Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans
2007; Elsevier BV; Volume: 81; Issue: 3 Linguagem: Inglês
10.1086/520705
ISSN1537-6605
AutoresNabil Enattah, Aimée Trudeau, Ville N. Pimenoff, Luigi Maiuri, Salvatore Auricchio, Luigi Greco, Mauro Rossi, Michael J. Lentze, Jieun Seo, Soheila Rahgozar, Insaf F. Khalil, Michael Alifrangis, Sirajedin Natah, Leif Groop, Nael Shaat, Andrew Kozlov, Galina Verschubskaya, David Comas, Kazima Bulayeva, S. Qasim Mehdi, Joseph D. Terwilliger, Timo Sahi, Erkki Savilahti, Markus Perola, Antti Sajantila, Irma Järvelä, Leena Peltonen,
Tópico(s)Diet and metabolism studies
ResumoA single-nucleotide variant, C/T-13910, located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T-13910 variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8–H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T-13910 H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T-13910 H98 allele (∼5,000–12,000 years old) is relatively older than the other geographically restricted LP alleles (∼1,400–3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T-13910 allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans. A single-nucleotide variant, C/T-13910, located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T-13910 variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8–H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T-13910 H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T-13910 H98 allele (∼5,000–12,000 years old) is relatively older than the other geographically restricted LP alleles (∼1,400–3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T-13910 allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans. The expression of the lactase enzyme (MIM 603202) in intestinal cells dramatically declines after weaning in mammals, when lactose is no longer an essential part of their diet.1Sahi T Isokoski M Jussila J Launiala K Pyorala K Recessive inheritance of adult-type lactose malabsorption.Lancet. 1973; 2: 823-826Abstract PubMed Scopus (127) Google Scholar In humans, this normal mammalian condition known as “lactase nonpersistence” (LNP, also known as “adult-type hypolactasia” or “lactose intolerance” [MIM 223100]) affects most of mankind and restricts the consumption of fresh milk among adults. However, among northern Europeans and a few other ethnic populations, intestinal lactase activity persists throughout life in a substantial proportion (up to 80%–90%) of adults, a condition known as lactase persistence (LP, or lactose tolerance [MIM 223100]). The LP/LNP phenotype is genetically determined, with LP being dominant over LNP.2Sahi T Genetics and epidemiology of adult-type hypolactasia.Scand J Gastroenterol Suppl. 1994; 202: 7-20Crossref PubMed Scopus (269) Google Scholar We previously identified a single-nucleotide variant, C/T-13910, completely correlating with the phenotype in Finns and in a cross-sectional sample of >600 individuals from five populations.3Enattah NS Sahi T Savilahti E Terwilliger JD Peltonen L Jarvelä I Identification of a variant associated with adult-type hypolactasia.Nat Genet. 