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Guide to Patagonia's Monsters & Mysterious beings

I have written a book on this intriguing subject which has just been published.
In this blog I will post excerpts and other interesting texts on this fascinating subject.

Austin Whittall


Thursday, May 1, 2014

Alcohol, genes and human migrations... Part 2


The first part of this post dealt with the different metabolization rates of alcohol found in different ethnic groups. We looked into the enzimes responsible for breaking down alcohol in the body, and focused on ALDH or Alehyde Dehydrogenase, which in East Asians tends to work slower than in other populations and as a consequence, aldehyde builds up in the body causing nause, headache, flush and all those nasty symptoms of hangover.


We went over the different alleles of ALDH found in different pouplations and tried to elaborate some conclusions.


Today we will look at the other enzyme, the one that breaks down alcohol into aldehyde, alcohol dehydrogenase (ADH), which acts before ALDH.


It is interesting to point out that "the distribution of ADH2, ADH3 and ALDH2 alleles in previously studied Native Americans appears to be more similar to that of Caucasians than to that of Asians." [1], which is unusual since one would expect Amerindians to resemble their alleged Asian ancestors.


On ADH or Alcohol Dehydrogenase


The seven ADH genes in humans are located on chromosome 4. And they are related to five enzyme classes:

  • class I, ADH1A, ADH1B, and ADH1C
  • class II, ADH4
  • class III, ADH5
  • class IV, ADH7
  • class V, ADH6

Of these, a variety of ADH1B: ADH1B*47His (previously named “ADH2*2”) seems to have a protective effect in East Asians, where it is the most common allele, found at very high frequencies. It apparently appeared quite recently in that region, and may have grown to its present prevalence due to chance drift or positive selection (the evidence is still ambiguous to be able to define what mechanism operated on it).


Distribution of ADH1B*47 His in the old world
The Map shows the frequencies of ADH1B*47His in Asia. From [9]

The map above shows the distirbution of the ADH1B*47His allele across Asia. It is quite similar to the one presented by Hui et al. [2] shown below (posted in Part 1 of my post):


map alcohol dehydrogenase distribution
Global contour plot of ADH1B*47His Allele. From Fig. 2 in [2]

The interesting part is that, just as with the ALDH2*487Lys enzyme (see previous post), we have in ADH1B*47His another very specific East Asian enzyme for metabolizing alcohol. Which, is not found among American natives, their alleged descendants!


As usual, a young age for Amerindians


A paper (Hui Li, et al., 2011) [2] studied ADH1B*47His and identified several haplotypes, the "ancestral" one and seven main others (there are also 6 "sub-haplotypes").


The paper is very interesting, however when it comes down to estimating the age of these haplotypes the age of the American lineage is, as orthodoxy expects, "young".


To estimate the age of each haplotype the authors use a formula based on an STRP downstream of the ADH1B SNPs (this is similar to Oota's analysis of ALDH2*487Lys, I explain it in detail there, in my previous post), by taking the number of repeats at the STRP.


"where Ne is the effective population size, V is the STRP variance observed, µ is the mutation rate of the STRP, and t is the resulting number of generations." [2]


But they encounter a problem when applying this formula to the H2 haplotype found in America: "The age of H2 is not reliable because the lengths of the STRP alleles of this haplogroup are about at the minimum limit and not appropriate to the formula". [2]


The data summarized in a table gives the following expansion ages for H2 haplotype as: 1,500 years. Which is clearly incorrect since America was peopled at least 15 kya.


It is more on mark for other haplotypes: H4: 110.8 kya. And even H5, which is two mutations away from the ancestral H1 variant (note that the American H2 is only one mutation away from it) is given a rather old age of 53,800 years.


The key of the matter is in the "Variance" of the repeat numbers found in the STRP allele downstream of ADH1B*47His.


Whenever a Native American sample is considered, variance is lower and this is due to the massive loss of lineages during the Spanish Conquest: war, exploitation and especially Old World diseases for which the Amerindians had no defense, decimated the native populations, erasing alleles for ever. Those that survived, expanded, but the original variance was lost. The 500 years that have elapsed since this genocide, has not been enough to allow evolution to create more diversity.


