Genetic Isolates in East Asia: A Study of Linkage Disequilibrium in the X Chromosome
2002; Elsevier BV; Volume: 71; Issue: 2 Linguagem: Inglês
10.1086/341608
ISSN1537-6605
AutoresToru Katoh, Shuhei Mano, Tomoki Ikuta, Batmunkh Munkhbat, Kenichi Tounai, Harue Ando, Namid Munkhtuvshin, Tadashi Imanishi, Hidetoshi Inoko, Gen Tamiya,
Tópico(s)Cancer-related molecular mechanisms research
ResumoThe background linkage disequilibrium (LD) in genetic isolates is of great interest in human genetics. Although many empirical studies have evaluated the background LD in European isolates, such as the Finnish and Sardinians, few data from other regions, such as Asia, have been reported. To evaluate the extent of background LD in East Asian genetic isolates, we analyzed the X chromosome in the Japanese population and in four Mongolian populations (Khalkh, Khoton, Uriankhai, and Zakhchin), the demographic histories of which are quite different from one another. Fisher’s exact test revealed that the Japanese and Khalkh, which are the expanded populations, had the same or a relatively higher level of LD than did the Finnish, European American, and Sardinian populations. In contrast, the Khoton, Uriankhai, and Zakhchin populations, which have kept their population size constant, had a higher background LD. These results were consistent with previous genetic anthropological studies in European isolates and indicate that the Japanese and Khalkh populations could be utilized in the fine mapping of both complex and monogenic diseases, whereas the Khoton, Uriankhai, and Zakhchin populations could play an important role in the initial mapping of complex disease genes. The background linkage disequilibrium (LD) in genetic isolates is of great interest in human genetics. Although many empirical studies have evaluated the background LD in European isolates, such as the Finnish and Sardinians, few data from other regions, such as Asia, have been reported. To evaluate the extent of background LD in East Asian genetic isolates, we analyzed the X chromosome in the Japanese population and in four Mongolian populations (Khalkh, Khoton, Uriankhai, and Zakhchin), the demographic histories of which are quite different from one another. Fisher’s exact test revealed that the Japanese and Khalkh, which are the expanded populations, had the same or a relatively higher level of LD than did the Finnish, European American, and Sardinian populations. In contrast, the Khoton, Uriankhai, and Zakhchin populations, which have kept their population size constant, had a higher background LD. These results were consistent with previous genetic anthropological studies in European isolates and indicate that the Japanese and Khalkh populations could be utilized in the fine mapping of both complex and monogenic diseases, whereas the Khoton, Uriankhai, and Zakhchin populations could play an important role in the initial mapping of complex disease genes. There are many debates among geneticists, concerning the utility of genetically isolated populations for the mapping of disease genes (Wright et al. Wright et al., 1999Wright AF Carothers AD Pirastu M Population choice in mapping genes for complex diseases.Nat Genet. 1999; 23: 397-404Crossref PubMed Scopus (276) Google Scholar; Shifman and Darvasi Shifman and Darvasi, 2001Shifman S Darvasi A The value of isolated populations.Nat Genet. 2001; 28: 309-310Crossref PubMed Scopus (129) Google Scholar). One type of genetic isolate—for example, the populations of Finland, Iceland, and Sardinia, which have undergone distinct population isolation and subsequent expansion—has modestly higher levels of background linkage disequilibrium (LD) on many chromosomal regions than do outbred populations (Dunning et al. Dunning et al., 2000Dunning AM Durocher F Healey CS Teare MD McBride SE Carlomagno F Xu CF Dawson E Rhodes S Ueda S Lai E Luben RN Van Rensburg EJ Mannermaa A Kataja V Rennart G Dunham I Purvis I Easton D Ponder BA The extent of linkage disequilibrium in four populations with distinct demographic histories.Am J Hum Genet. 2000; 67: 1544-1554Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar; Eaves et al. Eaves et al., 2000Eaves IA Merriman TR Barber RA Nutland S Tuomilehto-Wolf E Tuomilehto J Cucca F Todd JA The genetically isolated populations of Finland and Sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.Nat Genet. 2000; 25: 320-323Crossref PubMed Scopus (140) Google Scholar; Taillon-Miller et al. Taillon-Miller et al., 2000Taillon-Miller P Bauer-Sardina I Saccone NL Putzel J Laitinen T Cao A Kere J Pilia G Rice JP Kwok PY Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28.Nat Genet. 2000; 25: 324-328Crossref PubMed Scopus (216) Google Scholar; Zavattari et al. Zavattari et al., 2000Zavattari P Deidda E Whalen M Lampis R Mulargia A Loddo M Eaves I Mastio G Toddo JA Cucca F Major factors influencing linkage disequilibrium in distinct populations: demography, chromosome recombination frequency and selection.Hum Mol Genet. 