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

<div><p>The Bene Israel Jewish community from West India is a unique population whose history before the 18^th 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 F_ST, 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.</p></div

Founder events in Bene Israel population.

<p>(A) Total lengths of runs of homozygosity (ROH) in Jewish, Indian and HapMap populations. The larger variance in ROH values in some Indian populations is due to smaller sample size. (B-C) Autocorrelation in Bene Israel pairs, as a function of the genetic distance, after subtracting the autocorrelation between Bene Israel and other (B) Jewish and (C) Indian populations. Blue and red lines correspond to the fitted curve based on a single and two founder events, respectively.</p

IBD sharing between and within Jewish, Indian, Pakistani and Middle-Eastern populations.

<p>(A) Average IBD sharing between different populations. For each population we measured its average IBD with Bene Israel (purple) and all other Jewish (red) and Indian (blue) populations. (B) IBD sharing of Bene Israel with other Jewish and Indian populations. (C) Average IBD sharing between different populations. For each population from panel A, with the addition of Pakistani and Middle-Eastern populations, we measured its average IBD with Bene Israel (purple) and all other Jewish (red) and Indian (blue) populations. (D) IBD sharing of Bene Israel with other Jewish, Indian, Pakistani and non-Jewish Middle-Eastern populations. Analyses in panels C-D were performed on the dataset merged with HGDP dataset that contained smaller number of SNPs, and therefore the differences in IBD sharing values. (E) IBD sharing <i>within</i> populations.</p

ADMIXTURE analysis for Jewish, Indian, Pakistani, Middle Eastern (Druze, Bedouin and Palestinians) and representative HapMap (CEU, YRI, JPT and CHB) populations.

<p>K, the number of clusters, varies from K = 3 to K = 8. We colored some of the populations names based on the following groups: Bene Israel (purple), Jews (red), Indian (blue) and Middle-Eastern (green). See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s003" target="_blank">S3 Fig</a>.</p

Bene Israel as an admixed population with Indian and Jewish ancestry.

<p>(A) Bene Israel as an admixed population of Indian and Jewish origin. Admixture time (~19–33 generations ago) is after the ANI-ASI admixture of Indian populations (64–144 generations ago). The ANI side is associated with Eurasian populations while ASI is associated with indigenous Andaman Island people (e.g., Onge). Dotted lines correspond to admixture between populations. This is a schematic overview of Bene Israel genetic history and branch lengths are not proportional to actual time. (B) ALDER admixture proportions estimations for Indian and Jewish populations being ancestral populations of the Bene Israel community. Values (with standard errors) are based on ALDER analysis with one-reference population. See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s016" target="_blank">S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s017" target="_blank">S3</a> Tables. (C) GLOBETROTTER estimations for Indian (55%) and Jewish (45%) clusters proportions in Bene Israel admixture. The contribution of each population in each cluster is also presented.</p

Principal Component Analysis of Jewish, Indian and worldwide populations.

<p>Each panel presents the top two principal components for a set of populations that include Bene Israel together with: (A) Jewish, Indian, Pakistani, Middle Eastern and four worldwide HapMap populations (CEU, CHB, JPT and YRI); (B) Jewish, Middle-Eastern, Pakistani and Indian populations; (C) Indian and Pakistani populations; (D) Jewish, Middle-Eastern and Pakistani populations. Abbreviations of Jewish populations: Bene Israel (Bene), Algerian Jews (ALGJ), Ashkenazi Jews (ASHJ), Djerban Jews (DJEJ), Georgian Jews (GEOJ), Greek Jews (GRKJ), Iranian Jews (IRNJ), Iraqi Jews (IRQJ), Italian Jews (ITAJ), Libyan Jews (LIBJ), Moroccan Jews (MORJ), Syrian Jews (SYRJ), Tunisian Jews (TUNJ), Yemenite Jews (YMNJ).</p

Autosome to chromosome X genetic drift ratio between Bene Israel and other populations.

<p>The line represents the 3/4 ratio expected under the null hypothesis of similar demography of males and females in respect to the other populations examined (Jews and Indians, in our case). See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152056#pone.0152056.s019" target="_blank">S5 Table</a>.</p

Additional file 1 of African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Additional file 1. Contains Supplementary Methods, Supplementary Tables (Table S1-10), and Supplementary Figures (Fig. S1-14), and corresponding references. Supplementary Methods. Descriptions of Populations. Building Consensus Sequences in the Critical Region. Table S1. Characteristics of the APIC and URECA Cohorts. Table S2. Predicted Haplotypes in CREW. Table S3. Haplotype Frequencies in Whole Genome Sequences. Table S4. Worldwide Frequencies of African-specific SNPs. Table S5. cis-eQTL Results for SNPs in or near GSDMA. Table S6. ENCODE Cell Lines and DNAse Clustering at pcHi-C Region. Table S7. pcHi-C Target Genes for African-specific Variants in Airway Epithelial Cells. Table S8. pcHi-C Target Genes for African-specific Variants in Airway Immune Cells. Table S9. Quantitative Trait Association Results in the APIC and URECA Cohorts. Table S10. African American Adult Asthmatics by Severity and Genotype. Figure S1. Overview of Study Design. Figure S2. ChromoPainter Analysis. Figure S3. ChromoPainter Visualization of Haplotype Breakpoints. Figure S4. ChromoPainter Display of the 17q12-q21 Region in Haplotype 4 Homozygotes. Figure S5. Ancestry PCA plots for APIC and URECA Children. Figure S6. eQTL Box Plots of rs28623237 Genotype and GSDMA Expression in CAAPA2. Figure S7. LD Plot of African-specific Variants and SNPs in or near GSDMA. Figure S8. eQTL Box Plots of rs113282230 Genotype and GSDMA Expression Conditioned on GSDMA SNPs. Figure S9. eQTL Violin Plots of rs235480 and rs1132828830 Genotypes on GSDMA and GSDMB Expression. Figure S10. LD Plot of the African-specific Variants and SNPs in the Core Region of The 17q12-q21 Locus. Figure S11. Chromatin Annotations in the Region Encoding the African-specific SNPs in ENCODE Cell Lines. Figure S12. eGenes for rs113282230 in Immune Cells. Figure S13. pcHi-C Data for rs113282230 in Immune Cells. Figure S14. Rs113282230 Genotype Effect on Asthma Prevalence by rs2305480 AA And GG Genotypes in APIC and URECA

Additional file 2 of African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Additional file 2. Region-wide eQTL results in airway epithelial cells from 189 African American children in the URECA cohort