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Nakaoka H, et al.Detection of ancestry informative HLA alleles confirms the admixed origins of Japanese population．PLoS One. 2013; 8(4):e60793. Epub 2013 Apr 5.
Abstract:
The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A,-B,-C,-DRB1, and-DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula.
The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. Theserologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions．It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asianswho moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.
最近,现代日本流行的基因结构开云体彩官网ulation was examined by using genome-wide single nucleotide polymorphisms (SNPs) data [17]. They found that Japanese individuals were grouped into two clusters: mainland and Okinawa clusters. Furthermore, they found that the HLA region was one of the most differentiated region between mainland and Okinawa clusters [17], [18]. Population genetics studies using HLA alleles have demonstrated that Okinawa have close affinity to Ainu people who are indigenous Japanese and live in northernmost island [19], [20]. Mainland Japanese share a large part of HLA haplotypes with South Korean [21]–[23]. Multiple migration routes to Japan were deduced by examining HLA haplotype distribution among Asian populations at the 2-digit level of resolution [24]. Tokunaga and colleagues pointed out genetic links between East Asians and Native Americans [25].
The origin of modern Japanese has long been debated. It is thought that there are at least two waves of migrations to the Japanese Archipelago. The ancestors of the Jomon people migrated to the Japanese Archipelago in the Upper Paleolithic age (approximately 30,000 years ago). The new migrants, the Yayoi people, came through the Korean Peninsula in the Aeneolithic period (300 BC to 300 AD). The prevailing model for peopling of Japan is the admixture model or “dual structure model” in which modern Japanese was formed by admixture between the Jomon and Yayoi people[11]．Based on morphological studies of teeth and crania, Hanihara proposed that the earlier migrants were from southern Asian lineage whereas the subsequent migrants were from northern Asian lineage[11]．The validity of the admixture hypothesis was partly demonstrated by showing that Japanese populations had close affinity to East Asian populations, especially Korean, and mainland Japanese were located in the middle of Korean and indigenous Japanese populations by the phylogenic analysis[12]．The exhaustive search for the sharing of mitochondrial DNA and Y-Chromosome haplotypes among populations deduced that the ancestors of Jomon people originated from northern and central Asia and the ancestors of Yayoi people came from southern Asia, in contrast to the morphological studies[13]–[16]．整个archip外加剂的程度不同elago, which may influence genetic structure of modern Japanese[16]．
最近,现代日本流行的基因结构开云体彩官网ulation was examined by using genome-wide single nucleotide polymorphisms (SNPs) data[17]．They found that Japanese individuals were grouped into two clusters: mainland and Okinawa clusters. Furthermore, they found that the HLA region was one of the most differentiated region between mainland and Okinawa clusters[17],[18]．Population genetics studies using HLA alleles have demonstrated that Okinawa have close affinity to Ainu people who are indigenous Japanese and live in northernmost island[19],[20]．Mainland Japanese share a large part of HLA haplotypes with South Korean[21]–[23]．Multiple migration routes to Japan were deduced by examining HLA haplotype distribution among Asian populationsat the 2-digit level of resolution[24]．Tokunaga and colleagues pointed out genetic links between East Asians and Native Americans[25]．
在this article, we investigated genetic structure of Japanese population by using five-locus HLA genotype data for 2,005 subjects. We examined genetic differentiation among 10 geographical regions across Japan by using the principal component analysis (PCA) and we found a significant level of population substructure in Japanese population. By using a plot of the principal component scores (PCSs), we identified ancestry informative HLA alleles and haplotypes associated with the substructure. We demonstrated that the identified HLA alleles and haplotypes were informative to infer ancestral source populations of Japanese. The results of this study provide evidence to support the admixture model for peopling of Japanese Archipelago.