2002; 30: 233-237Crossref PubMed Scopus (828) Google Scholar, 4Kuokkanen M Enattah NS Oksanen A Savilahti E Orpana A Jarvela I Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia.Gut. 2003; 52: 647-652Crossref PubMed Scopus (164) Google Scholar, 5Rasinpera H Savilahti E Enattah NS Kuokkanen M Totterman N Lindhal H Jarvela I Kolho K-L A genetic test which can be used to diagnose adult-type hypolactasia in children.Gut. 2004; 53: 1571-1576Crossref PubMed Scopus (162) Google Scholar The T-13910 variant, which correlates with LP, is located 14 kb upstream of the LCT gene and has been shown to be the derived variant, compared with the C-13910 variant that represents the ancestral form of the human genome. Another variant, G/A-22018, farther upstream of LCT, was also strongly, although not completely, associated with the LP/LNP phenotype,3Enattah NS Sahi T Savilahti E Terwilliger JD Peltonen L Jarvelä I Identification of a variant associated with adult-type hypolactasia.Nat Genet. 2002; 30: 233-237Crossref PubMed Scopus (828) Google Scholar, 5Rasinpera H Savilahti E Enattah NS Kuokkanen M Totterman N Lindhal H Jarvela I Kolho K-L A genetic test which can be used to diagnose adult-type hypolactasia in children.Gut. 2004; 53: 1571-1576Crossref PubMed Scopus (162) Google Scholar most likely because of the substantial linkage disequilibrium (LD) in this genome region.3Enattah NS Sahi T Savilahti E Terwilliger JD Peltonen L Jarvelä I Identification of a variant associated with adult-type hypolactasia.Nat Genet. 2002; 30: 233-237Crossref PubMed Scopus (828) Google Scholar, 6Harvey CB Pratt WS Islam I Whitehouse DB Swallow DM DNA polymorphisms in the lactase gene: linkage disequilibrium across the 70-kb region.Eur J Hum Genet. 1995; 3: 27-41Crossref PubMed Scopus (36) Google Scholar, 7Harvey CB Hollox EJ Poulter M Wang Y Rossi M Auricchio S Iqbal TH Cooper BT Barton R Sarner M et al.Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism.Ann Hum Genet. 1998; 62: 215-223Crossref PubMed Google Scholar, 8Poulter M Hollox E Harvey CB Mulcare C Peuhkuri K Kajander K Sarner M Korpela R Swallow DM The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans.Ann Hum Genet. 2003; 67: 298-311Crossref PubMed Scopus (109) Google Scholar, 9Bersaglieri T Sabeti PC Patterson N Vanderploeg T Schaffner SF Drake JA Rhodes M Reich DE Hirschhorn JN Genetic signatures of strong recent positive selection at the lactase gene.Am J Hum Genet. 2004; 74: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar Functional evidence for the C/T-13910 variant in the regulation of lactase activity has since emerged, lending additional support for this nucleotide change as the true causative variant of regulation of transcription of the lactase gene in intestinal cells.4Kuokkanen M Enattah NS Oksanen A Savilahti E Orpana A Jarvela I Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia.Gut. 2003; 52: 647-652Crossref PubMed Scopus (164) Google Scholar, 10Olds LC Sibley E Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element.Hum Mol Genet. 2003; 12: 2333-2340Crossref PubMed Scopus (179) Google Scholar, 11Troelsen JT Olsen J Moller J Sjostrom H An upstream polymorphism associated with lactase persistence has increased enhancer activity.Gastroenterology. 2003; 125: 1686-1694Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Adult individuals with the LP T-13910 allele show significantly higher steady-state transcript levels of LCT in their intestinal mucosa when compared with individuals with the nonpersistence C-13910 allele, which implies a transcriptional regulation of LCT.4Kuokkanen M Enattah NS Oksanen A Savilahti E Orpana A Jarvela I Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia.Gut. 2003; 52: 647-652Crossref PubMed Scopus (164) Google Scholar This is in agreement with in vitro studies demonstrating a distinct increase in the LCT promoter activity in cells transfected with the T-13910 variant.10Olds LC Sibley E Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element.Hum Mol Genet. 