2000; 9: 2947-2957Crossref PubMed Scopus (96) Google Scholar; Angius et al. Angius et al., 2001Angius A Melis PM Morelli L Petretto E Casu G Maestrale GB Fraumene C Bebbere D Forabosco P Pirastu M Archival, demographic and genetic studies define a Sardinian sub-isolate as a suitable model for mapping complex traits.Hum Genet. 2001; 109: 198-209Crossref PubMed Scopus (58) Google Scholar). In contrast, another type of isolate—for example, the Scandinavian Saami isolate, which is from a small population that remained constant in size after isolation—shows very strong and long-range background LD (Laan and Pääbo Laan and Pääbo, 1997Laan M Pääbo S Demographic history and linkage disequilibrium in human populations.Nat Genet. 1997; 17: 435-438Crossref PubMed Scopus (139) Google Scholar; Lonjou et al. Lonjou et al., 1999Lonjou C Collins A Morton NE Allelic association between marker loci.Proc Natl Acad Sci USA. 1999; 96: 1621-1626Crossref PubMed Scopus (55) Google Scholar). These types of genetic isolates have led to the identification of disease genes (Hästbacka et al. Hästbacka et al., 1992Hästbacka J de la Chapelle A Kaitila I Sistonen P Weaver A Lander E Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland.Nat Genet. 1992; 2: 204-211Crossref PubMed Scopus (435) Google Scholar; de la Chapelle and Wright de la Chapelle and Wright, 1998de la Chapelle A Wright FA Linkage disequilibrium mapping in isolated populations: the example of Finland revisited.Proc Natl Acad Sci USA. 1998; 95: 12416-12423Crossref PubMed Scopus (176) Google Scholar), and, therefore, the value of genetic isolates has increasingly been appreciated during recent attempts at whole-genome LD mapping and association mapping (Wright et al. Wright et al., 1999Wright AF Carothers AD Pirastu M Population choice in mapping genes for complex diseases.Nat Genet. 1999; 23: 397-404Crossref PubMed Scopus (276) Google Scholar). However, most studies have mainly focused on particular populations from European regions, such as those from Finland and Sardinia. On the other hand, few data from Asian regions have been reported. It is necessary to investigate the properties of genetic isolates in East Asia and to compare these properties to those of genetic isolates in Europe. We focused on five populations from two regions of East Asia: Japan and Mongolia (fig. 1). All of the census data are available at the authors' Web site. The demographic history of the Japanese population has been described elsewhere (Koyama Koyama, 1978Koyama S Jomon subsistence and population.Senri Ethnol Stud. 1978; 2: 1-65Google Scholar; Hayami Hayami, 2001Hayami A The historical demography of pre-modern Japan. University of Tokyo Press, Tokyo2001Google Scholar; Statistics Bureau/Statistical Research and Training Institute Statistics Bureau/Statistical Research and Training Institute (ed), 2001Statistics Bureau/Statistical Research and Training Institute (ed) Japan statistical yearbook 2002. Japan Statistical Association, Tokyo2001Google Scholar). The population size in Japan ∼2,000 years ago was estimated to be ∼600,000 (Koyama Koyama, 1978Koyama S Jomon subsistence and population.Senri Ethnol Stud. 1978; 2: 1-65Google Scholar). After several gradual expansions, the modern Japanese population consists of ∼120 million people (Statistics Bureau/Statistical Research and Training Institute Statistics Bureau/Statistical Research and Training Institute (ed), 2001Statistics Bureau/Statistical Research and Training Institute (ed) Japan statistical yearbook 2002. Japan Statistical Association, Tokyo2001Google Scholar). Throughout the history of Japan, there seems to be no obvious recent admixture. The Mongolian population consists of ∼2.4 million people, which are divided into ∼20 ethnic groups (Tumen Tumen, 1992Tumen D (1992) Anthropology of the contemporary population of Mongolian People’s Republic. PhD thesis, MV Lomonosov Moscow State University, MoscowGoogle Scholar). Among them, the Khalkh is the largest population, with ∼1.8 million people. The Khalkh group is considered to be the direct descendant of the core Mongol tribes, which have inhabited the present-day climatically mild geographical territory of eastern Mongolia (Badamkhatan Badamkhatan, 1987Badamkhatan S Ethnography of Mongolia. Vol 1. Mongolian Academy of Sciences, Ulaanbaatar, Mongolia1987Google Scholar; Nyambuu Nyambuu, 1992Nyambuu K Introduction to the ethnography of Mongolia. Mongolian State Press, Ulaanbaatar, Mongolia1992Google Scholar). In contrast, the Khoton, Uriankhai, and Zakhchin are regarded as the young, isolated subpopulations of western Mongolia, where the Altai Mountains are located. The Khoton are an extremely small population, with ∼6,000 people living in northwestern Mongolia (fig. 1). They are a Turkish descendant population that has not experienced significant admixture and that migrated into Mongolia in the 12th century (Nyambuu Nyambuu, 1992Nyambuu K