wide scans in Europeans in three ethnic groups from the Volga-Ural region of Russia.

On the Distribution of Tract Lengths During Adaptive Introgression.

Admixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

Detecting fitness epistasis in recently admixed populations with genome-wide data

BackgroundFitness epistasis, the interaction effect of genes at different loci on fitness, makes an important contribution to adaptive evolution. Although fitness interaction evidence has been observed in model organisms, it is more difficult to detect and remains poorly understood in human populations as a result of limited statistical power and experimental constraints. Fitness epistasis is inferred from non-independence between unlinked loci. We previously observed ancestral block correlation between chromosomes 4 and 6 in African Americans. The same approach fails when examining ancestral blocks on the same chromosome due to the strong confounding effect observed in a recently admixed population.ResultsWe developed a novel approach to eliminate the bias caused by admixture linkage disequilibrium when searching for fitness epistasis on the same chromosome. We applied this approach in 16,252 unrelated African Americans and identified significant ancestral correlations in two pairs of genomic regions (P-value< 8.11 × 10− 7) on chromosomes 1 and 10. The ancestral correlations were not explained by population admixture. Historical African-European crossover events are reduced between pairs of epistatic regions. We observed multiple pairs of co-expressed genes shared by the two regions on each chromosome, including ADAR being co-expressed with IFI44 in almost all tissues and DARC being co-expressed with VCAM1, S1PR1 and ELTD1 in multiple tissues in the Genotype-Tissue Expression (GTEx) data. Moreover, the co-expressed gene pairs are associated with the same diseases/traits in the GWAS Catalog, such as white blood cell count, blood pressure, lung function, inflammatory bowel disease and educational attainment.ConclusionsOur analyses revealed two instances of fitness epistasis on chromosomes 1 and 10, and the findings suggest a potential approach to improving our understanding of adaptive evolution.

Testing an hypothesis of hybrid zone movement for toads in France.

Hybrid zone movement may result in substantial unidirectional introgression of selectively neutral material from the local to the advancing species, leaving a genetic footprint. This genetic footprint is represented by a trail of asymmetric tails and displaced cline centres in the wake of the moving hybrid zone. A peak of admixture linkage disequilibrium is predicted to exist ahead of the centre of the moving hybrid zone. We test these predictions of the movement hypothesis in a hybrid zone between common (Bufo bufo) and spined toads (B.spinosus), using 31 nuclear and one mtDNA SNPs along a transect in the northwest of France. Average effective selection in Bufo hybrids is low and clines vary in shape and centre. A weak pattern of asymmetric introgression is inferred from cline discordance of seven nuclear markers. The dominant direction of gene flow is from B.spinosus to B.bufo and is in support of southward movement of the hybrid zone. Conversely, a peak of admixture linkage disequilibrium north of the hybrid zone suggests northward movement. These contrasting results can be explained by reproductive isolation of the B.spinosus and B.bufo gene pools at the southern (B.spinosus) side of the hybrid zone. The joint occurrence of asymmetric introgression and admixture linkage disequilibrium can also be explained by the combination of low dispersal and random genetic drift due to low effective population sizes.

Revealing the impact of the Caucasus region on the genetic legacy of Romani people from genome-wide data.

Romani people are a significant minority in Europe counting about 10 million individuals scattered throughout the continent. They are a migratory group originating from Northwestern India. Their exodus from India occurred approximately 1000–1500 years ago. The migration route of the Romani people was reconstructed with the help of cultural anthropology, linguistics and historical records. Their migration made them through Central Asia, Middle East and the Caucasus region, prior to the arriving into Europe. Yet the significance of these regions, especially of the Caucasus, in Roma ancestry was a rather neglected topic. Contribution of the Caucasus and further affected regions to the ancestry of Roma was investigated based on genome-wide autosomal marker data. 158 European Roma samples and 41 populations from the Caucasus region, from Middle East, Central Asia and from South Asia were considered in our tests. Population structure and ancestry analysis algorithms were applied to investigate the relationship of Roma with these populations. Identical by descent DNA segment analyses and admixture linkage disequilibrium based tests were also applied. Our results suggest that the Caucasus region plays also a significant role in the genetic legacy of Romani people besides the main sources, Europe and South Asia, previously investigated by other population genetic studies. The Middle East and Central Asia seems slightly less important but far from negligible in connection with the sources of Roma ancestry. Our results point out that the Caucasus region and altogether the area of the Caspian and Black Seas had a significant role in the migration of Romani people towards Europe and contributed significantly to the genetic legacy of Roma rival to the European and Indian main sources.