As a consequence any formula based on variance or diversity will systematically underestimate the age of American haplogroups.


The authors recognize this but attribute the bottleneck to the peopling of America, and not to the much later event, the Discovery and Conquest: " H2b and H4 are predominant in the New World, while other haplogroups are almost absent, essentially lost along the way as modern humans entered the New World." [2]


They insist: "H1, H1b, H2, H3, and H4 formed a background for the Old World. Only H2, H2b, and H4 were introduced into the New World, where H2b and H4 became more common." [2]


Perhaps the other haplogroups were also introduced but got lost due to the attrition produced by European discovery in the XVIth century. To check this, samples would have to be taken from pre-Hispanic remains and sequenced. We need facts not assumptions.


Note that 18% of all humans belong to H2 haplogroup, but the proportion is variable: Sub Saharan Africans: 5.6%, Siberians: 31%, North American Natives: 45%, South American Natives: 72%. It is indeed an ancient lineage (since it is found in Subequatorial Africa).


Haplogroup H2b, derived from H2 is strongly American: half those carrying it are American, but the other half are distributed all over the world, even in Sub-Saharan Africa. A clear indication of its ancient origin.


H4 on the other hand is found in 31% of mankind, and also has an uneven distribution: Sub Saharan Africans: 52%, Siberians: 21%, North American Natives: 50%, South American Natives: 26%. The authors assign an age of 110,800 years to this haplogroup.


Another perspective on the same subject


Another study (Yi Han, et al., 2007) [3] sampled 42 populations from around the world analysing the haplotype pattern of SNPs 34–38 (ADH1B Arg47His, rs4147536, rs2075633, RsaI, and Val204Val) within the ADH1B gene. The authors identified the ancestral type (primates), 1CA1G haplotype (see image below, "ancestral") which is found in all non-East Asian populations at frequencies above 27% (exceptions, Micronesians: 12% and Samaritans: 8%). East Asians all have frequencies lower than 10%.


In contrast to that, South American Natives have values of around 65% (average) and peaks of 85%. For North American Indians, the values ranged from 30 to 62%.


So the "ancestral" type prevails in America. Notice that, as with other genetic traits, North American Natives are "closer" to Asians than South American Natives.


The 1CG2G ("old world") haplotype is found in all populations but is extremely rare among Native Americans. (Could it have become extinct during the Discovery-Conquest period?).


The 1AA1G haplotype is golbal too, but less frequent among East Asians, however it is the other important haplotype among Native Americans.


Haplotype 2CG2G ("asian") is rare all over the world and absent in America; it is predominant in East Asia at over 62% frequencies (except Cambodians: 34%). It is found in Siberians too.

The image below depicts these frequencies. In the green box, American Natives:


allele distribution
Global Haplotype distribution. From Fig. 5, in [3]

The study concludes that "selection has operated on the ADH1B gene in East Asia populations to increase one haplotype of the gene to high frequency" and adds that "It seems unlikely that the selection was recent and associated with alcoholism", it is more likely linked to resistance to mycotoxins and infectious disease (parasites). [3]


Why didn't these same selective forces not operate on other populations around the world? toxins and parasites are widespread, not only Asian? The explanation, in my opinion is lacking substance.


Note that alcohol which during the Neolithic was made out of fermented berries (Europe), mare's milk (Central Asia), coccoa beans (America), dates (Middle East) predates the discovery of agriculture (barley, rice, maize). And it only became problematic after the greeks invented the still to produce higher proof liquors about 2 kya. But, as expressed in my previous post, alcohol could have been a selective force (allowing to eat fermented fruits with a high alcoholic content).


American Natives


Among the Class 1 ADH genes, one in particular, ADH1C has a special allele at codon 351: ADH1C*351Thr, which is found in all Native Americans at frequencies above 11% (except the Surui: 0%). (Values range from 11% in the Ticuna to 38% in the Arizona Pima). In the rest of the world it has only been found twice (in a Russian and a Japanese), which leads the authors to conclude "that the mutation event happened before human migration into the Americas and the allele subsequently went to high frequency only in the Americas". [4] They do not explain why it disappeared in the rest of the world.


