Japanese and Korean populations’ genetic affinity to the ancient Silk Road populations of north-central China and Iran, highlighted by the shared ADH1B*47Arg ancestral allele

Researchers find that ancient Silk Road Northeast Asian populations (Chinese, Japanese and Koreans) and West Asians (Iran and Turkey) are connected by a common ancestral marker – the ADH1B*47His allele. The ancestral marker is highly prevalent in Asian populations, particularly in northeast Asians (i.e., Chinese, Japanese, and Koreans). Except for in East Asia, a high frequency of the ADH1B*47His allele is also found in Iran and Turkey. Such a worldwide double-peak pattern of frequency distribution of the ADH1B*47His allele was argued to be the result of independent increase of the derived allele in both western and eastern Asia after humans had spread across Eurasia.

Global distribution of the frequency for ADH1B*47His allele shows a clear east-to-west decline, where specifically it is dominant in East/West Asia, moderate in southeast Asia and rare in other continents. Such a distribution pattern was considered to be related to the selection of the Arg47His polymorphism of ADH1B, which was, it is alleged, along the emergence and expansion of rice domestication in East Asia [or was it along the nomadic trail of expanding rice-wine or rice alcohol consumption???]

The marker is related to disease susceptibility and natural selection as well. Researchers proposed the ADH1B*47His allele may serve better as an ancestral marker for understanding expansions and migrations of ancient Central China populations, and that ADH1B*47Arg is a risk factor for ESCC in Asian populations that stems from recent common ancestralness of them. The delineated populations with the common ancestries are said to dwell along the “Asian esophageal cancer belt”.

[In addition, another study tentatively concluded there was also a genetic association between mtDNA haplogroups (D4a and D5a) and esophageal cancer, and that the EC high-risk populations in three areas (the Taihang Mountain range of north-central China, the Minnan area of Fujian province, and the Chaoshan plain of Guangdong province ) share a similar matrilineal genetic background, and that D4a and D5a might be candidate genetic markers for screening populations susceptible to EC in the Chaoshan area.]

See source references and further readings below:

Zhang G, Mai R, Huang B (2010) ADH1B Arg47His Polymorphism Is Associated with Esophageal Cancer Risk in High-Incidence Asian Population: Evidence from a Meta-Analysis. PLoS ONE 5(10): e13679. doi:10.1371/journal.pone.0013679 (Excerpted below)

Both historical records of migration and genetic fingerprints of East Asians and ancient population in Central China suggested there were some common ancestries in populations along the “Asian esophageal cancer belt”. The ADH1B*47His allele is highly prevalent in Asian populations, particularly in northeast Asians (i.e., Chinese, Japanese, and Koreans). It was proposed the ADH1B*47His allele may serve better as an ancestral marker for understanding expansions and migrations of ancient Central China populations, and is related to disease susceptibility and natural selection as well [29]. Except for in East Asia, a high frequency of the ADH1B*47His allele is also found in West Asian countries such as Iran and Turkey, where high-incidence regions of ESCC exist, too [9]. Such a worldwide double-peak pattern of frequency distribution of the ADH1B*47His allele was argued to be the result of independent increase of the derived allele in both western and eastern Asia after humans had spread across Eurasia [9]. Based on these facts and findings, we propose that ADH1B*47Arg is a risk factor for ESCC in Asian populations that stems from recent common ancestralness of them.

Global distribution of the frequency for ADH1B*47His allele shows a clear east-to-west decline, where specifically it is dominant in East/West Asia, moderate in southeast Asia and rare in other continents [7], [8], [9], [10]. Such a distribution pattern was considered to be related to the selection of the Arg47His polymorphism of ADH1B, which was along the emergence and expansion of rice domestication in East Asia [11] [and/or rather to probably to the related expansion of rice-wine or rice alcohol consumption.]

The Arg47His (rs1229984) polymorphism of ADH1B is the highest in East Asians, and ancient migrations along the Silk Road were thought to be contributive to a frequent ADH1B*47His allele in Central Asians. This polymorphism was identified as responsible for susceptibility in the first large-scale genome-wide association study of ESCC and that’s explained by its modulation of alcohol oxidization capability…

ADH1B*47Arg as a common ancestral allele can interact with alcohol drinking and … significantly increase the risk of ESCC in Asians, especially when coupled with alcohol drinking or the ALDH2*504Lys allele.