2003; 12: 2333-2340Crossref PubMed Scopus (179) Google Scholar, 11Troelsen JT Olsen J Moller J Sjostrom H An upstream polymorphism associated with lactase persistence has increased enhancer activity.Gastroenterology. 2003; 125: 1686-1694Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 12Lewinsky RH Jensen TG Moller J Stensballe A Olsen J Troelsen JT T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro.Hum Mol Genet. 2005; 14: 3945-3953Crossref PubMed Scopus (139) Google Scholar Haplotype analysis in the Finnish families demonstrated that all LP alleles among Finns originated from one common ancestor identical by descent.3Enattah NS Sahi T Savilahti E Terwilliger JD Peltonen L Jarvelä I Identification of a variant associated with adult-type hypolactasia.Nat Genet. 2002; 30: 233-237Crossref PubMed Scopus (828) Google Scholar Other studies of additional European populations have also suggested the existence of one major allelic haplotype, named “haplotype A,” correlating with LP.7Harvey CB Hollox EJ Poulter M Wang Y Rossi M Auricchio S Iqbal TH Cooper BT Barton R Sarner M et al.Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism.Ann Hum Genet. 1998; 62: 215-223Crossref PubMed Google Scholar, 13Hollox EJ Poulter M Zvarik M Ferak V Krause A Jenkins T Saha N Kozlov AI Swallow DM Lactase haplotype diversity in the Old World.Am J Hum Genet. 2001; 68: 160-172Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar These data indicate a single global origin for the LP T-13910 allele. In this study, we monitored the global frequencies of the LP T-13910 allele and allelic haplotype signatures of the ∼30-kb LCT locus in diverse global populations, to study the allelic background of LP in humans. We genotyped eight SNPs and one indel polymorphism (GenBank accession number DQ109677) covering ∼30 kb of the LCT region and flanking the two LCT variants, C/T-13910 and G/A-22018, associated with LP/LNP (coverage rate of one SNP per 3.3 kb) in 1,611 samples from 37 global populations (fig. 1 and table 1). Except for the two SNPs C/T-13910 and G/A-22018, the genotyped SNPs represent common variants in all populations, with minor-allele frequencies >7% (table 2). Although this approach might not identify some rare allelic variants, especially among the LNP alleles, the most robust pattern of diversity among LP alleles—the target of our interest—will be identified in the global samples.Table 1SNPs Analyzed in the DNA Samples from 37 PopulationsSNPTypedbSNP Accession NumberChromosomal PositionDistance from LCT (kb)1IndelDQ109677aThe GenBank accession number is given.136424826+3.642C/Trs3754686136437008−8.543G/Crs3769005136437098−8.634C/T-13910rs4988235136442378−13.915C/Trs4954493136443707−15.2396G/Crs3099181136448545−20.0777G/A-22018rs182549136450486−22.0188C/Trs4988183136455779−27.3129A/Crs3087343136456274−27.807Note.