Principal component analysis for the identification of ancestry informative alleles
Figure 2Ashows the result of the PCA of 10 regional populations. Contributions of the first and second components were 49.1% and 15.1%, respectively. Each of the third and subsequent components explained less than 10%. A main cluster including Hokkaido, Tohoku, Kanto, Tokai, Kinki, Chugoku, and Kyushu was formed. The first component was related to the division between Okinawa and mainland groups. The second component seems to explain the variability among mainland groups. Hokuriku and Shikoku were slightly apart from the main cluster. This is consistent with the result shown inTable 2．As a reference, the result of single-locus PCA is shown inFigure S1．在all single-locus PCAs, both ends of the first component were Okinawa and Hokuriku, and Shikoku was closest to Okinawa in terms of the first component, suggesting that the result from the single-locus PCAs reflects the substructure underlying Japanese regional populations.
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25. Tokunaga K, Ohashi J, Bannai M, Juji T (2001) Genetic link between Asians and native Americans: Evidence from HLA genes and haplotypes. Hum Immunol 62: 1001–1008. [PubMed] [Ref list]
We focused on the alleles located in the middle of the bottom half of Figure 5B (A*24:02, C*03:04, C*07:02, B*40:02, and DRB1*09:01; referred to as CL5), which were characterized by higher frequency in Japanese compared to South Korean. Among them, C*03:04 and B*40:02 were in LD (D′=0.940 and 0.755 in Okinawa and mainland, respectively) (Figure 4E).The haplotype C*03:04-B*40:02 were frequent in mainland Japanese (6.30%) and Okinawa (8.72%) but infrequent in South Korean [21]. Therefore, we searched the prevalence of this haplotype in the AFND database (Table 5). The C*03:04-B*40:02 haplotype was observed in Aleuts (Bering Island [40]), Eskimos (Alaskan Yupik [39]), North-American Amerindians, Meso-American Amerindians (Tarahuara, Mixe, Mixtec, and Zapotec in Mexico [41], [42]), Taiwanese (Minnan), Taiwan’s aborigines (Tao, Ami, Paiwan, and Siraya), and Philippine aborigines (Ivatan)．For Taiwan’s populations except for the Tao people, the C*03:04-B*40:02 haplotype frequencies were not so high although the frequencies of C*03:04 and B*40:02 were high, indicating the difference in the LD structure (Table 5). The Tao (or Yami) people live on the Orchid Island off the east coast of Taiwan, and therefore are considered to be genetically isolated from the other Taiwan’s aborigines [43]. It is well known that the Tao and Ivatan people have close affinities in terms of genetic and linguistic characteristics [44].The Tao was the only population among Taiwan’s aborigines who had the haplotype A24-Cw10-B61 that was the serological equivalent encoded by A*24:02-C*03:04-B*40:02 and commonly observed in the Orochon, Mongolians, Inuit, Yakut, and Buryats [43]. The frequencies of A*24:02-C*03:04-B*40:02 haplotype were 2.41% and 3.21% in mainland and Okinawa, respectively. The aforementioned Aleuts, Eskimos and Amerindian populations carried A*24:02-C*03:04-B*40:02 at the high frequencies ranging from 1.9% to 6.9% (Table 5). These results suggest shared ancestry of early Japanese with the ancestral northern Asian lineage who crossed the Bering Strait land bridge and became founder population of the Native Americans.
The ten most frequent five-locus HLA haplotype made up only 19.9% of chromosomes in mainland Japanese, implying that the decay of LD generated segmented haplotypes during a long period of isolation of the Japanese population. The alleles characterized by high frequency in Okinawa (CL1) and by high frequency in Japanese compared to South Korean (CL5) showed lower levels of LD as depicted in Figure 4D and 4E, respectively, and did not form common five-locus haplotypes. Therefore, consideration on segmented haplotypes seems to be a straightforward approach to infer shared ancestry of prehistoric Japanese.The haplotype A*24:02-C*03:04-B*40:02 was observed in Japanese, Aleuts, Eskimos, North-American Amerindians and Meso-American Amerindians. The A24-Cw10-B61 haplotype, the serological equivalent encoded by A*24:02-C*03:04-B*40:02, was also frequent in Orchid Island in Taiwan, Mongol, Siberia and Arctic regions [43]. These findings suggest that the haplotype A*24:02-C*03:04-B*40:02 had been derived from early Japanese (Jomon people) who existed prior to the migration wave from the Korean Peninsula and this haplotype is one of the genetic footprints of the migration route of prehistoric ancient population from Asia to the New World.