A significantly increased risk was found for ADH1B*47Arg when combined with moderate or heavy alcohol consumption. For example, ADH1B Arg/Arg was found associated with 1.2 and 74 times increased risk in non-drinkers and drinkers, respectively, compared to non-drinkers with the ADH1B His/His genotype …

Hui Li, Namita Mukherjee, […], and Kenneth K. Kidd Geographically Separate Increases in the Frequency of the Derived ADH1B*47His Allele in Eastern and Western Asia, American Society of Human Genetics

Abstract

The ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived ADH1B*47His allele reaches high frequencies only in western and eastern Asia. To pursue this pattern, we report here new frequency data for 37 populations. Most of our data are from South and Southeast Asia and confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia.

It has been >30 years since variation in alcohol dehydrogenase (ADH) was shown to be associated with alcoholism.1 The ADH1B (MIM 103720) and ADH1C (MIM 103730) genes, which encode the primary ADH enzymes for alcohol metabolism in the liver, both harbor polymorphisms resulting in functional differences in their respective enzymes. The evolutionarily derived ADH1B*47His allele (previously called “ADH2*2”) results in enhanced catalytic activity, increased blood levels of acetaldehyde, flushing, and protection from alcoholism.2–5 These phenotypic changes are also associated with some other polymorphisms in the ADH region, but the associations are weaker or are not consistently replicated.6,7 Variants at ADH1C may be responsible for weak effects in Europeans, and linkage disequilibrium between variants in either gene may explain these results. In any case, the ADH1B Arg47His polymorphism (rs1229984) is the SNP generally regarded as the most important with respect to alcoholism (or alcoholism protection) in the ADH gene family in Asia.

The frequency of the evolutionarily derived ADH1B*47His allele is particularly high in eastern Asian populations (often exceeding 80%), but the allele is almost absent in sub-Saharan, European, and Native American populations. The high frequency of the derived allele in Asia could have resulted from either of two possible evolutionary processes: (1) a selective advantage existing only in eastern Asia for the allele or (2) random genetic drift increasing the frequency of the allele in eastern Asia. Indeed, we recently showed8 that positive selection led to the high frequency in some eastern Asian populations, most especially in Japanese and Koreans. However, we have also observed that there is another region of relatively high frequency (>40%) of the ADH1B*47His allele in southwestern Asia and in populations deriving from southwestern Asia.9 However, the few population samples we have studied from central Asia lacked or had very low frequencies of ADH1B*47His…

A discontinuity between two high-frequency regions, western Asia and eastern Asia, appears in South Asia and the western part of Southeast Asia. The route from western Asia, via South Asia and Southeast Asia, to eastern Asia is one of the supposed routes of modern human expansion in Asia.13 The observed gap supports an argument against maintenance of the high western Asian frequency throughout this expansion. Another supposed route of expansion is via central Asia. Although there are few samples in the region and the frequencies are somewhat higher than those in South Asia, the frequencies are still much lower than those to the west and the east. Historic events such as travel along the Silk Road, Ghengis Khan’s conquests, and recent migrations—such as the movement of the Han Chinese to Xinjiang and the Xibo population from northeastern China to Xinjiang during the Qing Dynasty—could all have contributed to these somewhat higher central Asian frequencies. It is noteworthy that the derived allele frequencies in two central Asian populations, the Uygur and Kazakh, are not high. Similarly, the Khanty from western Siberia lack the allele. These data strongly support the argument that a significantly lower frequency exists in central Asia, with two separate flanking regions of high frequency of the ADH1B*47His allele.

Plausible explanations for the observed high frequencies of ADH1B*47His in eastern and western Asia but not in between involve separate increases in frequency in the two regions. Either drift or natural selection could have been the cause of these high frequencies. There is strong evidence that natural selection is responsible in Koreans, Japanese, and Han Chinese8 but not in other eastern Asian populations in that study. However, a selective force could have been too weak to be detected but still strong enough to have resulted in the widespread distribution of the ADH1B*47His allele in eastern Asia. Or, gene flow could have spread the allele into populations in which selection was not operating, since there seem to be no strongly detrimental fitness consequences of having the allele in areas where natural selection could not be detected. In this expanded study, which combines all known data from the literature with new data about many relevant populations, we have shown that the pattern of the ADH1B*47His distribution is more complicated than was previously apparent. In western Asia, the highest frequencies appear in the Persians, Turks, Samaritans, and Jews from a variety of regions. These populations belong to three different linguistic families—Indo-European (Iranian), Altaic (Turks), and Afro-Asiatic (Semitic). This linguistic difference provides an argument against a recent common origin of these groups, although their geographic proximity may have allowed considerable gene flow among them in more recent millennia.