Introduction to the ethnography of Mongolia. Mongolian State Press, Ulaanbaatar, Mongolia1992Google Scholar). The Uriankhai and Zakhchin populations consist of ∼23,000 and ∼25,000 people, respectively. They are independent descendants of mixed populations formed by western tribes of Mongolian and Turkish origin (Nyambuu Nyambuu, 1992Nyambuu K Introduction to the ethnography of Mongolia. Mongolian State Press, Ulaanbaatar, Mongolia1992Google Scholar; Badamkhatan Badamkhatan, 1996Badamkhatan S Ethnography of Mongolia. Vols 2 and 3. Mongolian Academy of Sciences, Ulaanbaatar, Mongolia1996Google Scholar). These subpopulations, especially the Khoton, have been separated by severe geographic factors and have become isolates. We collected samples from 182 healthy unrelated Japanese individuals from the Kanto region of the central part of the mainland, which includes Kanagawa and Tokyo (fig. 1). From Mongolia, we collected 146 Khalkh from eastern Mongolia, as well as 74 Khoton, 58 Uriankhai, and 59 Zakhchin from western Mongolia (fig. 1); all individuals were unrelated or at least second cousins. After the mtDNA analysis, we chose 100 Japanese, 83 Khalkh, 40 Khoton, 55 Uriankhai, and 59 Zakhchin male samples for the X-chromosome analysis, including the 49 European Americans (Human variation panel, Caucasian, HD100CAU) as a control population. To verify the demographic history of our five tested populations, we first tested Tajima’s D statistic, using the nucleotide sequence variations of hypervariable region 1 (HVR1) in mtDNA; this statistic can identify a past expansion in population size (Tajima Tajima, 1989aTajima F The effect of change in population size on DNA polymorphism.Genetics. 1989a; 123: 597-601PubMed Google ScholarTajima, 1989bTajima F Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.Genetics. 1989b; 123: 585-595Crossref PubMed Google Scholar). As is illustrated in table 1, this test showed that the values were significantly negative in the Japanese and Khalkh (P<.05), as well as in the Finnish and European Americans, indicating that these two East Asian populations had expanded in size in the past. In contrast, the D statistics did not significantly deviate from zero in the Khoton (P>.10), Uriankhai, and Zakhchin (P>.05) or in the Saami, indicating that these three young subpopulations have kept their sizes small and constant over time.Table 1Sequence Variation of HVR1 in mtDNAPopulationSample SizeNo. of HaplotypesNucleotide DiversityTajima's DP ValueaSignificant values (P<.05) are given in boldface italics.Japanese182123.018 ± .001−1.925<.05Khalkh146106.018 ± .001−1.979<.05Khoton7423.012 ± .001−1.491>.10Uriankhai5838.017 ± .001−1.619>.05Zakhchin5943.020 ± .001−1.608>.05European American5044.014 ± .001−2.241<.05FinnishbData are from Sajantila et al. (1995).5035.011 ± .001−1.820<.05SaamibData are from Sajantila et al. (1995).2511.009 ± .001−.986>.10Western PygmycData are from Vigilant et al. (1991).178.023 ± .0031.219>.10a Significant values (P<.05) are given in boldface italics.b Data are from Sajantila et al. (Sajantila et al., 1995Sajantila A Lahermo P Anttinen T Lukka M Sistonen P Savontaus ML Aula P Beckman L Tranebjaerg L Godde-Dahl T Issel-Tarver L DiRienzo A Pääbo S Genes and languages in Europe: an analysis of mitochondrial lineages.Genome Research. 1995; 5: 42-52Crossref PubMed Scopus (202) Google Scholar).c Data are from Vigilant et al. (Vigilant et al., 1991Vigilant L Stoneking M Harpending H Hawkes K Wilson AC African populations and the evolution of human mitochondrial DNA.Science. 1991; 253: 1503-1507Crossref PubMed Scopus (930) Google Scholar). Open table in a new tab To compare these results with those from the European isolates studied elsewhere (Laan and Pääbo Laan and Pääbo, 1997Laan M Pääbo S Demographic history and linkage disequilibrium in human populations.Nat Genet. 1997; 17: 435-438Crossref PubMed Scopus (139) Google Scholar; Zavattari et al. Zavattari et al., 2000Zavattari P Deidda E Whalen M Lampis R Mulargia A Loddo M Eaves I Mastio G Toddo JA Cucca F Major factors influencing linkage disequilibrium in distinct populations: demography, chromosome recombination frequency and selection.Hum Mol Genet. 2000; 9: 2947-2957Crossref PubMed Scopus (96) Google Scholar), we analyzed the extent of background LD among the East Asian males through use of seven microsatellite markers on Xq13 (DXS983, DXS8092, DXS8037, DXS8082, DXS1225, DXS986, and DXS995). Detailed data for number of alleles in the populations are listed in table 2, and the distribution of haplotypes among populations is detailed in an online-only table. Fisher’s exact test was used to detect significant LD between every pair of the microsatellite markers. All of the uncorrected P values are listed in table 3. The results showed that the Japanese population exhibited a relatively higher level of background LD than did the Finnish, European American, and Sardinian populations. Before correction, the Japanese had 5 of 21 pairs with significant LD (P<.05), and the other 3 pairs had suggestive LD (.05≤P<.10). The rapid expansion of the Japanese population to a size of 120 million occurred at a rate of 108%, which is slightly higher than that of the Finnish population (106%). Such a rapid expansion might reduce the LD level in the Japanese, compared with the Finnish. This inconsistency could be explained by population structure differences (Kittles et al. Kittles et al., 1998Kittles RA Perola M Peltonen L Bergen AW Aragon RA Virkkunen M Linnoila M Goldman D Long J Dual origins of Finns revealed by Y chromosome haplotype variation.Am J Hum Genet. 