—The 3,954-bp indel polymorphism is located within intron 1 of the LCT gene. Accurate chromosomal positions and locations from LCT are given. The SNPs are also shown in figure 1.a The GenBank accession number is given. Open table in a new tab Table 2SNP Frequencies Analyzed in 37 Population SamplesDerived Allele 2 Frequency (SD)Region or PopulationNSNP 1 (Indel; in=1, del=2)SNP 2 (C/T; T=1, G=2)SNP 3 (G/C; G=1, C=2)SNP 4 (C/T-13910; C=1, T=2)SNP 5 (C/T; T=1, C=2)SNP 6 (G/C; G=1, C=2)SNP 7 (G/A -22018; G=1, A=2)SNP 8 (A/C; C=1, A=2)SNP 9 (G/A; G=1, A=2)South Korea23.07 (.04).28 (.06).28 (.06).00 (.00).28 (.06).28 (.06).00 (.00).52 (.07).89 (.05)Han Chinese100.38 (.03).36 (.03).36 (.03).00 (.00).36 (.03).36 (.03).00 (.00).64 (.03).77 (.03)Ob-Ugric speakers20.45 (.04).43 (.05).43 (.05).03 (.02).43 (.05).42 (.02).03 (.02).43 (.05).81 (.04)Komi10.40 (.09).50 (.11).50 (.11).15 (.07).50 (.11).50 (.11).15 (.07).65 (.10).85 (.08)Udmurts30.53 (.06).48 (.07).48 (.07).33 (.06).50 (.06).50 (.06).37 (.07).58 (.06).85 (.04)Mokshas30.27 (.06).30 (.06).30 (.06).28 (.06).27 (.06).27 (.06).27 (.06).37 (.07).57 (.06)Erzas30.48 (.06).42 (.06).42 (.06).27 (.06).42 (.06).38 (.05).22 (.05).40 (.06).68 (.06)Saami30.53 (.06).51 (.07).51 (.07).17 (.04).51 (.07).51 (.07).13 (.04).60 (.06).85 (.05)Finns, eastern77.69 (.04).69 (.04).69 (.03).55 (.04).68 (.03).66 (.04).55 (.04).70 (.04).88 (.03)Finns, western154.73 (.02).71 (.03).71 (.03).62 (.02).72 (.02).71 (.03).62 (.02).73 (.02).88 (.02)Daghestan Druss17.23 (.07).23 (.07).18 (.07).12 (.06).21 (.07).21 (.07).12 (.06).26 (.07).62 (.09)Daghestan Nog20.40 (.08).40 (.08).37 (.08).07 (.04).40 (.08).40 (.08).07 (.04).40 (.08).60 (.08)Daghestan mixed23.35 (.07).35 (.07).35 (.07).13 (.05).35 (.07).35 (.07).13 (.05).37 (.07).67 (.07)Pakistan Balti23.24 (.06).17 (.06).26 (.06).00 (.00).17 (.06).17 (.06).00 (.00).26 (.07).44 (.07)Pakistan Burusho30.33 (.07).33 (.07).33 (.07).02 (.01).33 (.07).23 (.06).05 (.03).28 (.06).77 (.06)Pakistan Kashmiri20.37 (.08).42 (.08).42 (.08).12 (.05).42 (.08).37 (.08).15 (.06).42 (.08).78 (.07)Pakistan Kalash30.25 (.06).27 (.06).25 (.05).00 (.00).25 (.06).22 (.05).03 (.02).38 (.08).62 (.06)Pakistan Pathan28.45 (.07).41 (.07).43 (.07).30 (.06).39 (.07).41 (.07).32 (.06).48 (.07).71 (.06)Pakistan Hazara14.36 (.09).32 (.09).32 (.09).04 (.04).32 (.09).29 (.09).11 (.06).46 (.10).64 (.09)Pakistan Baluch19.47 (.08).47 (.08).47 (.08).34 (.08).47 (.08).47 (.08).39 (.08).50 (.08).79 (.06)Pakistan Sindi28.50 (.07).52 (.07).50 (.07).41 (.07).50 (.07).50 (.07).43 (.07).52 (.07).75 (.06)Pakistan Brahui30.43 (.07).42 (.07).43 (.06).27 (.06).43 (.06).40 (.06).28 (.06).43 (.07).82 (.05)Pakistan Makrani Baluch29.35 (.06).35 (.06).35 (.06).17 (.05).35 (.06).33 (.06).18 (.05).48 (.07).77 (.06)Pakistan Mohannes29.38 (.06).38 (.06).36 (.07).28 (.06).36 (.07).36 (.06).28 (.06).36 (.06).67 (.07)Pakistan Parsi29.21 (.05).19 (.05).19 (.05).14 (.05).22 (.06).17 (.05).03 (.02).33 (.06).55 (.07)Iranians21.26 (.07).21 (.06).21 (.06).10 (.05).24 (.07).21 (.06).07 (.04).26 (.07).57 (.08)Iran Qashqai10.10 (.07).10 (.07).10 (.07).05 (.05).10 (.07).10 (.07).05 (.05).10 (.07).40 (.11)Arabs50.17 (.04).25 (.04).18 (.04).10 (.03).16 (.04).15 (.04).10 (.03).19 (.04).52 (.05)Southern Italy100.22 (.03).26 (.03).25 (.03).05 (.02).26 (.03).26 (.03).06 (.02).29 (.04).60 (.03)French17.44 (.08).44 (.08).44 (.08).34 (.07).44 (.08).44 (.08).37 (.08).50 (.08).62 (.09)Basques85.71 (.03).70 (.03).73 (.03).66 (.04).72 (.04).69 (.03).64 (.04).70 (.03).86 (.03)Utah92.83 (.03).83 (.03).83 (.03).74 (.03).83 (.03).82 (.03).76 (.03).83 (.03).90 (.02)Somalia79.18 (.03).19 (.03).22 (.03).03 (.01).18 (.03).17 (.03).01 (.01).28 (.04).68 (.03)Fulani Sudanese44.80 (.05).57 (.06).57 (.05).48 (.06).56 (.06).56 (.05).55 (.06).82 (.05).94 (.02)Morocco90.35 (.03).33 (.04).33 (.03).18 (.03).35 (.03).33 (.03).16 (.03).41 (.04).64 (.03)Saharawi57.36 (.05).36 (.04).37 (.04).26 (.04).36 (.05).36 (.04).29 (.04).36 (.04).72 (.04)African Americans50.25 (.04).18 (.04).21 (.04).09 (.03).20 (.04).18 (.04).09 (.03).62 (.05).80 (.04)Note.