There is a particular genetic signal that is unique to Native Americans and is only found among some Western Siberian groups, it is thd 9-repeat allele. As with all unique Amerindian traits, I wonder why was it lost elsewhere and conserved in America.
A paper by Kari B. Schroeder et al., (2009) [Haplotypic Background of a Private Allele at High Frequency in the Americas. Mol. Biol. Evol. 26(5):995–1016. doi:10.1093/molbev/msp024.🔓] looked into its uniqueness and tried to explain why it is exclusive to a specific geographic region, and where, and when did it originate.
The paper notes the presence of a "high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population... All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH)." (underlined is mine).
Interstingly this AMH is found elsewhere at low frequencies (7.44%) versus 39.39% in the Americas and Western Siberia. The paper suggests that this "dramatically higher frequency of the AMH in populations possessing the 9-repeat allele is consistent with the high frequency of the 9-repeat allele in these populations and with the presence of the 9-repeat allele on the AMH." Suggesting a link between both AMH and the 9-repeat allele.
The AMH vairant is found at the following frequencies elsewhere:
- 12.63% South Asia
- 5.79% in East-Central Asia
- 9.54% in Europe
It is an out of Africa mutation because "the AMH was only observed on a single chromosome in Africa, in the Mandenka population" (they live in Western Africa: Senegal, Ivory Coast, Gambia). Interestingly, "it was not observed in Oceania."
What is the 9-repeat Allelle?
The 9-repeat allele, or "9RA" is located at a specific spot on chromosome 9, (called a locus), known as the D9S1120 locus.
It is a short tandem repeat or STR or "microsatellite", which means that 2 to 6 base pairs of DNA sequence are repeated several times, in this case, nine times. Base pairs, these bases are the building blocks of DNA, made of nitrognous bases: Adenine (A), Guanine (G), Thymine (T), and Cytosine (C). They link A with T and G with C. Below is an example, the base pairs GA and TA 2bp-long is repeated four times (top). There are processes by which they can expand by mutations (in this case, from 4 to 8 repeats as shown on the bottom of the image). They can also contract, say from 12 repeats to 9, a "slippage diminution" mutation (More on this below).
Many Repeats!
As Fig. 4 in the paper shows, the 9-repeat is one of many. See Fig. 4 below: The caption is important, it reads "(A) Native American and Western Beringian populations and in (B) Asian populations. Only populations in which the AMH was observed are shown. The overall height of the bars represents the total frequency of the AMH by population."
The study noted that the AMH occurs with a 12-repeat allele in 62% of the sampled populations of South Asia. It is the shortest allele outside of America-Western Siberia found at frequencies higher than 1%. As you can see, there are 10, 4, 15, 16, 17, 19, etc. repeats across the globe.
The authors suggest that the 12-repeat lost 3 of them to become the 9-repeat found in Amerindians: "...the 12-repeat allele is the shortest allele that could have been ancestral to the 9-repeat allele. It is possible that a longer allele was ancestral to the 9-repeat allele... Because STR contractions greater than three steps are less likely than three-step contractions (Xu et al. 2000), we therefore view the 12-repeat allele as the most likely ancestor for the 9-repeat allele. Given that the 12-repeat allele on the AMH is most frequent and widespread in South Asia, the mutation that resulted in the 9-repeat allele possibly occurred in an ancient population that shared relatively recent ancestry with the ancestors of modern South Asians."
This loss (from 12 to 9 repeats), is called a "slippage-diminution mutation" or a "contraction via slipped strand mispairing" or "polymerase slippage". This mutation reduces the numbers of repeats and can happen spontaneously in a random manner (See Phillips, C. et al. (2008), D9S1120, a simple STR with a common Native American-specific allele: Forensic optimization, locus characterization and allele frequency studies, Forensic Science International: Genetics, Vol 3:1, 7. 13🔒)
Origin
Based on the fact that the 12-repeat allele is the most frequent one in the Old World, the authors ask where did it come from? Their answer is the following:
"The relatively low frequency of the AMH and the absence of the 12-repeat allele on the AMH in East-Central Asia have potentially interesting implications for our current understanding of Native American source populations. The frequency of the AMH in South Asia is more than twice that in East-Central Asia. Although the highest population frequency of the AMH outside of the Americas/Western Beringia is observed in the Uygur, a group of Turkic speakers who live primarily in northwestern China, and in Mongolians sampled in Outer Mongolia, the AMH reaches similarly high frequencies in populations farther to the southwest (Burusho, Kalash, and Sindhi of Pakistan). Moreover, across the world, the shortest alleles on the AMH (aside from the 9-repeat allele) are widespread in South Asia and in the Middle East."
This is interesting! its origin is to the south and west of the supposed Siberians that peopled America! The authors add:
"The possible origin of the 9-repeat allele on the AMH in a population that shared recent ancestry with the ancestors of modern South Asian populations suggests an early divergence of the ancestors of modern Native Americans from those of modern Asian."