At least three hypotheses may explain the observed allele-frequency pattern of ADH1B*47His: two independent mutations, loss of the allele from intervening populations, and local selective factors. We can confidently exclude independent mutation, because the haplotype phylogeny clearly shows overall strong linkage disequilibrium but a recombination event on one side of the Arg47His site that distinguishes the southwestern Asian from eastern Asian haplotypes.9,14,15 Hypothesizing the loss of the allele from central and South Asian populations requires explanation of several facts. Implicit is the assumption that the high frequency arose in southwestern Asia and was carried into eastern Asia. However, if the derived allele were always frequent, the western Asian haplotype should also be found in eastern Asia, because it would have been the common haplotype initially, and total replacement by the recombinant haplotype would have been very unlikely. The western Asian haplotype has never been observed in the several eastern Asian populations studied for the necessary polymorphisms.9 Also, there has never been evidence that ADH1B*47His itself was selected against and, therefore, no reason to speculate that selection eliminated the allele in South and central Asia. Local selection focused on the genomic region containing ADH1B*47His is already strongly supported for eastern Asian populations.8 We speculate that a low allele frequency had been maintained in different Asian populations after the settlements of western, central, South, and eastern Asia. Because the allele frequency was quite low, different haplotypes easily drifted to different frequencies, including complete loss, in different geographic regions. Then, at a relatively recent time, local selective factors on this allele or on one tightly linked increased the allele frequency in eastern Asia.8 The high frequency in western Asia might have resulted from local selection or might have simply resulted from random drift during population expansion but after human expansion into Europe. So far, there is no evidence of selection in western Asia, but the data are incomplete. In either case, the data presented here support the argument that the high allele frequency must have occurred independently…

We can confidently exclude independent mutation, because the haplotype phylogeny clearly shows overall strong linkage disequilibrium but a recombination event on one side of the Arg47His site that distinguishes the southwestern Asian from eastern Asian haplotypes.9,14,15 Hypothesizing the loss of the allele from central and South Asian populations requires explanation of several facts. Implicit is the assumption that the high frequency arose in southwestern Asia and was carried into eastern Asia. However, if the derived allele were always frequent, the western Asian haplotype should also be found in eastern Asia, because it would have been the common haplotype initially, and total replacement by the recombinant haplotype would have been very unlikely. The western Asian haplotype has never been observed in the several eastern Asian populations studied for the necessary polymorphisms.9 Also, there has never been evidence that ADH1B*47His itself was selected against and, therefore, no reason to speculate that selection eliminated the allele in South and central Asia. Local selection focused on the genomic region containing ADH1B*47His is already strongly supported for eastern Asian populations.8 We speculate that a low allele frequency had been maintained in different Asian populations after the settlements of western, central, South, and eastern Asia.

Borinskaya S, Distribution of the alcohol dehydrogenase ADH1B*47His allele in Eurasia. Am J Hum Genet. 2009 Jan;84(1):89-92; author reply 92-4. doi: 10.1016/j.ajhg.2008.12.007.

The data were based on meta-analysis of the published results for 131 populations and the results of genotyping of samples from 37 additional populations, performed by the authors. The authors made the suggestion that there had been separate and independent increases in the frequency of the ADH1B*47His allele in Eastern and Western Asia. Their worldwide-frequency-distribution diagram for this allele also includes the previous reports that there is a regional elevation in the ADH1B*47His allele for Eastern Europeans (Russians). The authors acknowledged that Central Asian population data that would support their conclusion about this distribution are, as yet, absent.

The allele-frequency data derived from the two previous studies2,3 were essential for the hypothesis that a local maxima for distribution of ADH1B*47His might exist on the Russian Plain and in Southwest Asia.1 We noted, however, that the frequencies of the ADH1B*47His allele presented in these studies for Russians2 and Iranian populations3 are significantly distinct from the allele frequency for the same or neighboring population groups reported in other studies.4–7

As indicated by Li et al.,1 “the Moscow Russian sample appears anomalous with a fairly high frequency (41%) of ADH1B*47His” resulting in a local maximum in the central part of the Russian Plain on the allele-frequency map (Figure 2 in Li et al.1). In addition, in another study,8 the frequency of the allele for Russians in Siberia was also found to be relatively high (∼20%), which is significantly different from other European populations. To estimate the frequency among Russians more extensively, we have carried out further genotyping in Muscovites and in other Russian populations from different geographic regions (Table 1). The frequency of the ADH1B*47His allele in Russians across the country (including both European and Asian parts of Russia) varies between 1.9% and 7.6%, with a mean frequency of 4.9% in the total group of 1019 Russian individuals. These data agree with other data on ADH1B*47His allele frequency for Northern Russian populations of Archangelsk (5%)9 and Vologda (6%)4, and are similar to the frequencies that we estimated for the closest relative Slavic groups (Ukrainians and Byelorussians; see Table 1).