1998; 62: 1171-1179Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar; Jorde et al. Jorde et al., 2001Jorde LB Watkins WS Bamshad MJ Population genomics: a bridge from evolutionary history to genetic medicine.Hum Mol Genet. 2001; 10: 2199-2207Crossref PubMed Scopus (86) Google Scholar). Our Japanese samples were collected in the Kanto region, which is inhabited by the Japanese homogeneous majority. Our Japanese samples may show stronger LD, reflecting that genetic homogeneity. It should be noted that the Japanese sample size (100) was somewhat larger than that of the Finnish (80) and Sardinians (73). To avoid an overestimation due to the effect of sample size on LD, the equilibration of sample size by the randomization test described by Varilo et al. (Varilo et al., 2000Varilo T Laan M Hovatta I Wiebe V Terwilliger JD Peltonen L Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo.Eur J Hum Genet. 2000; 8: 604-612Crossref PubMed Scopus (46) Google Scholar) was applied to the Fisher’s exact test. The sample size equilibration in the Japanese showed that similar LD results were obtained between the original and adjusted Japanese population sizes in table 3, indicating that the larger sample size is not responsible for the strong LD in the Japanese.Table 2Gene Diversity and Haplotype Mismatch Based on Seven Microsatellite Markers on Xq13No. of Alleles (Diversity), Based on MarkerPopulationSample SizeNo. of HaplotypesDXS983DXS986DXS8092DXS8082DXS1225DXS8037DXS995Mean ± SD Gene DiversityMean Haplotype MIsmatchVariance of Haplotype MismatchJapanese100945 (.45)14 (.90)16 (.91)8 (.7)7 (.69)3 (.06)3 (.51).60 ± .334.211.46Khalkh83805 (.43)12 (.87)13 (.90)9 (.80)9 (.74)6 (.41)4 (.53).67 ± .374.671.78Khoton40326 (.66)11 (.89)11 (.88)7 (.84)9 (.86)3 (.53)4 (.55).74 ± .415.212.21Uriankhai55503 (.35)14 (.91)13 (.90)10 (.84)9 (.82)6 (.61)6 (.64).72 ± .405.071.51Zakhchin59546 (.49)14 (.91)14 (.91)8 (.81)10 (.81)5 (.46)5 (.56).71 ± .394.951.43European American49498 (.76)7 (.69)10 (.81)8 (.78)10 (.77)6 (.68)6 (.59).73 ± .405.091.54FinnishaData are from Laan and Pääbo (1997). SDs were unavailable.80756 (.70)11 (.80)12 (.85)9 (.75)9 (.73)8 (.71)6 (.63).745.151.38SaamiaData are from Laan and Pääbo (1997). SDs were unavailable.54324 (.58)10 (.80)8 (.83)6 (.79)6 (.76)5 (.50)3 (.44).674.593.08a Data are from Laan and Pääbo (Laan and Pääbo, 1997Laan M Pääbo S Demographic history and linkage disequilibrium in human populations.Nat Genet. 1997; 17: 435-438Crossref PubMed Scopus (139) Google Scholar). SDs were unavailable. Open table in a new tab Online-Only TableHaplotype Data for Six PopulationsNo. of IndividualsbThe shared haplotypes are double-counted.Haplotype NumberHaplotypeaThe composition of each haplotype is DXS983-DXS986-DXS8092-DXS8082-DXS1225-DXS8037-DXS995.JapaneseKhalkhKhotonUriankhiZakhchinEuropean AmericanTotalHap001168-159-277-228-198-247-19311Hap002170-159-273-218-210-247-19711Hap003170-161-273-218-214-247-19911Hap004170-161-281-218-210-247-19711Hap005170-163-277-218-210-249-19711Hap006170-167-271-216-202-249-19711Hap007172-147-271-218-210-247-19711Hap008174-143-281-224-200-237-19311Hap009174-153-263-218-212-237-19311Hap010174-153-273-218-202-237-19311Hap011174-155-279-218-208-249-19111Hap012174-157-271-218-206-247-19711Hap013174-165-289-232-192-237-19311Hap014174-167-267-218-210-249-19711Hap015174-173-281-224-198-237-19711Hap016174-173-283-218-202-237-19311Hap017176-147-267-218-210-247-19311Hap018176-155-267-216-216-245-19311Hap019176-155-273-218-212-237-19711Hap020176-155-275-224-198-237-19311Hap021176-155-283-224-198-237-19711Hap022176-159-271-218-210-249-19311Hap023176-159-271-228-192-249-19711Hap024176-159-273-218-216-249-19311Hap025176-159-273-220-198-247-19311Hap026176-159-273-222-210-247-19311Hap027176-159-273-228-192-247-19711Hap028176-159-277-218-210-247-19711Hap029176-159-285-218-214-237-19711Hap030176-161-271-218-206-245-19711Hap031176-161-273-220-198-247-19711Hap032176-161-275-224-192-245-19711Hap033176-161-277-216-202-237-19322Hap034176-161-277-218-210-249-19311Hap035176-161-277-224-198-237-19711Hap036176-161-279-216-202-245-19711Hap037176-161-279-220-198-237-19711Hap038176-161-281-210-202-237-19311Hap039176-161-289-216-202-237-19711Hap040176-163-279-224-198-237-19711Hap041176-163-279-226-202-237-19711Hap042176-163-285-224-200-237-19711Hap043176-165-277-218