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Recent Selection on a Class I ADH Locus Distinguishes Southwest Asian Populations Including Ashkenazi Jews

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Recent Selection on a Class I ADH Locus Distinguishes Southwest Asian Populations Including Ashkenazi Jews G C A T T A C G G C A T genes Article Recent Selection on a Class I ADH Locus Distinguishes Southwest Asian Populations Including Ashkenazi Jews Sheng Gu 1,2, Hui Li 2, Andrew J. Pakstis 1, William C. Speed 1, David Gurwitz 3, Judith R. Kidd 1 and Kenneth K. Kidd 1,* 1 Department of Genetics, School of Medicine, Yale University, New Haven, CT 06520, USA; [email protected] (S.G.); [email protected] (A.J.P.); [email protected] (W.C.S.); [email protected] (J.R.K.) 2 Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China; [email protected] 3 Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; [email protected] * Correspondence: [email protected]; Tel.: +1-203-785-2654 Received: 23 July 2018; Accepted: 21 August 2018; Published: 7 September 2018 Abstract: The derived human alcohol dehydrogenase (ADH)1B*48His allele of the ADH1B Arg48His polymorphism (rs1229984) has been identified as one component of an East Asian specific core haplotype that underwent recent positive selection. Our study has been extended to Southwest Asia and additional markers in East Asia. Fst values (Sewall Wright’s fixation index) and long-range haplotype analyses identify a strong signature of selection not only in East Asian but also in Southwest Asian populations. However, except for the ADH2B*48His allele, different core haplotypes occur in Southwest Asia compared to East Asia and the extended haplotypes also differ. Thus, the ADH1B*48His allele, as part of a core haplotype of 10 kb, has undergone recent rapid increases in frequency independently in the two regions after divergence of the respective populations. Emergence of agriculture may be the common factor underlying the evident selection. Keywords: alcohol dehydrogenase; population genetics; genetic selection 1. Introduction The human alcohol dehydrogenase (ADH) gene cluster has been widely studied for association with diseases, especially alcoholism [1–3] and for population diversity studies [4–8]. The protective effect against alcoholism of the ADH1B*48His (previously named ADH2*2) allele at rs1229984 is considered one of the most strongly confirmed associations [1,9–12]. Also strongly confirmed is the evidence that the derived-protective allele (ADH1B*48His) has undergone recent positive selection in East Asia [13–17]. Different geographic regions differ in the frequencies of the genetic polymorphisms in ADH1B and ADH1C, the genes for the primary ethanol metabolizing enzymes [18,19]. We originally found that the ADH1B*48His allele reaches high frequencies not only in East Asia but also in Southwest Asia, while the frequency of this derived allele remains lower between these two geographic regions [20,21]. We also found ethnic-specific variation in the haplotypes with ADH1B*48His within East Asia and different haplotypes in Southwest Asia [14]. Subsequently, Peng et al. [15] has associated the rise of the allele frequency with domestication and spread of rice. We speculated that this derived allele increased in frequency independently in East Asia and Southwest Asia after humans had spread across Eurasia. We suspected that the ADH1B locus in Southwest Asia had also undergone positive Genes 2018, 9, 452; doi:10.3390/genes9090452 www.mdpi.com/journal/genes Genes 2018, 9, 452 2 of 16 Genes 2018, 9, x FOR PEER REVIEW 2 of 16 selection.had also undergone Therefore, wepositive undertook selection. to examine Therefore, this regionwe undertook using the to long-range examine this haplotype region (LRH)using testthe forlong-range populations haplotype in Southwest (LRH) test Asia for [22 populations]. in Southwest Asia [22]. Initially, wewe studiedstudied aa globalglobal samplingsampling ofof 4242 populationspopulations (Figure(Figure1 1,, additional additional informationinformation inin Table S1)S1) andand examinedexamined the the linkage linkage disequilibrium disequilibrium (LD) (LD) pattern pattern across across the the whole wholeADH ADHgene gene cluster cluster in allin all populations populations (Figure (Figure2). 