Perhaps it was found at low frequencies elsewhere and by chance drifted towards higher frequencies in America? Was it an archaic allele found in Neanderthals and admixed into Americans and some Asians but not into other populations? Let's check out this possibility:


Zhang et al., (2011) [5] compared the genomes of chimpanzees, modern humans, Neanderthals and Denisovans and found several common genes, but one in particular is of interest to us:


The gene ADH1C is one of the potentially compensated mutations (PCM) covered by Denisovans but not found in the Neanderthal sequence; they type it as "Ancestral" because "the Denisovan nucleotide and the chimpanzee nucleotide were identical to the human DM/disease-associated mutation".


This is indeed interesting we share a gene with Denisovans and chimps which Neanderthals did not carry! I was expecting to find Neanderthal not Denisovan genes!


Actually, after checking out different online genome data sources the fact is that there is no Neanderthal DNA sequence covering chromosome 4 at the site mentioned by Zhang et al., the available data covers chimps, humans and Denisovans. So maybe the Neanderthals (since chimps also carry it) also had this same ancestral gene.


For those interested, the wild type (natural, common and non-mutated type) in humans is "T" (Global average frequency: 82%) and the modern human mutation , the Denisovan and the chimp is "C". [5]. Further reading: see below in Sources: USC Genome Browser [6], and the Denisova High Coverage Sequence Reads [7].


Interestingly note that there is a strong "T" frequency among Africans, East Asians while it is lower among Europeans, S.W. Asians and Mexicans, where the "C" mutation has higher frequencies [8] :


T frequency: Europeans 52.7 to 66.5%, Africans 92.5 to 77.6 (East Africans in Kenya - maybe some S.W. Asian -Neanderthal introgression here?), East Asia 93.4 to 91.7 (Chinese and Japanese), Indians 73.2%, Mexicans 73.7% (note Mexicans have admixture of Amerindian, European and a touch of African - more of this in part 3). [8]


So there is a prevalence of the wild type (+52.5% of "T") in all modern humans, but it is higher among Africans and Asians, lower in S.W. Asia, Amerindians and Europeans (could this be due to the Neanderthal presence in these regions?).


Continues in Part 3.


Sources


[1] Tamara L. Wall et al., (1996). Alcohol Dehydrogenase Polymorphism in Native Americans: Identification of the ADH2*3 allele. Alcohol & Alcoholism Vol. 32, No. 2, pp. 129-132
[2] Hui Li, et al., (2011). Diversification of the ADH1B Gene during Expansion of Modern Humans. Annals of Human Genetics (2011) 75,497–507, doi: 10.1111/j.1469-1809.2011.00651.x
[3] Yi Han, Sheng Gu, Hiroki Oota, Michael V. Osier, Andrew J. Pakstis, William C. Speed, Judith R. Kidd, and Kenneth K. Kidd, (2007) Evidence of Positive Selection on a Class I ADH Locus, Am J Hum Genet. 2007 Mar;80(3):441-56. http://www.ncbi.nlm.nih.gov/pubmed/17273965
[4] Michael V. Osier, Andrew J. Pakstis, David Goldman, Howard J. Edenberg, Judith R. Kidd, and Kenneth K. Kidd., (2002). A Proline-Threonine Substitution in Codon 351 of ADH1C Is Common in Native Americans. DOI: 10.1097/01.ALC.0000042013.13899.75, Alcohol Clin Exp Res, Vol 26, No 12, 2002: pp 1759–1763
[5] Guojie Zhang, et al., (2011). Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations. Human Genomics 2011, 5:453-484 doi:10.1186/1479-7364-5-5-453
[6] USC Genome Browser Source, and Source.
[7] Denisova High-Coverage Sequence Reads (M_SOLEXA-GA04_00025_PEdi_MM_SR_2:2:3:9474:4156#GGCGGAG,CTCTGCA) Source.
[8] The PharmGKB is a pharmacogenomics knowledge resource
[9] Svetlana Borinskaya et al., (2009).Distribution of the Alcohol Dehydrogenase ADH1B*47His Allele in Eurasia. The American Journal of Human Genetics 84, 89–94, January 9, 2009.



Patagonian Monsters - Cryptozoology, Myths & legends in Patagonia Copyright 2009-2014 by Austin Whittall © 

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