—Alleles coded as 1 in every SNP site were the ancestral alleles, on the basis of the sequence of the primate samples, that cosegregated with the LNP phenotype, and alleles coded as 2 in every SNP site were the derived alleles that cosegregated with the LP phenotype. Open table in a new tab Note.— The 3,954-bp indel polymorphism is located within intron 1 of the LCT gene. Accurate chromosomal positions and locations from LCT are given. The SNPs are also shown in figure 1. Note.— Alleles coded as 1 in every SNP site were the ancestral alleles, on the basis of the sequence of the primate samples, that cosegregated with the LNP phenotype, and alleles coded as 2 in every SNP site were the derived alleles that cosegregated with the LP phenotype. The frequency of the LP T-13910 allele in various populations was systematically correlated with the reported prevalence of LP determined elsewhere by disaccharidase activities in intestinal biopsy samples and/or lactose-tolerance tests in these populations (fig. 2 and table 3).1Sahi T Isokoski M Jussila J Launiala K Pyorala K Recessive inheritance of adult-type lactose malabsorption.Lancet. 1973; 2: 823-826Abstract PubMed Scopus (127) Google Scholar, 2Sahi T Genetics and epidemiology of adult-type hypolactasia.Scand J Gastroenterol Suppl. 1994; 202: 7-20Crossref PubMed Scopus (269) Google Scholar, 14Simoons FJ The geographic hypothesis and lactose malabsorption: a weighing of the evidence.Am J Dig Dis. 1978; 23: 963-980Crossref PubMed Scopus (223) Google Scholar, 15Swallow DM Genetics of lactase persistence and lactose intolerance.Annu Rev Genet. 2003; 37: 197-219Crossref PubMed Scopus (386) Google Scholar, 16Holden C Mace R Phylogenetic analysis of the evolution of lactose digestion in adults.Hum Biol. 1997; 69: 605-628PubMed Google Scholar, 17Flatz G Rotthauwe HW The human lactase polymorphism: physiology and genetics of lactose absorption and malabsorption.Prog Med Genet. 1977; 2: 205-249PubMed Google Scholar Among the 37 populations studied (fig. 3), we identified 21 populations for which the prevalence of the LP trait was known and could establish a strong correlation (coefficient of correlation r=0.973, P<.0001) with the frequency of the T-13910 allele (fig. 2). The allele frequencies of the analyzed markers are shown in table 2, and the complete list of all observed haplotypes constructed using all nine markers with the Arlequin program18Schneider S Roessli D Excoffier L Arlequin version 2.000: a software for population genetic data analysis. Genetics and Biometry Laboratory, University of Geneva, Geneva2000Google Scholar are provided in table 4. We restricted further analysis to those haplotypes with population frequency >4% in at least one of the populations, as inferred by the Arlequin program, to avoid misleading conclusions based on rare haplotypes, which could represent artifacts of the algorithm used for the construction of the haplotypes (table 5). We identified 9 different haplotypes (H8, H9, H11, H12, H48, H49, H95, H97, and H98) with alleles carrying the T-13910 LP variant and 14 haplotypes (H1, H2, H4, H27, H34, H46, H51, H52, H54, H55, H81, H82, H84, and H87) with alleles carrying the C-13910 LNP variant (table 5). Comparison of the resulting haplotypes with the haplotypes estimated by the maximum-likelihood algorithm implemented in the PHASE program v2.1 did not reveal discrepancies (data not shown).Table 3Population Frequencies