Admixture Mapping of Diabetic Nephropathy Genetic Variants

The goal of our research study is to identify diabetes dependent genetic variants that confer susceptibility or resistance to the development of kidney disease. It is thought, based on previous studies, that the susceptibility is associated with African ancestry. We therefore hypothesized that the risk variants might be enriched on African‐derived chromosomal segments in cases. A genome‐wide, agnostic method to search for susceptibility variants that are more common in one ancestral group than others is to compare ancestry of chromosomal segments in admixed populations. By identifying these African‐derived enriched chromosomal regions in cases compared to controls or to the rest of the genome in a case‐only study, we can localize risk variants. Puerto Ricans are thought to have 3‐way ethnicity admixture (Indigenous, European, and African). In view of this wide admixture, researching in a population like Puerto Rico allows a broader study of variants and their ancestral origin. The underlying goal is to identify chromosomal regions associated with disease phenotype, followed by fine‐mapping to identify the causal gene. The human subjects in this study are End‐Stage Kidney Disease (ESKD) patients from the West side of Puerto Rico. We anticipate enrolling over 1,000 patients from dialysis centers. DNA from the saliva samples from the ESKD patients will be genotyped for over 10,000 Single Nucleotide Polymorphisms (SNP) using Illumina Technology at the National Cancer Institute in Frederick, Maryland. Among these SNPs there is Ancestry Informative Markers (AIM) that will be analyzed using Mapping by Admixture Linkage Disequilibrium (MALD) technique as an approach. This technique is used to determine the extent of African, European, and Native American ancestry across the 23 chromosomes. Chromosomal regions showing significantly increased or decreased ancestry will be considered candidate regions for harboring susceptibility or resistant genes. We will also use a candidate approach and genotype known genes found to associate with kidney disease, including single nucleotide polymorphisms rs60910145, rs71785313 (allele variant G1) and rs73885319 (allele variant G2) from the APOL1 gene (apolipoprotein L1). The APOL1 gene variant is found only on African‐derived chromosomes, and was associated with kidney disease on previous studies. This research should result in the discovery of new variants associated with diabetic nephropathy. Approximately 300 have already volunteered. All 300 samples were already genotyped for all SNPs of the APOL1 gene. Analysis on the data retrieved reveals a relationship with diabetic nephropathy and all three variants. Once other diabetic nephropathy associated variants are determined, we expect them to have an increase in African ancestry, as well to observe the relationship already established with the APOL1 gene.Support or Funding InformationThis research was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number T34GM008419 and by an Institutional developmental Award (IDeA) from the National Institute Of General Medical Sciences of the National Institutes of Health under grant number P20 GM103475‐15.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Locus on Chromosome 5 Is Associated with Red Cell Allo-Immunization in Adults with Sickle Cell Disease

Background: Transfusion is a standard treatment for acute and chronic complications of sickle cell disease (SCD). This therapy is limited by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patient populations. Reasons for this increased prevalence have not been elucidated. One model based study suggested a genetic predisposition in all patient populations. Other studies have provided evidence that antigen mismatches occur commonly between blood donors of European ancestry and SCD patients and that this is a primary cause for alloimmunization. Accordingly, limited phenotypic antigen matching is a standard practice used to minimize alloimmunization risk. We hypothesized that if these population differences are the biologic basis for this phenomenon that admixture mapping could identify significant susceptibility loci.Methods: A cohort study consisting of adults evaluated at NIH and Howard University between 2001-2015 (n=721) had allo-antibody status confirmed with the blood bank at the hospital where the most recent transfusion was performed. Genomic DNA was genotyped for a panel of 1622 ancestry informative SNPs in 359 patients. Genotypes were used to infer ancestry proportions using Structure software assuming a 3 population model. Ancestry was analyzed by regression along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where ancestry differences between cases and controls suggested an association. We used AncestryMap for a log-additive case control study assuming various risk models.Results: Five hundred fifty four subjects (77% of cohort) had a transfusion history with 153 (27.6 %) with allo-antibodies and 65 (11.7 %) with no prior transfusions. Antibodies directed against RH, Kell, MNS and Duffy antigens were the most prevalent. Clinical factors associated with alloimmunization in regression models were only significant for lifetime transfusion history by both logistic (antibody status, β=0.56, P=6.31 x 10-6) and linear (number of antibodies, β=0.35, P=0.0004) regressions. When considering genotype data, Amerindian ancestry was associated with antibody status (logistic, β=4.60, P=0.03) and number of antibodies (linear, β=4.92, P=0.006), while African and European ancestry were not. The association between ancestry and alloimmunization risk remained unchanged when the number of prior transfusions was also included in both multivariable models for alloimmunization status and number of antibodies, P=0.09 and P=0.06, respectively. Genome wide mapping by admixture linkage disequilibrium compared 91 allo-Ab cases to 210 controls with prior transfusions under 10 different risk models (range 0.25-9.0). The most significant result was the 0.25 risk model which was highly suggestive for association (genome log factor 10.96, P<0.001; Figure 1A). This scan identified region of chromosome 5 (5q21.3-5q31.1) defined by 14 snps spanning 21.685 Mb and a highly significant peak LOD score of 13.5 (Figure 1B). While this region contains >540 genes, the linkage region is noteworthy for a cytokine gene cluster implicated in hematopoiesis and immune responses.Conclusions: In a large cohort of adults with SCD, the prevalence of red cell alloimmunization is 27.6%. Amerindian ancestry is a risk factor and suggests a genetic component to this phenotype. The number of prior transfusions is also a significant risk factor. Genome wide admixture mapping identified a strong association at chromosome 5q21.3-5q31.1 using a 0.25 risk model. This chromosome 5 association is particularly interesting given the presence a cytokine gene cluster within a portion of the associated region. Analysis of larger, admixed populations will help to fine map allo-immunization susceptibility variants within specific genes that underlie these loci. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Joint genotype- and ancestry-based genome-wide association studies in admixed populations.