-202-237-19711Hap044176-165-293-216-202-237-19711Hap045176-167-275-220-200-247-19711Hap046176-167-275-224-200-237-19711Hap047176-167-279-210-202-237-19711Hap048176-167-279-224-200-237-19711Hap049176-169-273-224-198-249-19311Hap050176-169-279-224-198-237-19711Hap051176-169-281-226-200-237-19711Hap052176-169-285-224-198-237-20111Hap053176-171-275-210-206-247-19311Hap054176-171-277-224-196-237-19311Hap055176-171-283-228-198-237-19511Hap056176-171-287-216-204-237-19311Hap057176-175-281-224-198-237-19711Hap058176-175-283-216-202-237-19711Hap059178-143-289-224-200-237-19311Hap060178-147-269-216-210-247-19711Hap061178-147-269-220-210-247-19711Hap062178-153-267-210-204-247-19711Hap063178-153-271-218-202-247-19322Hap064178-153-271-218-206-237-19311Hap065178-153-275-210-206-237-19711Hap066178-153-277-224-212-237-19711Hap067178-153-281-216-202-237-19711Hap068178-153-281-224-200-237-19711Hap069178-153-281-224-210-237-19711Hap070178-153-283-220-202-237-19711Hap071178-153-283-224-212-237-19311Hap072178-153-285-224-212-237-19311Hap073178-153-287-224-210-237-19311Hap074178-155-269-210-204-237-19711Hap075178-155-273-224-198-237-19311Hap076178-155-275-218-210-247-19711Hap077178-155-275-228-192-249-19711Hap078178-155-277-228-198-237-19311Hap079178-155-279-218-208-249-19311Hap080178-155-279-226-198-237-19711Hap081178-155-283-204-200-237-19311Hap082178-155-283-218-202-237-19311Hap083178-155-283-224-200-237-19311Hap084178-155-291-224-200-237-19311Hap085178-157-271-216-202-237-19711Hap086178-157-271-218-206-247-19711Hap087178-157-271-220-198-247-19711Hap088178-157-271-220-210-247-19711Hap089178-157-279-228-198-245-19311Hap090178-157-283-218-212-237-197112Hap091178-159-265-218-210-247-19711Hap092178-159-267-218-210-245-19311Hap093178-159-267-218-210-247-19311Hap094178-159-269-226-198-245-19711Hap095178-159-273-210-202-247-19711Hap096178-159-273-210-202-253-19711Hap097178-159-273-216-210-247-19711Hap098178-159-273-218-210-247-19711Hap099178-159-273-220-210-245-19711Hap100178-159-273-224-198-245-19511Hap101178-159-273-228-192-247-19311Hap102178-159-275-218-210-251-19711Hap103178-159-275-220-210-247-19911Hap104178-159-277-210-202-249-19311Hap105178-159-277-218-210-247-19311Hap106178-159-277-226-198-237-19733Hap107178-159-277-228-192-249-19711Hap108178-159-279-210-202-245-19711Hap109178-159-279-210-202-249-19311Hap110178-159-279-218-210-247-19311Hap111178-159-281-216-198-237-19311Hap112178-159-283-224-200-237-19311Hap113178-159-285-220-210-243-19711Hap114178-161-267-230-198-249-19711Hap115178-161-269-218-210-249-19711Hap116178-161-269-226-198-247-19311Hap117178-161-271-218-210-249-19311Hap118178-161-273-216-202-247-19311Hap119178-161-273-216-202-249-19311Hap120178-161-273-226-192-247-19111Hap121178-161-275-210-206-247-19711Hap122178-161-275-216-202-237-19311Hap123178-161-275-216-202-249-19311Hap124178-161-275-224-192-245-19711Hap125178-161-275-224-200-237-19311Hap126178-161-275-228-192-249-19311Hap127178-161-275-228-198-249-19311Hap128178-161-277-210-202-237-19911Hap129178-161-277-216-190-249-19311Hap130178-161-277-216-202-237-19322Hap131178-161-277-216-202-237-19711Hap132178-161-277-216-204-237-19511Hap133178-161-277-224-192-245-19711Hap134178-161-277-224-198-237-193112Hap135178-161-277-224-200-237-19711Hap136178-161-277-226-198-237-19711Hap137178-161-279-216-202-237-193123Hap138178-161-279-216-202-247-19711Hap139178-161-281-210-202-237-19311Hap140178-161-281-216-202-237-193112Hap141178-161-283-216-202-237-19311Hap142178-161-283-216-202-237-19711Hap143178-161-283-220-200-237-19911Hap144178-161-285-216-202-237-19511Hap145178-161-285-218-206-237-19311Hap146178-161-285-220-202-237-19311Hap147178-161-287-216-202-237-19311Hap148178-161-287-216-202-237-19711Hap149178-161-287-224-214-237-19311Hap150178-161-289-216-202-237-19311Hap151178-161-289-216-202-237-19711Hap152178-161-291-216-202-237-19311Hap153178-163-267-216-202-237-19711Hap154178-163-267-218-210-249-19311Hap155178-163-271-216-202-237-19711Hap156178-163-277-210-202-243-19311Hap157178-163-277-216-202-237-19711Hap158178-163-277-224-200-239-19311Hap159178-163-277-228-198-237-19711Hap160178-163-279-214-202-237-19711Hap161178-163-279-226-198-247-19311Hap162178-163-279-226-202-237-19311Hap163178-163-281-210-202-237-19711Hap164178-163-283-216-202-237-19711Hap165178-163-283-216-204-237-19711Hap166178-163-283-226-202-237-19711Hap167178-163-285-216-202-237-19311Hap168178-163-285-224-198-237-19722Hap169178-163-285-226-198-237-19711Hap170178-163-287-216-202-237-19311Hap171178-163-287-228-202-237-19311Hap172178-163-289-216-200-237-19311Hap173178-163-289-216-202-237-19711Hap174178-163-289-216-204-239-19711Hap175178-165-259-216-202-237-19511Hap176178-165-271-216-202-237-19711Hap177178-165-271-218-210-237-19711Hap178178-165-273-216-202-237-19711Hap179178-165-273-224-198-237-19711Hap180178-165-273-224-200-237-19311Hap181178-165-275-224-200-237-19711Hap182178-165-277-216-202-237-19322Hap183178-165-277-216-202-237-19711Hap184178-165-279-216-202-237-19311Hap185178-165-279-216-202-237-19711