of LP Alleles C/T-1391No. with GenotypeAllele Frequency (%)DesignationRegion or PopulationThree-Letter CodeNCCCTTTCTPrevalence of LP (% [SD])1South KoreaSKo23230010000 (.00)2Han ChineseHan1001000010000 (.00)3Ob-Ugric speakersObU62584096.83.26 (3.02)4KomiKom10730851530 (14.50)5UdmurtsUdm301216266.633.460 (8.90)6MokshasMok301317071.628.456.6 (9.01)7ErzasErz301710373.326.743.3 (9.05)8SaamiSaa302010083.316.733.3 (8.60)9Finns, easternFiE7718352446.153.976.6 (4.75)10Finns, westernFiW15425686138.361.783.7 (2.98)11Daghestan DrussDaD17134088.211.823.5 (10.30)12Daghestan NogDaN20155087.512.525 (9.70)13Daghestan mixedDaM23193189.111.917.4 (7.90)14BaltiBal23230010000 (.00)15BurushoBur30291098.31.73.3 (3.26)16KashmiriKas20155087.512.525 (9.68)17KalashKal30300010000 (.00)18PathanPat281215169.630.457.1 (9.35)19HazaraHaz14131096.43.67.1 (6.86)20BaluchBlu19106368.431.647.4 (11.46)21SindiSin281013558.941.164.3 (9.11)22BrahuiBra301710373.326.743.3 (9.05)23Makrani BaluchMaB291910082.817.234.5 (8.83)24MohannesMoh291610372.427.644.8 (9.23)25ParsiPar29218086.213.827.6 (8.30)26IraniansIra21174090.59.519 (8.56)27QashqaiQas1091095510 (9.49)28ArabsAra51428190.29.817.6 (5.33)29Southern ItalySIt1008911094.55.511 (3.13)30FrenchFra1769161.738.358.8 (11.94)31BasquesBas857443434.165.991.7 (2.99)32UtahUta927335225.574.592.4 (2.76)33SomaliaSom79745096.83.26.3 (2.73)34Fulani SudaneseFul44132011524870.4 (6.88)35SaharawiSah572926273.726.349.1 (6.62)36MoroccoMor906225382.717.331.1 (4.88)37African AmericansAam50443391912 (4.60) Open table in a new tab Figure 3Population frequencies for the T-13910 allele associated with LP in worldwide populations. For each population, the pie chart denotes the frequency of the T-13910 allele (green shading). Populations and frequency details are shown in table 3.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 4The Complete List of the 30-kb Haplotype Frequencies in 37 PopulationsPopulation Frequency (SD)HaplotypeaThe fourth position in each haplotype is the common LNP/LP variant, C/T-13910, where 1 denotes C-13910 and 2 denotes T-13910. The seventh position denotes the SNP G/A-22018, where 1 denotes G-22018 and 2 denotes A-22018.SKo (N=46)Han (N=200)ObU (N=124)Kom (N=20)Udm (N=60)Mok (N=60)Erz (N=60)Saa (N=60)FiW (N=306)FiE (N=154)DaD (N=34)DaN (N=40)DaM (N=46)Bal (N=46)Bur (N=60)Kas (N=40)Kal (N=60)Pat (N=56)Haz (N=28)Blu (N=38)Sin (N=56)Bra (N=60)MaB (N=58)Moh (N=58)Par (N=58)Ira (N=42)Qas (N=20)Ara (N=102)SIt (N=200)Fra (N=34)Bas (N=170)Uta (N=184)Som (N=158)Mor (N=180)Sah (N=114)Aam (N=100)Ful (N=88)H1111111111.11 (.05).21 (.03).19 (.04).15 (.09).04 (.03).32 (.06).17 (.05).12 (.04).10 (.02).11 (.02).23 (.07).40 (.07).33 (.07).54 (.07).18 (.04).18 (.07).37 (.08).21 (.07).36 (.09).17 (.06).21 (.06).17 (.05).22 (.06).29 (.07).39 (.07).38 (.09).60 (.12).41 (.05).32 (.04).34 (.09).12 (.03).10 (.02).27 (.04).31 (.03).25 (.05).19 (.04).01 (.01)H2111111112.35 (.08).12 (.02).31 (.04).10 (.08).19 (.06).18 (.05).25 (.07).25 (.05).12 (.02).16 (.03).50 (.09).15 (.05).26 (.07).13 (.07).44 (.07).31 (.08).22 (.05).27 (.06).11 (.06).33 (.07).23 (.06).33 (.06).30 (.06).31 (.06).21 (.06).26 (.08).30 (.11).26 (.05).21 (.03).13 (.06).09 (.02).05 (.02).38 (.04).20 (.03).34 (.05).17 (.04).07 (.04)H3111111121.01 (.01).01 (.01).01 (.01)H4111111122.26 (.08).28 (.03).02 (.01).25 (.12).07 (.04).07 (.04).03 (.01).05 (.01).03 (.03).05 (.04).07 (.04).04 (.03).03 (.03).15 (.05).07 (.03).18 (.08).03 (.02).02 (.02).03 (.02).13 (.04).12 (.04).02 (.02).03 (.01).06 (.05).01 (.01).02 (.01).04 (.02).06 (.02).01 (.01).32 (.05).05 (.02)H5111111211.02 (.02).01 (.01).01 (.01)H6111111212.02 (.02).05 (.03).01 (.01).02 (.01)H7111111222.02 (.02).01 (.01)H8111211111.02 (.02).05 (.03)H9111211112.02 (.02).05 (.04).01 (.01).01 (.00).01 (.01).02 (.01).01 (.01)H10111211122.02 (.01).00 (.00)H11111211211.07 (.04).11 (04).02 (.02).02 (.02)H12111211212.06 (.05)H13111211222.03 (.03)H14111212222.01 (.01)H15111222212.01 (01)H16111221111.02 (.02)H17111221122.02 (02).01 (.01)H18111121111.00 (.00).02 (.02).02 (.01)H19111121112.00 (.00).01 (.01).01 (.01).01 (.01).01 (.01).02 (.01)H20111121122.00 (.00).01 (.01).01 (.00)H21111122111.00 (.00)H22111112111.01 (.01).01 (.01)H23111112112.01 (.01)H24121111111.02 (.02).02 (.02.01 (.00).01 (.01)H25121111121.02 (.01)H26121111112.01 (.00).02 (.01).01 (.01)H27121111122.07 (.03).04 (.02).02 (.01).01 (.01).05 (02)H28121111222.01 (.01)H29121122122.01 (.01)H30121122211.01 (.01)H31121211112.01 (.01)H32121211122.01 (.01)H33121222222.01 (.01)H34112111111.02 (.01).02 (.02).06 (.02).01 (.01).01 (.01).02 (.01)H35112111121.02 (.02)H36112111112.02 (.02)H37112111122.01 (.01).01 (.01).01 (.00)H38112122112.01 (.01)H39112122122.01 (.01)H40112212212.01 (.01)H41112222122.01 (.01)H42111112111.01 (.01)H43122111111.00 (.00)H44122111112.02(.02).01 (.01)H45122111122.02 (.02).00 (.00).04 (.03)H46122122122.22 (.07).03 (.02).02 (.02).02 (.02).02 (.02).05 (.04).12 (.03).01 (.01)H47122122222.01 (.01)H48122222212.10 (.7)H49122222222.02 (.02).06 (.04).03 (.01).03 (.03)H50122211111.00 (.00)H51211111111.08 (.04).03 (.02).01 (.01).04 (.03).02 (.02).02 (.02).02 (.02).06 (.02).01 (.01)H52211111112.03 (.02).00 (.00).03 (.03)H53211111211.04 (.03).01 (.01).01 (.01).01 (.01).07 (.02).14 (.05)H54211111122.02 (.01).01 (.01).02 (.02).03 (.02).06 (.03)H55211111222.01 (.01)H56211121111H57211112112.00 (.00)H58211122111.01 (.01)H59211122112.00 (.00)H60211122121.03 (.03).01 (.00)H61211122122.02 (.02).02 (.01).02 (.02)H62211122212H63211211222.02 (.02).02 (.02)H64211222111.01 (.01)H65211222222.02 (.02).02 (.03)H66211211222.03 (.03).00 (.00)H67212111111.01 (.01).00 (.00).01 (.01).01 (.01)H68212122122.02 (.02).01 (.01)H69212222211.01 (.01)H70212212222.02 (.02).02 (.02).03 (.02)H71212222222.02 (.02).02 (.02)H72221122122.01 (.01)H73221122222.01 (.01)H74221222211.01 (.01)H75221222222.02 (.02)H76222111111.00 (.00).01 (.01).01 (.00)H77222111112.01 (.01)H78222112122.02 (.02).00 (.00).03 (.03)H79222121122.02 (.02).01 (.01).02 (.02).00 (.00).02 (.01)H80222121212.02 (.02)H81222121112.02 (.01).00 (.00).03 (.01).09 (.04).05 (.04).03 (.02).04 (.03).02 (.01).01 (.01).02 (.01).01 (.01).02 (.01)H82222122112.02 (.03).02 (.01).05 (.04).05 (.03).02 (.02).01 (.01)H83222122121.03 (.03).04 (.04)H84222122122.04 (.03)36 (.03).33 (.04).35 (.12).35 (.07).09 (.04).13 (.05).33 (.08).06 (.01).11 (.02).05 (.05).08 (.04).19 (.06).15 (.06).18 (.05).20 (.08).18 (.05).07 (.04).18 (.10).04 (.03).09 (.04).08 (.04).17 (.06).09 (.04).11 (.04).17 (.07).05 (.04).04 (.02).04 (.02).09 (.06).03 (.01).04 (.02).15 (.03).15 (.03).06 (.02).09 (.03).06 (.03)H85222122212.01 (.01)H86222122221.03 (.02).01 (.01)H87222122222.00 (.00).08 (.04).03 (.02).02 (.02).07 (.06).05 (.04).02 (.02).01 (.02).02 (.01).03 (.03).02 (.01).02 (.01)H88222211221.01 (.01)H89222212221.02 (.02)H90222212222.01 (.01).00 (.00).02 (.01).02 (.01)H91222221221.02 (.01)H92222221222.01 (.00)H93222221112.00 (.00).03 (.03)H94222222121.01 (.01)H95222222122.03 (.02).05 (.03).02 (.01).01 (.01).01 (.01).01 (.01)H96222222212.01 (.01).01 (.01)H97222222221.09 (.05).02 (.02).01 (.01).01 (.01)H98222222222.03 (.02).05 (.06).14 (.05).14 (.05).20 (.06).12 (.04).61 (03).53 (.04).13 (.06).11 (.05).06 (.05).27 (.06).04 (.03).34 (.08).39 (.07).25 (.06).15 (.05).28 (.06).01 (.01).02 (.02).05 (.05).05 (.02).01 (.01).31 (.09).56 (.04).74 (.03).01 (.01).12 (.02).26 (.04).06 (.03).47 (.06)H103212112110.02 (.02)H104221221220.02 (.02)Note.