In genome-wide association studies (GWAS) genetic loci that influence complex traits are localized by inspecting associations between genotypes of genetic markers and the values of the trait of interest. On the other hand, admixture mapping, which is performed in case of populations consisting of a recent mix of two ancestral groups, relies on the ancestry information at each locus (locus-specific ancestry). Recently it has been proposed to jointly model genotype and locus-specific ancestry within the framework of single marker tests. Here, we extend this approach for population-based GWAS in the direction of multimarker models. A modified version of the Bayesian information criterion is developed for building a multilocus model that accounts for the differential correlation structure due to linkage disequilibrium (LD) and admixture LD. Simulation studies and a real data example illustrate the advantages of this new approach compared to single-marker analysis or modern model selection strategies based on separately analyzing genotype and ancestry data, as well as to single-marker analysis combining genotypic and ancestry information. Depending on the signal strength, our procedure automatically chooses whether genotypic or locus-specific ancestry markers are added to the model. This results in a good compromise between the power to detect causal mutations and the precision of their localization. The proposed method has been implemented in R and is available at http://www.math.uni.wroc.pl/~mbogdan/admixtures/.

Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with polynomial functions.

To infer the histories of population admixture, one important challenge with methods based on the admixture linkage disequilibrium (ALD) is to remove the effect of source LD (SLD), which is directly inherited from source populations. In previous methods, only the decay curve of weighted LD between pairs of sites whose genetic distance were larger than a certain starting distance was fitted by single or multiple exponential functions, for the inference of recent single- or multiple-wave admixture. However, the effect of SLD has not been well defined and no tool has been developed to estimate the effect of SLD on weighted LD decay. In this study, we defined the SLD in the formularized weighted LD statistic under the two-way admixture model and proposed a polynomial spectrum (p-spectrum) to study the weighted SLD and weighted LD. We also found that reference populations could be used to reduce the SLD in weighted LD statistics. We further developed a method, iMAAPs, to infer multiple-wave admixture by fitting ALD using a p-spectrum. We evaluated the performance of iMAAPs under various admixture models in simulated data and applied iMAAPs to the analysis of genome-wide single nucleotide polymorphism data from the Human Genome Diversity Project and the HapMap Project. We showed that iMAAPs is a considerable improvement over other current methods and further facilitates the inference of histories of complex population admixtures.

Genetic epidemiology in kidney disease.

Familial aggregation of chronic kidney disease and its component phenotypes-reduced glomerular filtration rate, proteinuria and renal histologic changes-has long been recognized. Rates of severe kidney disease are also known to differ markedly between populations based on ancestry. These epidemiologic observations support the existence of nephropathy susceptibility genes. Several molecular genetic technologies are now available to identify causative loci. The present article summarizes available strategies useful for identifying nephropathy susceptibility genes, including candidate gene association, family-based linkage, genome-wide association and admixture mapping (mapping by admixture linkage disequilibrium) approaches. Examples of loci detected using these techniques are provided. Epigenetic studies and future directions are also discussed. The identification of nephropathy susceptibility genes, coupled with modifiable environmental triggers impacting their function, is likely to improve risk prediction and transform care. Development of novel therapies to prevent progression of kidney disease will follow.

The Analysis of Ethnic Mixtures.