Hap186178-165-279-224-202-237-19311Hap187178-165-279-226-202-237-19711Hap188178-165-281-210-202-237-19711Hap189178-165-281-216-198-237-19311Hap190178-165-281-216-202-237-1971315Hap191178-165-281-224-200-237-19311Hap192178-165-283-216-202-237-19322Hap193178-165-285-216-202-237-1931113Hap194178-167-269-216-202-237-19733Hap195178-167-273-216-200-237-19722Hap196178-167-273-226-210-237-19311Hap197178-167-275-210-206-247-19311Hap198178-167-275-216-198-237-19322Hap199178-167-275-224-192-237-19322Hap200178-167-277-216-202-237-19711Hap201178-167-277-224-198-237-19733Hap202178-167-279-224-198-237-193112Hap203178-167-281-210-200-237-19111Hap204178-167-281-216-202-237-19311Hap205178-167-281-216-202-237-19711Hap206178-167-281-224-200-237-19711Hap207178-167-281-226-202-237-19711Hap208178-167-283-216-202-237-19311Hap209178-167-283-224-198-237-19311Hap210178-167-283-224-198-237-19711Hap211178-167-287-216-202-237-19711Hap212178-167-287-222-198-237-19711Hap213178-167-289-224-198-237-19711Hap214178-167-289-224-200-237-19311Hap215178-167-291-216-202-237-20111Hap216178-169-265-224-212-237-19311Hap217178-169-269-218-210-237-19311Hap218178-169-269-224-198-237-19711Hap219178-169-273-210-204-247-19311Hap220178-169-273-218-210-249-19711Hap221178-169-273-220-198-247-19711Hap222178-169-277-218-210-249-19711Hap223178-169-279-216-202-237-19711Hap224178-169-281-224-200-237-19311Hap225178-169-281-226-200-237-19311Hap226178-169-283-216-202-237-19311Hap227178-169-283-222-198-237-19711Hap228178-169-285-216-202-237-19711Hap229178-169-285-216-204-237-20111Hap230178-169-285-226-200-239-19711Hap231178-169-287-218-202-237-19311Hap232178-169-289-228-198-237-19711Hap233178-171-271-216-202-237-19711Hap234178-171-273-210-204-237-19311Hap235178-171-273-224-198-237-19733Hap236178-171-275-210-202-247-19922Hap237178-171-275-210-206-247-19311Hap238178-171-275-214-210-247-19711Hap239178-171-275-224-198-237-19311Hap240178-171-275-224-200-237-19711Hap241178-171-275-224-200-247-19711Hap242178-171-277-210-198-237-19311Hap243178-171-277-216-202-237-19711Hap244178-171-277-218-202-237-197123Hap245178-171-277-218-210-237-19311Hap246178-171-277-224-196-237-19711Hap247178-171-277-224-200-237-197112Hap248178-171-279-216-202-237-19711Hap249178-171-281-224-198-237-197112Hap250178-171-281-228-202-237-19711Hap251178-171-283-216-202-237-193112Hap252178-171-283-218-202-237-19711Hap253178-171-283-228-198-237-19311Hap254178-171-285-224-196-237-19711Hap255178-171-285-224-210-237-19311Hap256178-171-289-218-212-237-19711Hap257178-171-289-224-198-237-19711Hap258178-171-293-216-202-237-19311Hap259178-173-265-224-198-237-19511Hap260178-173-265-224-198-237-19711Hap261178-173-273-224-200-247-19311Hap262178-173-275-224-198-237-19311Hap263178-173-277-224-200-237-19311Hap264178-173-277-226-198-237-19711Hap265178-173-279-224-198-237-19311Hap266178-173-279-224-198-237-19711Hap267178-173-279-224-200-237-19711Hap268178-173-279-224-202-237-19711Hap269178-173-279-226-198-237-19711Hap270178-173-281-216-202-237-19311Hap271178-173-281-224-200-237-19311Hap272178-173-283-224-198-237-19311Hap273178-173-285-216-202-237-19311Hap274178-173-285-224-198-237-19311Hap275178-173-285-224-200-237-19711Hap276178-173-285-228-198-237-19311Hap277178-173-287-226-202-237-19711Hap278178-173-289-226-198-237-19711Hap279178-175-279-216-202-237-19311Hap280178-175-283-210-202-237-19311Hap281178-175-283-226-198-237-19711Hap282178-175-285-216-202-237-19311Hap283178-177-271-222-200-237-19711Hap284178-179-283-210-202-237-19311Hap285178-197-291-224-200-237-19511Hap286180-153-271-218-202-247-19311Hap287180-153-273-218-202-237-19311Hap288180-153-279-224-200-237-19311Hap289180-153-279-224-210-237-19711Hap290180-155-267-220-198-249-19311Hap291180-155-273-218-210-249-19711Hap292180-155-287-216-202-237-19311Hap293180-157-265-220-208-247-19711Hap294180-157-277-228-192-245-19711Hap295180-159-267-228-196-249-19711Hap296180-159-269-218-208-247-19311Hap297180-159-269-218-210-251-19311Hap298180-159-269-220-198-247-19311Hap299180-159-273-218-210-247-19311Hap300180-159-275-218-210-247-19711Hap301180-159-275-218-210-255-19311Hap302180-159-275-228-192-247-19711Hap303180-159-277-226-198-237-19711Hap304180-159-285-228-192-247-19311Hap305180-161-267-228-198-247-19311Hap306180-161-273-218-210-249-19911Hap307180-161-273-228-198-247-19711Hap308180-161-277-210-198-247-19311Hap309180-161-279-216-202-237-19311Hap310180-161-283-220-202-237-19311Hap311180-161-283-224-200-237-19311Hap312180-161-287-216-202-237-19711Hap313180-163-273-216-202-237-19311Hap314180-163-277-210-202-237-19711Hap315180-165-271-216-202-237-19711Hap316180-167-273-218-208-245-19711Hap317180-167-275-216-204-249-19711Hap318180-167-279-216-202-237-19711Hap319180-167-279-224-198-237-19311Hap320180-167-283-220-204-237-19711Hap321180-169-277-216-202-237-19711Hap322180-169-277-224-198-237-19711Hap323180-169-277-226-198-237-19711Hap324180-169-279-220-198-247-19311Hap325180-171-271-228-192-245-193213Hap326180-171-275-218-210-247-19311Hap327180-171-275-224-198-247-19711Hap328180-171-277-224-200-237-19711Hap329180-175-273-216-202-237-19711Hap330180-175-275-216-202-237-19311Hap331180-177-273-224-198-247-19311Hap332182-159-271-218-210-251-20111Hap333182-159-275-218-210-247-19311Hap334182-161-275-218-210-247-19711Hap335182-161-277-210-202-237-19711Hap336182-161-283-228-200-247-19355Hap337182-163-283-228-200-247-19311Hap338182-163-287-226-202-237-19711Hap339182-165-273-224-198-237-19311Hap340182-167-287-224-198-237-19311Hap341182-167-293-216-202-237-19711Hap342182-175-279-226-198-237-19311Hap343184-155-277-210-202-245-19111Hap344184-161-285-224-198-237-19711Hap345184-167-287-224-200-237-19311 