—Haplotypes >4% in any population have been included in the table. Alleles coded as 1 are based on the sequence of the primate samples and were cosegregated with the LNP phenotype, and alleles coded as 2 represent the alleles cosegregated with the LP phenotype. The SNPs used in constructing the haplotypes are shown in table 2. The three-letter codes for the populations are used; the complete names are given in table 3.a The fourth position in each haplotype is the common LNP/LP variant, C/T-13910, where 1 denotes C-13910 and 2 denotes T-13910. The seventh position denotes the SNP G/A-22018, where 1 denotes G-22018 and 2 denotes A-22018. Open table in a new tab Table 5A List of the Population Haplotype Frequencies Depicted in the MJ Network of Figure 4Population Frequency (% [SD])HaplotypeSKoHanObUKomUdmMokErzSaaFiWFiEDaDDaNDaMBalBurKasKalPatHazN462001242060606060154306344046466040605628LNP: H111 (5)21 (3)19 (4)15 (9)4 (3)32 (6)17 (5)12 (4)10 (2)11 (2)23 (7)40 (7)33 (7)54 (7)18 (4)18 (7)37 (8)21 (7)36 (9) H235 (8)12 (2)31 (4)10 (8)19 (6)18 (5)25 (7)25 (5)12 (2)16 (2)50 (9)15 (5)26 (7)13 (7)44 (7)31 (8)22 (5)27 (6)11 (6) H426 (8)28 (3)2 (1)25 (12)…7 (4)…7 (4)3 (1)5 (1)3 (3)5 (4)7 (4)…4 (3)3 (3)15 (5)7 (3)18 (8) H27…………………………………7 (3)…………… H34………………………………………………… H4622 (7)…3 (2)……2 (2)2 (2)2 (2)…………………5 (4)……… H51………………8 (4)3 (2)1 (1)………………4 (3)……… H52……3 (2)……………0 (0)…………2 (2)…………4 (3) H54…2 (1)1 (1)…………2 (2)……………4 (3)…………… H55………………………………………3 (2)……… H81………………2 (1)…0 (0)3 (1)…………9 (4)5 (4)3 (2)…4 (3) H822 (3)…2 (1)……………………5 (4)5 (3)2 (2)…………… H844 (3)36 (3)33 (4)35 (12)35 (7)9 (4)13 (5)33 (8)6 (1)11 (2)5 (5)8 (4)19 (6)15 (6)18 (5)20 (8)18 (5)7 (4)18 (10) H87……………………0 (0)……8 (4)…………3 (2)2 (2)7 (6)LP: H8…………2 (2)…5 (3)……………………………… H9………………………………………………… H11…………7 (4)11 (4)………………………………… H12…………6 (5)…………………………………… H48………10 (7)……………………………………… H49…………………2 (2)…………………6 (4)……… H95…………………3 (2)…………………………… H97…………………………9 (5)………2 (2)1 (1)……… H98……3 (2)5 (6)14 (5)14 (5)20 (6)12 (4)61 (4)53 (3)…13 (6)11 (5)……6 (5)…27 (6)4 (3)Note.—Haplotypes presented are restricted to the haplotypes with frequency >4% in any of the populations analyzed. The SNPs used for haplotype construction are SNPs 1–9 (table 1). The three-letter codes for the populations are used; the complete names are given in table 3. Open table in a new tab Note.— Haplotypes >4% in any population have been included in the table. Alleles coded as 1 are based on the sequence of the primate samples and were cosegregated with the LNP phenotype, and alleles coded as 2 represent the alleles cosegregated with the LP phenotype. The SNPs used in constructing the haplotypes are shown in table 2. The three-letter codes for the populations are used; the complete names are given in table 3. Note.— Haplotypes presented are restricted to the haplotypes with frequency >4% in any of the populations analyzed. The SNPs used for haplotype construction are SNPs 1–9 (table 1). The three-letter codes for the populations are used; the complete names are given in table 3. One of the ni
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