The origin of East Asian has long been debated. The study based on genome-wide SNPs support the hypothesis that a single wave of migration coming from southern route populated East Asian populations.
Recent studies based on HLA alleles demonstrate that the pincer model fit better [54].The population entered Siberia by 45-40 thousand years ago (ka), and the offshoots of the population gave rise to early Japanese populat离子[55]。permafros的全基因组测序t-preserved hair from an ancient individual in Greenland demonstrated that early modern human who entered the New World was Asian rather than European [56]. It is thought that the first people crossed the Bering Strait land bridge to America by 15 ka. Recent genome-wide SNP study shows that the “First American” ancestry distributed through Native Americans but two additional waves of gene flow affected Eskimo-Aleut populations in the Arctic region and Na-Dene-speaking population in Canada [57]. Some authors identified genetic variants shared between Eurasia and North America [58]. These findings fit our result, suggesting that the haplotype A*24:02-C*03:04-B*40:02 originated from Asiaand diverged through the North to Central America by the “First American”.
The fact that Japanese have the haplotype, which was not detected in the Chinese and Korean but dispersed through the migration route of Americans, suggests prehistoric shared ancestry of Japanese with Northern Asian lineage. It is possible that East Asian populations including Chinese and Korean had shared this haplotype at the prehistoric age. During a long period, the haplotype might have disappeared from East Asians except for the isolated populations, Japanese and the Tao people in Orchid Island of Taiwan. At the same time, we detected the haplotypes whose constituent alleles are tightly linked, indicating the recent gene flow from the Korean Peninsula. There are two possible migration routes of the haplotypes whose constituent alleles show intermediate levels of LD: i) northern route through the Korean Peninsula or ii) southern route through Taiwan. If the latter is true, modern Japanese descend from at least three waves of migration from Asia. These results may support the admixed model for the peopling of Japan.
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We sought shared ancestry of the alleles in the CL1. The alleles with higher frequency in Okinawa (CL1) did not form common haplotypes. In Ainu people who were descendants of indigenous Japanese, some of the alleles were frequent (A*02:06, 20.0%;B*35:01, 11.0%) but the others were not so frequent (B*40:01, 6.0%; andDRB1*15:01, 2.0%)[20]．We scrutinized the prevalence of haplotypes carrying alleles that were frequent in Okinawa and Ainu and found that the haplotypeA*02:06–B*35:01was frequent in the Yupik people in Alaska (2.9%)[39]．
Finally, we performed the PCA approach including both Japanese and South Korean to identify the alleles that were differentiated between these populations (Figure 5). The first and second components explained 33.9% and 31.6% of variability, respectively. The first component distinguished between mainland and Okinawa. The second component captured differentiation between Japanese and South Korean (Figure 5A). According to the PCS plot (Figure 5B), we can find highly differentiated alleles between Japanese and South Korean at either end of the second component (e.g.,HLA-C*03:02,A*24:02, andA*33:03). We focused on the alleles located in the middle of the bottom half ofFigure 5B(A*24:02,C*03:04,C*07:02,B*40:02, andDRB1*09:01; referred to as CL5), which were characterized by higher frequency in Japanese compared to South Korean. Among them,C*03:04andB*40:02were in LD (D′= 0.940 and 0.755 in Okinawa and mainland, respectively) (Figure 4E). The haplotypeC*03:04-B*40:02were frequent in mainland Japanese (6.30%) and Okinawa (8.72%) but infrequent in South Korean[21]．