A second study3 used by Li et al. for their comparative allele-frequency estimation in Western Asia shows that the frequency of ADH1B*47His in Iran is also relatively high (46% in Turks from Iran, 68% in Persian Zoroastrians from Iran, and 51% in Turkmen from Northeastern Iran bordering Turkmenistan) compared with the main part of other populations from the same geographic area…. Because ADH1B, ADH1A, and ADH1C are highly homologous genes, the genotyping requires highly specific PCR primers for the ADH1B gene. We previously genotyped a limited number of individuals from Iran and found a significantly lower frequency of the allele (24%),5 a value that is close to the allele frequency in another population in the region (Druze, 27%).4 We have also tested samples from Southern Turkmen native to a region bordering Northern Iran and found a similar frequency (20.4%). Given the ADH1B*47His frequency in Turks that was reported earlier (12.5%),7 the general frequency of the allele in Western Asia is at least 2- to 3-fold lower than that in the data from the literature used by Li et al.1 for the estimation of geographic distribution. The Samaritans are another population group from Southwest Asia who have a very high frequency of the allele and were also employed in their analysis.1,4 They are a genetic isolate with an apparent bottleneck in their recent evolutionary history, which results in marked genetic differences between Samaritans and other populations in the region.10,11 In other Southwest Asian groups, Yemenites and Sephardic Jews, the frequency of the allele reached a maximum of 41%,4 with an average frequency ∼30% in this region. The mean is much lower than that used for genogeography reconstruction.1

To estimate the detailed geographic distribution of the ADH1B*47His allele, we genotyped 23 populations across Asia, including Central Asian populations (Table 1). The overall allele frequencies in Southwestern Asia were relatively close to those in Central Asia (∼19%–32%). Thus, the discontinuity between West and East Asia seems to be less pronounced than previously suggested1 (Figure 1).

As was shown, Southeast Asia has the highest recorded allele frequency (70% and higher), whereas South Asia as a whole has a relatively low frequency of the ADH1B*47His allele (∼10% or lower). According to our data, the Southwest Asian local maximum reaches 30% frequency and is connected with the Southeast Asian maximum via the Asian steppe belt, where the average allele frequency is ∼20%–30%. The frequency from the steppe region toward the North and West reduces gradually in the range of ∼10%–16% in populations across the Caucasus and Volga-Ural regions. The only exception is the Kalmyk population (26.3%), with ancestor roots from Mongol-Oirat tribes, who migrated to this region from Central Asia approximately 300 years ago. This frequency is similar to those in other related Mongoloid groups (Altaians and Buryats) (Table 1) and might reflect a relatively high frequency of the allele in ancestor Mongoloid groups in Central Asia.

Xiao-Yun Lia,et al., mtDNA evidence: Genetic background associated with related populations at high risk for esophageal cancer between Chaoshan and Taihang Mountain areas in China DOI: 10.1016/j.ygeno.2007.06.006

There are three major geographic regions in China known for their high incidences of esophageal cancer (EC): the Taihang Mountain range of north-central China, the Minnan area of Fujian province, and the Chaoshan plain of Guangdong province. Historically, waves of great population migrations from north-central China through coastal Fujian to the Chaoshan plain were recorded. To study the genetic relationship among the related EC high-risk populations, we analyzed mitochondrial DNA (mtDNA) haplogroups based on 30 EC patients from Chaoshan and used control samples from the high-risk populations, including 48, 73, and 89 subjects from the Taihang, Fujian, and Chaoshan areas, respectively. The principal component of all haplogroups, correlation analysis of haplogroup frequency distributions between populations, and haplogroup D network analysis showed that compared with other Chinese populations, populations in the three studied areas are genetically related. The highest haplogroup frequency shared by all studied populations was haplogroup D, with much higher frequency in the Chaoshan area EC patients. The majority of haplogroup D individuals among the Chaoshan area EC patients belonged to subhaplogroups D4a and D5a, with the total frequency of these two haplogroups significantly higher than that in the high-risk population in the same area (χ2 = 9.017, p < 0.01). In conclusion, EC high-risk populations in these three areas share a similar matrilineal genetic background, and D4a and D5a might be candidate genetic markers for screening populations susceptible to EC in the Chaoshan area. Ours is the first report to show the association between mtDNA haplogroups (D4a and D5a) and esophageal cancer.