Population of ethnic mixtures can be useful in genetic studies. Admixture mapping, or mapping by admixture linkage disequilibrium (MALD), is specially developed for admixed populations and can supplement traditional genome-wide association analyses in the search for genetic variants underlying complex traits. Admixture mapping tests the association between a trait and locus-specific ancestries. The locus-specific ancestries are in linkage disequilibrium (LD), which is generated by an admixture process between genetically distinct ancestral populations. Because of the highly correlated-locus specific ancestries, admixture mapping performs many fewer independent tests across the genome than current genome-wide association analysis. Therefore, admixture mapping can be more powerful because it reduces the penalty due to multiple tests. In this chapter, we introduce the theory behind admixture mapping and explain how to conduct the analysis in practice.

The Effects of Migration and Assortative Mating on Admixture Linkage Disequilibrium.

Statistical models in medical and population genetics typically assume that individuals assort randomly in a population. While this simplifies model complexity, it contradicts an increasing body of evidence of nonrandom mating in human populations. Specifically, it has been shown that assortative mating is significantly affected by genomic ancestry. In this work, we examine the effects of ancestry-assortative mating on the linkage disequilibrium between local ancestry tracks of individuals in an admixed population. To accomplish this, we develop an extension to the Wright-Fisher model that allows for ancestry-based assortative mating. We show that ancestry-assortment perturbs the distribution of local ancestry linkage disequilibrium (LAD) and the variance of ancestry in a population as a function of the number of generations since admixture. This assortment effect can induce errors in demographic inference of admixed populations when methods assume random mating. We derive closed form formulae for LAD under an assortative-mating model with and without migration. We observe that LAD depends on the correlation of global ancestry of couples in each generation, the migration rate of each of the ancestral populations, the initial proportions of ancestral populations, and the number of generations since admixture. We also present the first direct evidence of ancestry-assortment in African Americans and examine LAD in simulated and real admixed population data of African Americans. We find that demographic inference under the assumption of random mating significantly underestimates the number of generations since admixture, and that accounting for assortative mating using the patterns of LAD results in estimates that more closely agrees with the historical narrative.

The genetic history of Cochin Jews from India.

Cochin Jews form a small and unique community on the Malabar coast in southwest India. While the arrival time of any putative Jewish ancestors of the community has been speculated to have taken place as far back as biblical times (King Solomon’s era), a Jewish community in the Malabar coast has been documented only since the 9th century CE. Here, we explore the genetic history of Cochin Jews by collecting and genotyping 21 community members and combining the data with that of 707 individuals from 72 other Indian, Jewish, and Pakistani populations, together with additional individuals from worldwide populations. We applied comprehensive genome-wide analyses based on principal component analysis, FST, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing, allele sharing autocorrelation decay and contrasting the X chromosome with the autosomes. We find that, as reported by several previous studies, the genetics of Cochin Jews resembles that of local Indian populations. However, we also identify considerable Jewish genetic ancestry that is not present in any other Indian or Pakistani populations (with the exception of the Jewish Bene Israel, which we characterized previously). Combined, Cochin Jews have both Jewish and Indian ancestry. Specifically, we detect a significant recent Jewish gene flow into this community 13–22 generations (~470–730 years) ago, with contributions from Yemenite, Sephardi, and Middle-Eastern Jews, in accordance with historical records. Genetic analyses also point to high endogamy and a recent population bottleneck in this population, which might explain the increased prevalence of some recessive diseases in Cochin Jews.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1698-y) contains supplementary material, which is available to authorized users.

Admixture mapping of serum vitamin D and parathyroid hormone concentrations in the African American—Diabetes Heart Study

Vitamin D and intact parathyroid hormone (iPTH) concentrations differ between individuals of African and European descent and may play a role in observed racial differences in bone mineral density (BMD). These findings suggest that mapping by admixture linkage disequilibrium (MALD) may be informative for identifying genetic variants contributing to these ethnic disparities. Admixture mapping was performed for serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, vitamin D-binding protein (VDBP), bioavailable vitamin D, and iPTH concentrations and computed tomography measured thoracic and lumbar vertebral volumetric BMD in 552 unrelated African Americans with type 2 diabetes from the African American—Diabetes Heart Study. Genotyping was performed using a custom Illumina ancestry informative marker (AIM) panel. For each AIM, the probability of inheriting 0, 1, or 2 copies of a European-derived allele was determined. Non-parametric linkage analysis was performed by testing for association between each AIM using these probabilities among phenotypes, accounting for global ancestry, age, and gender. Fine-mapping of MALD peaks was facilitated by genome-wide association study (GWAS) data. VDBP levels were significantly linked in proximity to the protein coding locus (rs7689609, LOD=11.05). Two loci exhibited significant linkage signals for 1,25-dihydroxyvitamin D on 13q21.2 (rs1622710, LOD=3.20) and 12q13.2 (rs11171526, LOD=3.10). iPTH was significantly linked on 9q31.3 (rs7854368, LOD=3.14). Fine-mapping with GWAS data revealed significant known (rs7041 with VDBP, P=1.38×10−82) and novel (rs12741813 and rs10863774 with VDBP, P<6.43×10−5) loci with plausible biological roles. Admixture mapping in combination with fine-mapping has focused efforts to identify loci contributing to ethnic differences in vitamin D-related traits.