2). A A total total of of 118 118 single single nucleotide nucleotide polymorphisms polymorphisms (SNPs) (SNPs) were were genotyped genotyped in thisthis genomicgenomic regionregion (Figure(Figure2 ).2). ForFor thethe detectiondetection ofof selection,selection, wewe focusfocus onon SouthwestSouthwest AsianAsian populations since selection in EastEast AsianAsian populationspopulations hashas beenbeen wellwell documented.documented. Three southwestsouthwest Asian populations,populations, Yemenite Yemenite Jews Jews (YMJ), (YMJ), Druze Druze (DRU), (DRU), and Samaritansand Samaritans (SAM), (SAM), were initially were selected.initially Consideringselected. Considering the genetic the proximity genetic ofproximity Ethiopian of Jews Ethiopian (ETJ) to Jews those (ETJ) Southwest to those Asian Southwest populations, Asian as wellpopulations, as the original as well geographic as the original origins geographic of Ashkenazi origins Jews of (ASH) Ashkenazi [23–26 ],Jews we also(ASH) extended [23–26], our we study also toextended these two our populations. study to these Though two geographicallypopulations. Th ETJough belong geographically to a different ETJ continent belong andto a ASH different have livedcontinent in Europe and ASH for somehave time,lived wein Europe shall refer for tosome all five time, populations, we shall refer YMJ, to DRU,all five SAM, populations, ETJ, and ASH,YMJ, collectivelyDRU, SAM, asETJ, Southwest and ASH, Asia. collectively as Southwest Asia. Figure 1.1. AllAll 42 42 populations populations used used in thisin this study. study. Populations Populations are geographically are geographically categorized categorized and colored and intocolored eight into groups: eight groups: Africa (BIA,Africa MBU, (BIA, YOR,MBU, IBO, YOR, HAS, IBO, CGA,HAS, MAS,CGA, MAS, AAM, AAM, and ETJ), and SouthwestETJ), Southwest Asia (YMJ,Asia (YMJ, DRU, DRU, and SAM), and SAM), Europe Europe (ASH, (ASH, ADY, ADY, CHV, RUA,CHV, RUV,RUA, FIN,RUV, DAN, FIN, IRI,DAN, and IRI, EAM), and EAM), Siberia Siberia (KMZ, KTY,(KMZ, and KTY, YAK), and PacificYAK), IslandsPacific Islands (NAS and (NAS MCR), and MCR) East Asia, East (CBD, Asia (CBD, CHS, CHT,CHS, HKA,CHT, HKA, KOR, KOR, JPN, AMI,JPN, andAMI, ATL), and ATL), North North America America (NPA, (NPA, SWA, SWA, PMM, PMM, and MAY,) and MAY,) and South and South America America (QUE, (QUE, TIC, TIC, SUR, SUR, and KAR).and KAR). The three-characterThe three-character population population symbols symbols and correspondingand corresponding full names full names are listed are listed in pairs. in pairs. No single algorithm is able to capturecapture allall possiblepossible signaturessignatures ofof positivepositive selection.selection. We appliedapplied both FFstst (Sewall(Sewall Wright’s fixationfixation index) index) [ 27[27]] and and LRH LRH [22 [22]] analyses analyses to to our our data. data. An An unusually unusually high highFst canFst can be thebe signaturethe signature of local of local positive positive selection selection driving driving substantial substantial changes changes in allele in frequencies allele frequencies [28,29], and[28,29], the LRHand the analysis, LRH includinganalysis, theincluding extended the haplotype extended homozygosity haplotype homozygosity (EHH) test and (EHH) Relative test EHH and (REHH)Relative EHH test, detects(REHH) a test, rapid detects rise in a haplotyperapid rise frequencyin haplotype interpreted frequency as interpreted detecting anas detecting allele under an positiveallele under selection positive that selection has recently that has been recently rapidly been driven rapidly to high driven frequency to high frequency and tends and to lie tends on anto extendedlie on an haplotypeextended haplotype with low diversitywith low[ 22diversity]. However, [22]. highHowever,Fst values high canFst values occur incan the occur absence in the of selectionabsence of [30 selection] and positive [30] and LRH positive analysis LRH is considered analysis tois beconsidered a stronger to indication be a stronger of selection. indication of selection. Genes 2018, 9, 452 3 of 16 Genes 2018, 9, x FOR PEER REVIEW 3 of 16 Figure 2. The schematic representation of regions of high linkage disequilibrium (LD) across the human alcohol dehydrogenase (ADH) clusters. HAPLOT and the default rr22 algorithmalgorithm werewere used. used. All All 118 118 genetic genetic markers markers (including (including one one insert-deletion insert-deletion site site treated treated as a singleas a single nucleotide nucleotide polymorphism polymorphism (SNP)) ( areSNP)) listed are at listed the bottom. at the Thebottom. locations The locations of two short of two tandem short repeattandem polymorphisms repeat polymorphisms (STRP) loci (STRP) are indicated loci are indicated at the bottom at the by bottom the black by the triangles. black triangles. The arrow The above arrow each above gene each symbol gene indicates symbol indicatesthe downstream the downstream direction; direction; the region the is plotted region fromis plotted centromere from centromere to telomere. to Generallytelomere. Generally speaking, populationsspeaking, populations of the same of group the same have group similar have LD similar structure LD with structure some variation.with some Highlightedvariation. Highlighted within the bluewithin box, the Southwest blue box, AsianSouthwes populationst Asian
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