 
Li H.et al., Geographically Separate Increases in the Frequency of the Derived ADH1B*47His Allele in East and West Asia. Am. J. Hum. Genet. 2007;81:842–846.

The ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived ADH1B*47His allele reaches high frequencies only in western and eastern Asia It has been >30 years since variation in alcohol dehydrogenase (ADH) was shown to be associated with alcoholism.1 The ADH1B (MIM 103720) and ADH1C (MIM 103730) genes, which encode the primary ADH enzymes for alcohol metabolism in the liver, both harbor polymorphisms resulting in functional differences in their respective enzymes. The evolutionarily derived ADH1B*47His allele (previously called “ADH2*2”) results in enhanced catalytic activity, increased blood levels of acetaldehyde, flushing, and protection from alcoholism.2–5 These phenotypic changes are also associated with some other polymorphisms in the ADH region, but the associations are weaker or are not consistently replicated.6,7 Variants at ADH1C may be responsible for weak effects in Europeans, and linkage disequilibrium between variants in either gene may explain these results. In any case, the ADH1B Arg47His polymorphism (rs1229984) is the SNP generally regarded as the most important with respect to alcoholism (or alcoholism protection) in the ADH gene family in Asia.

The frequency of the evolutionarily derived ADH1B*47His allele is particularly high in eastern Asian populations (often exceeding 80%), but the allele is almost absent in sub-Saharan, European, and Native American populations. The high frequency of the derived allele in Asia could have resulted from either of two possible evolutionary processes: (1) a selective advantage existing only in eastern Asia for the allele or (2) random genetic drift increasing the frequency of the allele in eastern Asia. Indeed, we recently showed8 that positive selection led to the high frequency in some eastern Asian populations, most especially in Japanese and Koreans. However, we have also observed that there is another region of relatively high frequency (>40%) of the ADH1B*47His allele in southwestern Asia and in populations deriving from southwestern Asia.9…

Plausible explanations for the observed high frequencies of ADH1B*47His in eastern and western Asia but not in between involve separate increases in frequency in the two regions. Either drift or natural selection could have been the cause of these high frequencies. There is strong evidence that natural selection is responsible in Koreans, Japanese, and Han Chinese8 but not in other eastern Asian populations in that study. However, a selective force could have been too weak to be detected but still strong enough to have resulted in the widespread distribution of the ADH1B*47His allele in eastern Asia. Or, gene flow could have spread the allele into populations in which selection was not operating, since there seem to be no strongly detrimental fitness consequences of having the allele in areas where natural selection could not be detected. In this expanded study, which combines all known data from the literature with new data about many relevant populations, we have shown that the pattern of the ADH1B*47His distribution is more complicated than was previously apparent. In western Asia, the highest frequencies appear in the Persians, Turks, Samaritans, and Jews from a variety of regions. These populations belong to three different linguistic families—Indo-European (Iranian), Altaic (Turks), and Afro-Asiatic (Semitic). This linguistic difference provides an argument against a recent common origin of these groups, although their geographic proximity may have allowed considerable gene flow among them in more recent millennia.

At least three hypotheses may explain the observed allele-frequency pattern of ADH1B*47His: two independent mutations, loss of the allele from intervening populations, and local selective factors. We can confidently exclude independent mutation, because the haplotype phylogeny clearly shows overall strong linkage disequilibrium but a recombination event on one side of the Arg47His site that distinguishes the southwestern Asian from eastern Asian haplotypes.9,14,15 Hypothesizing the loss of the allele from central and South Asian populations requires explanation of several facts. Implicit is the assumption that the high frequency arose in southwestern Asia and was carried into eastern Asia. However, if the derived allele were always frequent, the western Asian haplotype should also be found in eastern Asia, because it would have been the common haplotype initially, and total replacement by the recombinant haplotype would have been very unlikely. The western Asian haplotype has never been observed in the several eastern Asian populations studied for the necessary polymorphisms.9 Also, there has never been evidence that ADH1B*47His itself was selected against and, therefore, no reason to speculate that selection eliminated the allele in South and central Asia. Local selection focused on the genomic region containing ADH1B*47His is already strongly supported for eastern Asian populations.8 We speculate that a low allele frequency had been maintained in different Asian populations after the settlements of western, central, South, and eastern Asia. Because the allele frequency was quite low, different haplotypes easily drifted to different frequencies, including complete loss, in different geographic regions. Then, at a relatively recent time, local selective factors on this allele or on one tightly linked increased the allele frequency in eastern Asia.8 The high frequency in western Asia might have resulted from local selection or might have simply resulted from random drift during population expansion but after human expansion into Europe…

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