Total Haplotypes948032505449359 Total Individuals1008340555949386a The composition of each haplotype is DXS983-DXS986-DXS8092-DXS8082-DXS1225-DXS8037-DXS995.b The shared haplotypes are double-counted. Open table in a new tab Table 3Pairwise LD Based on Fisher's Exact Test Using Seven Microsatellite Markers on Xq13UncorrectedPValuebThe values that are significant only before correction are underlined, whereas the values that are significant even after the step-down Holm-Sidack correction (Ludbrook 1998) are given in boldface italics. The correction of P values in Finnish, Saami, and Sardinian was recalculated to amend the mistakes by Zavattari et al. (2000).inLocus PairDistanceaData are from Laan and Pääbo (1997). (cM)Japanese (n=100)Japanese (n=80)cReduced sample was obtained by the randomization test described by Varilo et al. (2000).Khalkh (n=83)Khoton (n=40)Uriankhai (n=55)Zakhchin (n=59)European American (n=49)Finnish (n=80)aData are from Laan and Pääbo (1997).Saami (n=54)aData are from Laan and Pääbo (1997).Sardinian (n=73)dData are from Zavattari et al. (2000).DXS995-DXS9834.0.480.2911.000.003.097.927.030.508.012.394DXS995-DXS9862.5.068.051.326.011.482.402.328.729.000.482DXS995-DXS80922.4.120.055.076.047.185.625.755.115.104.829DXS995-DXS80822.3.034.033.095.013.579.021.662.128.000.430DXS1225-DXS9832.0.227.151.165.000.773.449.243.630.000.169DXS995-DXS80372.0.517.310.072.070.563.907.182.874.124.650DXS8037-DXS9832.0.515.342.449.000.019.521.604.683.300.036DXS995-DXS12252.0.910.388.062.002.654.469.282.154.001.355DXS8082-DXS9831.7.064.096.556.002.922.970.448.565.000.142DXS8092-DXS9831.6.383.065.318.051.154.796.458.314.000.876DXS986-DXS9831.5.276.071.407.011.835.210.530.829.000.825DXS8037-DXS986.5.139.179.150.035.046.190.929.620.000.302DXS1225-DXS986.5.003.002.000.000.019.098.233.393.000.166DXS1225-DXS8092.4.002.004.105.000.047.211.583.283.000.921DXS8037-DXS8092.4.426.294.000.086.025.000.723.180.000.285DXS8037-DXS8082.3.373.353.008.000.000.001.219.238.012.630DXS1225-DXS8082.3.000.000.000.000.000.000.000.000.000.000DXS8082-DXS986.2.000.000.001.000.001.004.524.092.000.322DXS8092-DXS986.1.612.003.161.000.021.004.502.331.000.125DXS8082-DXS8092.1.051.014.910.000.017.300.115.044.000.319DXS8037-DXS1225.0.372.301.000.000.000.000.198.836.091.710a Data are from Laan and Pääbo (Laan and Pääbo, 1997Laan M Pääbo S Demographic history and linkage disequilibrium in human populations.Nat Genet. 1997; 17: 435-438Crossref PubMed Scopus (139) Google Scholar).b The values that are significant only before correction are underlined, whereas the values that are significant even after the step-down Holm-Sidack correction (Ludbrook Ludbrook, 1998Ludbrook J Multiple comparison procedures updated.Clin Exp Pharmacol Physiol. 1998; 25: 1032-1037Crossref PubMed Scopus (455) Google Scholar) are given in boldface italics. The correction of P values in Finnish, Saami, and Sardinian was recalculated to amend the mistakes by Zavattari et al. (Zavattari et al., 2000Zavattari P Deidda E Whalen M Lampis R Mulargia A Loddo M Eaves I Mastio G Toddo JA Cucca F Major factors influencing linkage disequilibrium in distinct populations: demography, chromosome recombination frequency and selection.Hum Mol Genet. 2000; 9: 2947-2957Crossref PubMed Scopus (96) Google Scholar).c Reduced sample was obtained by the randomization test described by Varilo et al. (Varilo et al., 2000Varilo T Laan M Hovatta I Wiebe V Terwilliger JD Peltonen L Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo.Eur J Hum Genet. 2000; 8: 604-612Crossref PubMed Scopus (46) Google Scholar).d Data are from Zavattari et al. (Zavattari et al., 2000Zavattari P Deidda E Whalen M Lampis R Mulargia A Loddo M Eaves I Mastio G Toddo JA Cucca F Major factors influencing linkage disequilibrium in distinct populations: demography, chromosome recombination frequency and selection.Hum Mol Genet. 