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Wednesday, March 25, 2015

Neanderthals, Psoriasis and Native Americans... a Link


A very interesting paper by Yen-Lung Lin, Pavlos Pavlidis, Emre Karakoc, Jerry Ajay, and Omer Gokcumen, " Variants Shared with Archaic Hominin Genomes" takes a look at "polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human–Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed)...", some of these deletions are the cause of well known diseases.


I decided to see if there were any hints at a link between Native Americans and diseases prevalent among Neanderthals and this is what I found:


The previous paper by the same team (The Evolution and Functional Impact of Human Deletion Variants Shared with Archaic Hominin Genomes by Yen-Lung Lin, Pavlos Pavlidis, Emre Karakoc, Jerry Ajay, and Omer Gokcum. Mol. Biol. Evol. doi:10.1093/molbev/msu405 Advance Access publication January 2, 2015) states that one of the deleted sequences shared by humans and Neanderthals is the LCE3C gene deletion: "...which has been strongly associated with psoriasis (de Cid et al. 2009). The allele frequency of LCE3C gene deletion is extremely high among Eurasians, reaching to over 70% allele frequency in some European and Asian populations..." it is the authors' "understanding that this deletion has been maintained in high allele frequencies since before Human– Neandertal divergence."


So According to this study, the genetic risk factor that causes psoriasis has been in our family tree for some 500,000 years. It was carried by our ancestors and the ancestors of Neandertals and Denisovans too. In fact, it was carried by our common ancestor.


The interesting part is that it prevails among Eurasians... But what about our African ancestors. Do they have it in high proportion too as would be expected from this genetic variant that appeared before humans and Neandertals split?


Lets see what variant of the psoriasis risk gene is found in Africa: The paper Worldwide population distribution of the common LCE3C-LCE3B deletion associated with psoriasis and other autoimmune disorders, by Laia Bassaganyas et al. (2013) BMC Genomics 2013, 14:261 doi:10.1186/1471-2164-14-261. Gives us some data:


This paper finds that "...most populations tend to have a higher frequency of the deleted allele than Sub-Saharan Africans." Which at first sight means that Africa, the land where the deletion is supposed to have appeared 500 kya, now has a lower prevalence of it. Surprising and unexpected.


The paper adds that "The deleted allele (LCE3C_LCE3B-del) is common in patients with psoriasis among populations of European ancestry, and in Chinese and Mongolian populations", ratifying what Lin et al mention in their study. Furthermore, Bassaganyas found that "Populations from Eastern-Asia, America and Oceania had greater differences in signal intensity with respect to the YRI (Yoruba) population than other Sub-Saharan African, European, Northern African and Middle East populations, as well as more copy-number variable regions...". So East Asians, Africans and Oceanians are the most distinct when compared to Africans.


But there is more: Amerindians are, once again among them most different. "The aCGH data for the LCE3C_LCE3B-del showed lower intensity values for all the studied populations respect to YRI, and five of them (Pima (PIMA), Brahui (BRA), Mozabite (ALG), Maya (MAYA) and Chinese Han (CHB)) presented log2 ratios ≤0.25, limit considered significantly low for a copy-number loss ..."; these groups are Maya, Pima (America), Brahui (India), Chinese and Mozabite (North Africa).


These are the deletion ratios found by Bassaganyas et al: (bold mine)


The highest frequency of the deletion was detected in the PIMA population, with an allele deletion frequency of 75% (log2 ratio in the sample pool of −0.67). The ALG population also had a high frequency of the LCE3C_LCE3B-del (67% with an intensity log2 ratio of −0.30). As expected from the aCGH data, Sub-Saharan populations have low frequencies of the deleted allele (28% in Bantu (BAN), 34% in YRI, and 35% in Pygmies (PYG)). However, two Asian populations (Hazara (HAZ) and Yakut (YAK)) have a LCE3C_LCE3B-del frequency lower than that of Sub-Saharan Africans (21% in HAZ and 23% in YAK), although the small number of samples for these two population groups (17 and 11 samples) made the estimation of their low frequency unreliable. The frequency of the LCE3C_LCE3B-del in the other populations varied between 50% and 62%.


I find it interesting that the Central Siberian Yakut have an even lower deletion frequency than Africans do. Because the Yakuts are supposedly realted to the source of Native Americans. They would be expected to have a high deletion frequency. Instead, theirs is among the lowest.


The authors then took a look at the genotype frequencies for the LCE3C_LCE3B CNV and found that the most common variant in all populations isthe heterozygous state. The Sub-Saharian Africans have the non-deletion homozygous state at higher frequencies (which they share with some curious outliers: the Karitiana Native Americans, Italians and Yakults). The rest of non-Sub-Saharians have higer frequencies of the deletion homozygous state.


There is a clear Sub-Saharian vs. Rest of the World cut. But why woudl Yakults and Karitiana share this feature with Africans?


An explanation is: those groups provided small sample sets, and they are isolated from other people and therefore less admixed with others and with a higher inbreeding ratio. Genetic drift and restricted gene flow led to the current pattern of global distriburion, where the result of genetic drift or recent selective pressure.


However Lin et al. suggest that these deletions have been with us for half a million years and despite causing psoriasis (as well as lupus and reumatoid arthritis),they have resisted selection against them.


Bassaganyas' team notes that this deletion behaves differently to other genetic traits: "While the trend observed for general LD consists of a successive increase in the LD in Middle East-North Africa, Central South Asia, Europe, East Asia, Oceania and America with respect to Sub-Saharan Africa, we essentially detect low r2 values in African populations and similar high values for the rest of the world." In other words it is not the typical bottleneck of an Out of Africa migration.




I did expect the "founder effect" and "bottleneck" explanations, and it is clear that Psoriasis is high out of Africa, as would be expected by the higher deletion frequency outside that continent.


If the ancestor of Neanderthals, Denisovans and Modern Humans carried the deletion and in turn we all carried it too, why is it so much lower in Africa? Why would other groups keep it while Sub Saharian Africans lost it? Can we imagine a scenario that explains this?.... Yes:


Lets imagine a more distant human relative like H. erectus, carrying the deletion, which gave it an adaptative advantage in its conquest of Eurasia. Erectus' descent, Neanderthals, Denisovans and us, carried this deletion of Asian origin. Some back migration into Africa took the deletion there too, where its lower frequency reflects less introgression and a recent admixture. Older populations with the deletion have it at higher frequencies, and those who peopled America have it at highest ratios. It is clear that its adaptative advantages were handy when conquering the New World too.


Later Out of Africa humans mixed with the Eurasians and watered down the deletion with a west to east cline. Maybe the Yakuts aand Italians have a higher frequency of African input. The Karitiana too... slaves escaped from Brazilian plantations into the Amazonian jungles....



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