The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry.

The Bene Israel Jewish community from West India is a unique population whose history before the 18th century remains largely unknown. Bene Israel members consider themselves as descendants of Jews, yet the identity of Jewish ancestors and their arrival time to India are unknown, with speculations on arrival time varying between the 8th century BCE and the 6th century CE. Here, we characterize the genetic history of Bene Israel by collecting and genotyping 18 Bene Israel individuals. Combining with 486 individuals from 41 other Jewish, Indian and Pakistani populations, and additional individuals from worldwide populations, we conducted comprehensive genome-wide analyses based on FST, principal component analysis, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing and allele sharing autocorrelation decay, as well as contrasted patterns between the X chromosome and the autosomes. The genetics of Bene Israel individuals resemble local Indian populations, while at the same time constituting a clearly separated and unique population in India. They are unique among Indian and Pakistani populations we analyzed in sharing considerable genetic ancestry with other Jewish populations. Putting together the results from all analyses point to Bene Israel being an admixed population with both Jewish and Indian ancestry, with the genetic contribution of each of these ancestral populations being substantial. The admixture took place in the last millennium, about 19–33 generations ago. It involved Middle-Eastern Jews and was sex-biased, with more male Jewish and local female contribution. It was followed by a population bottleneck and high endogamy, which can lead to increased prevalence of recessive diseases in this population. This study provides an example of how genetic analysis advances our knowledge of human history in cases where other disciplines lack the relevant data to do so.

The genetic basis of color-related local adaptation in a ring-like colonization around the Mediterranean.

Uncovering the genetic basis of phenotypic variation and the population history under which it established is key to understand the trajectories along which local adaptation evolves. Here, we investigated the genetic basis and evolutionary history of a clinal plumage color polymorphism in European barn owls (Tyto alba). Our results suggest that barn owls colonized the Western Palearctic in a ring-like manner around the Mediterranean and meet in secondary contact in Greece. Rufous coloration appears to be linked to a recently evolved nonsynonymous-derived variant of the melanocortin 1 receptor (MC1R) gene, which according to quantitative genetic analyses evolved under local adaptation during or following the colonization of Central Europe. Admixture patterns and linkage disequilibrium between the neutral genetic background and color found exclusively within the secondary contact zone suggest limited introgression at secondary contact. These results from a system reminiscent of ring species provide a striking example of how local adaptation can evolve from derived genetic variation.

Quantitating and dating recent gene flow between European and East Asian populations.

Historical records indicate that extensive cultural, commercial and technological interaction occurred between European and Asian populations. What have been the biological consequences of these contacts in terms of gene flow? We systematically estimated gene flow between Eurasian groups using genome-wide polymorphisms from 34 populations representing Europeans, East Asians, and Central/South Asians. We identified recent gene flow between Europeans and Asians in most populations we studied, including East Asians and Northwestern Europeans, which are normally considered to be non-admixed populations. In addition we quantitatively estimated the extent of this gene flow using two statistical approaches, and dated admixture events based on admixture linkage disequilibrium. Our results indicate that most genetic admixtures occurred between 2,400 and 310 years ago and show the admixture proportions to be highly correlated with geographic locations, with the highest admixture proportions observed in Central Asia and the lowest in East Asia and Northwestern Europe. Interestingly, we observed a North-to-South decline of European gene flow in East Asians, suggesting a northern path of European gene flow diffusing into East Asian populations. Our findings contribute to an improved understanding of the history of human migration and the evolutionary mechanisms that have shaped the genetic structure of populations in Eurasia.

387 Immunochip Implicates Multiple Genetic Loci for African American IBD Including HLA-DRB1*1502 for UC, NOD2, PTGER4, IL23R, LZKF3 and STAT5A/STAT3 for CD and Several Regions of Significant Admixture Linkage Disequilibrium

387 Immunochip Implicates Multiple Genetic Loci for African American IBD Including HLA-DRB1*1502 for UC, NOD2, PTGER4, IL23R, LZKF3 and STAT5A/STAT3 for CD and Several Regions of Significant Admixture Linkage Disequilibrium