2000; 9: 2947-2957Crossref PubMed Scopus (96) Google Scholar). Open table in a new tab The Khalkh showed a relatively higher level of LD than the Japanese. The largest genetic distance for the significant LD was 2.3 cM, and that for the suggestive LD was 2.5 cM. Three pairs still showed the significant LD even after correction, with a largest distance of 0.4 cM (DXS1225-DXS8092). Of the three Mongolian subpopulations, the Khoton had the largest number of pairs, almost all of which showed significant LD even after the correction, with an extent similar in magnitude to that in the Saami population. Before the correction, 18 of 21 pairs showed significant LD, with the remaining pairs showing suggestive LD. After the correction, 13 pairs remained significant for the largest distance reached, 4.0 cM (DXS995-DXS983). In contrast, the two remaining subpopulations, the Uriankhai and Zakhchin, had four pairs showing significant LD after correction, with largest distances of 0.3 cM (DXS8037-DXS8082) and 0.4 cM (DXS8037-DXS8092), respectively. The strongest statistical significance and largest distance for LD in this study was observed in the Khoton. The background LD in the Khoton could be explained by strong isolation and constant population size. On the other hand, it should be noted that the microsatellite allelic diversity was generally greater in the Khoton than in the other Asian populations and that the average haplotype mismatch distance in the Khoton was also high, with a large variance (table 2). Moreover, the FST values obtained using SNPs on mtDNA and microsatellites on the X chromosome showed the close relationship between the Khoton and either the Europeans and Asians (see Appendix 4 at the authors' Web site). Therefore, the long-range LD in the Khoton may be the result of admixture between the Asian and European populations. However, many data from historical, ethnological, and anthropological studies previously performed in Mongolia suggest that the Khoton population was of Turkish origin and that there was no obvious admixture between the Khoton and other Mongolian populations (Batsuuri Batsuuri, 1977Batsuuri J Anthropological characteristics of the ethnic group “Khoton.”.Proceedings of the Institute of General and Experimental Biology, Mongolian Academy of Sciences, Ulaanbaatar, Mongolia. 1977; 12: 111-127Google Scholar; Nyambuu Nyambuu, 1992Nyambuu K Introduction to the ethnography of Mongolia. Mongolian State Press, Ulaanbaatar, Mongolia1992Google Scholar). It is worth mentioning that, in contrast to the high allelic diversity of microsatellites, the mtDNA nucleotide diversity in the Khoton was the smallest of the values among the Asian populations (table 1). Taken together with the similar propensity for these diversities in the Saami, the inconsistency could be explained by the difference between the marker types. In addition, the average pairwise mismatch of haplotypes in the Khoton was not a bimodal distribution, which is the distribution that would be predicted for an admixed population (see online-only figure). The Khoton population was known to have the closest genetic relationship with the Turkish Kyrgyz (Batsuuri Batsuuri, 1978Batsuuri J Genetic structure of the ethnic group “Khoton.”.Proceedings of the Institute of General and Experimental Biology, Mongolian Academy of Sciences, Ulaanbaatar, Mongolia. 1978; 13: 115-129Google Scholar). The bilaterally close relationship in the Khoton that is implied by the FST value may reflect the original character of an ancestral population, such as the Kyrgyz, rather than admixture in the Khoton. Moreover, although the Uriankhai and Zakhchin are obviously admixed populations with constant sizes, the extent of their LD was smaller than that of the Khoton. These facts suggest that the strong LD with long distance in the Khoton was contributed mainly by the isolation and constant size rather than by the admixture, even if there was some minor admixture. Our analysis is, to our knowledge, the first report on genetic isolates in East Asia. Although our results were restricted to the X chromosome and mtDNA, they were consistent with demographic, historical, ethnological, and anthropological studies of these populations. Studies of the Khoton, Uriankhai, and Zakhchin populations could play an important role in initial gene mapping of complex diseases, and studies of the Japanese and Khalkh populations could be applied to the fine mapping of either complex or monogenic diseases (Yu et al. Yu et al., 1996Yu CE Oshima J Fu YH Wijsman EM Hisama F Alisch R Matthews S Nakura J Miki T Ouais S Martin GM Mulligan J Schellenberg GD Positional cloning of the Werner's syndrome gene.Science. 1996; 272: 258-262Crossref PubMed Scopus (1440) Google Scholar; Graham and Thompson Graham and Thompson, 1998Graham J Thompson EA Disequilibrium likelihoods for fine-scale mapping of a rare allele.Am J Hum Genet. 1998; 63: 1517-1530Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). We would like to thank R. Sato, A. Yamamoto, S. Adachi, M. Tomizawa, and A. Denda, in our laboratory, for technical assistance. We also thank Dr. N. Saito, in the National Institute for Genetics, for his valuable suggestions. This work was partly supported by a Grant-in-Aid for Scientific Research on Priority Areas (C) “Medical Genome Science,” from the Ministry of Education, Science, Sports, and Culture of Japan.
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