Therefore, we searched the prevalence of this haplotype in the AFND database (Table 5). TheC*03:04-B*40:02单体型在反对者(白令海峡岛[40]), Eskimos (Alaskan Yupik[39]), North-American Amerindians, Meso-American Amerindians (Tarahuara, Mixe, Mixtec, and Zapotec in Mexico[41],[42]), Taiwanese (Minnan), Taiwan’s aborigines (Tao, Ami, Paiwan, and Siraya), and Philippine aborigines (Ivatan). For Taiwan’s populations except for the Tao people, theC*03:04–B*40:02haplotype frequencies were not so high although the frequencies ofC*03:04andB*40:02were high, indicating the difference in the LD structure (Table 5). The Tao (or Yami) people live on the Orchid Island off the east coast of Taiwan, and therefore are considered to be genetically isolated from the other Taiwan’s aborigines[43]．It is well known that the Tao and Ivatan people have close affinities in terms of genetic and linguistic characteristics[44]．The Tao was the only population among Taiwan’s aborigines who had the haplotypeA24-Cw10-B61that was the serological equivalent encoded byA*24:02-C*03:04-B*40:02and commonly observed in the Orochon, Mongolians, Inuit, Yakut, and Buryats[43]．The frequencies ofA*24:02-C*03:04-B*40:02haplotype were 2.41% and 3.21% in mainland and Okinawa, respectively. The aforementioned Aleuts, Eskimos and Amerindian populations carriedA*24:02-C*03:04-B*40:02at the high frequencies ranging from 1.9% to 6.9% (Table 5). These results suggest shared ancestry of early Japanese with the ancestral northern Asian lineage who crossed the Bering Strait land bridge and became founder population of the Native Americans.
consideration on segmented haplotypes seems to be a straightforward approach to infer shared ancestry of prehistoric Japanese. The haplotypeA*24:02-C*03:04-B*40:02was observed in Japanese, Aleuts, Eskimos, North-American Amerindians and Meso-American Amerindians. TheA24-Cw10-B61haplotype, the serological equivalent encoded byA*24:02-C*03:04-B*40:02, was also frequent in Orchid Island in Taiwan, Mongol, Siberia and Arctic regions[43]．These findings suggest that the haplotypeA*24:02-C*03:04-B*40:02had been derived from early Japanese (Jomon people) who existed prior to the migration wave from the Korean Peninsula and this haplotype is one of the genetic footprints of the migration route of prehistoric ancient population from Asia to the New World.
Another hypothesis known as “pincer model” of a separate migratory route from Central Asia together with southern route has been proposed for the origin of East Asian populations[52],[53]．Recent studies based on HLA alleles demonstrate that the pincer model fit better[54]．The population entered Siberia by 45-40 thousand years ago (ka), and the offshoots of the population gave rise to early Japanese population[55]．permafros的全基因组测序t-preserved hair from an ancient individual in Greenland demonstrated that early modern human who entered the New World was Asian rather than European[56]．It is thought that the first people crossed the Bering Strait land bridge to America by 15 ka. Recent genome-wide SNP study shows that the “First American” ancestry distributed through Native Americans but two additional waves of gene flow affected Eskimo-Aleut populations in the Arctic region and Na-Dene-speaking population in Canada[57]．Some authors identified genetic variants shared between Eurasia and North America[58]．These findings fit our result, suggesting that the haplotypeA*24:02-C*03:04-B*40:02originated from Asia and diverged through the North to Central America by the “First American”.
The fact that Japanese have the haplotype, which was not detected in the Chinese and Korean but dispersed through the migration route of Americans, suggests prehistoric shared ancestry of Japanese with Northern Asian lineage. It is possible that East Asian populations including Chinese and Korean had shared this haplotype at the prehistoric age. During a long period, the haplotype might have disappeared from East Asians except for the isolated populations, Japanese and the Tao people in Orchid Island of Taiwan. At the same time, we detected the haplotypes whose constituent alleles are tightly linked, indicating the recent gene flow from the Korean Peninsula. There are two possible migration routes of the haplotypes whose constituent alleles show intermediate levels of LD: i) northern route through the Korean Peninsula or ii) southern route through Taiwan. If the latter is true, modern Japanese descend from at least three waves of migration from Asia. These results may support the admixed model for the peopling of Japan.
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