Age
The paper then considers its age, which is always a problem, because the scholars have to fit this date somewhere between 13ky (the orthodox date for the entry into America) and 40ky (the date when humans reached eastern Asia on their way to America).
Their first "simple point estimate was 8,699 generations. Then they computed and calculated (i.e. fiddled with the data) and "Under the different best models, the mean TMRCA of the 9-repeat allele ranged from 293 generations to 1,596 generations; using a generation time of 25 years resulted in a TMRCA of 7,325–39,900 years ago."
Intersting how their Best models agree with the orthodox window of 13 - 40 ky!! for the arrival of modern humans in western Siberia and their entry into America.
They continue and refine the timeline: "Averaging over all of our best models, the mean TMRCA is 513 generations ago or about 12,825 years ago. The 95% confidence intervals for all of the best models produced ages for the MRCA of the 9-repeat allele, that range from 144 to 1951 generations ago, or approximately 3,600–48,775 years ago."
And conclude, conveniently, that: "Our point estimate of 12,825 years is also similar to recent estimates from mtDNA data, using a substitution rate based on an internal rather than interspecific calibration, for a population expansion in the Americas between about 10,000 and 12,000 years ago."
But with the simple point estmate of 8,699 generations the age would have been: 217,475 years BP, and furthermore, the paper states that "Our less conservative estimate of eight recombination events since the MRCA of all sampled copies of the 9-repeat allele doubles the genealogy length for the 9-repeat allele to 17,426 generations." This would mean an age of 435,650 years!
These two older dates of 217 and 435 ky are far older than the accepted date for Modern Humans in East Asia, but fine if we consider Denisovans or Neanderhtals. Were they the source of thiss 9-repeat allele in our autosomal DNA?
Beringian isolation - again!
They also justify the Beringian standstill theory! "our observations are best explained by a period of isolation for the founding population, during which multiple mutations may have reached a high frequency and some loci may have experienced multiple mutations, followed by a range expansion".
Natural Selection
If this 9-repeat allele gave those carrying it a better chance at surviving and passing it on to their offspring, you would expect natural selection to act, increasing this allele's frequency (as it did in Amerindians) within the population. However, the authors state that they did not find andy selection forces acting upon it.
The repeat is found on chromosome 9, and the notation to define its location is 9q21.31. This means it is on the long (q) arm of chromosome 9, within band 21, sub-band 3, sub-sub-band 1).
The paper states that "high-density genomic data... has led to the detection of regions of the genome that show potential evidence of natural selection. Analyses of such data have not identified any regions on 9q21.33 that show strong evidence of selection... In conclusion, there is no evidence from functional considerations that would lead to a hypothesis of selection in the region of D9S1120 for Native Americans."
Further on, however they revisit natural selection: "One could imagine that the 9-repeat allele rose to high frequency, due to positive selection, in a population ancestral to both modern Native Americans and Western Beringians prior to an expansion into different habitats within the Americas. However, this scenario would still support our primary assertion that the distribution of the 9-repeat allele is best explained by descent from a single population. Hence, in the absence of compelling evidence for selection, the existence of plausible neutral models by which the observed distribution of the 9-repeat allele could have occurred suggests that the simplest explanation for the unusual distribution of the 9-repeat allele is that all Native American and Western Beringian populations have inherited a very large portion of their ancestry from a single population."
My Comments
This final phrase "a single population" and the age that was omitted (200 - 400 ky) points at an ancestor of modern humans, found in Southern, Eastern, and Central Asia, the Denisovans. They also admixed with Neandertals who could have contributed to the presence of this allele in Europe and the Levant.
Regarding Natural Selection, the gene closest to the 9-repeat is AGTPB1, shown in Fig. 2C in this paper. This gene is critical for correct neurological functions, and also "In addition to its role in neuronal maintenance, AGTPBP1 is critical for spermatogenesis; disruption in its function leads to defects in germ cell development and male infertility" (Source). If the repeat somehow preserved these functions, it would make it a target for selective pressure (ensuring fertility and brainpower).
The presence in one Western African is intriguing. Its absence in Polynesians too! Did it come from some archaic hominin in Africa, at very low frequencies and is found at extremely low proportions in Africa. The first Out Of Africa event (that led to H. georgicus) probably took the AMH variant with it. It survived in Eurasia, did not make it into Melanesia or Polynesia, but was carried across Siberia into America before the arrival of modern humans. That is why it is only found in America (the Western Siberians are surely a back migration).
Did Denisovans or Neandertals carry it? Is it found in ancient remains of Amerindians? At what frequency? Did the "Great Dying" after 1492 increase its prevalence or was it always high? These are some questions that may clarify the history of this allele.
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