26 February 2016

The health of Homo sapiens and the genes of its "cousins"

Neanderthal genes affect the health of modern humans

Alexander Markov, "Elements"

The gene pool of modern non-African humanity contains a small admixture of Neanderthal genes obtained as a result of hybridization with Neanderthals 47-65 thousand years ago. Little is still known about the effect of these impurities on the phenotype of modern humans. The emergence of large electronic databases on medical genetics allowed American scientists to assess the relationship between the presence of certain Neanderthal alleles in modern Europeans and various diseases. It turned out that Neanderthal genes significantly, although not very strongly, affect the risk of certain disorders, such as depression, actinic keratosis (pathological skin changes under the influence of solar radiation), increased blood clotting and nicotine dependence. Many of these genes could have been useful to our Paleolithic ancestors, but then became harmful due to changes in living conditions.

Interspecific hybridization has repeatedly occurred between the species of ancient people who inhabited different areas of the Old World in the Middle and Upper Paleolithic (Sapiens, Denisovans, Neanderthals, Heidelberg people). To date, six episodes of such hybridization have been convincingly substantiated (Fig. 1). The most important evolutionary and genetic consequences were one of them, which occurred in Near Asia 47-65 thousand years ago between the ancestors of modern non-African humanity, who had recently left their African ancestral homeland, and the indigenous inhabitants of the Middle East – Neanderthals. As a result of this episode, a small (on average about 2%) Neanderthal admixture is present in the genomes of all modern Sapiens, with the exception of the indigenous population of sub-Saharan Africa.

Ancient gene1.jpg 

Fig. 1. Six episodes of hybridization of Sapiens, Neanderthals, Denisovans and "archaic Homo" according to the latest data of paleogenetics and comparative genomics. Blue arrow: influx of genes from archaic Homo (H. heidelbergensis or relict late H. erectus) into the Denisovan genome; red arrow: newly discovered influx of genes from an archaic Sapiens population (most likely, early immigrants from Africa to the Middle East, who left no descendants among modern humans) into the Altai Neanderthal genome, which occurred about 100 thousands of years ago; black arrows: gene flows from Neanderthals to the ancestors of modern non-African humanity (an episode of hybridization that occurred 47-65 thousand years ago, shortly after the second, successful exit of Sapiens from Africa), from Neanderthals to Denisovans, as well as later gene flows from Denisovans to the ancestors of Papuans, Australians and East Asians. The separation of Sapiens ancestors from the ancestors of Neanderthals and Denisovans occurred 550-765 thousand years ago, Denisovans separated from Neanderthals 381-473 thousand years ago, Altai Neanderthals separated from European (Vindia and El Sidron) a little more than 100 thousand years ago. Drawing and dating from the article by M. Kuhlwilm et al., 2016. Ancient gene flow from early modern humans into Eastern Neanderthals.

How did this admixture affect the future fate of non-African Sapiens? Did Neanderthal genes help our ancestors during their settlement in the Old World or, conversely, did they interfere? What phenotypic traits of modern humans are influenced by Neanderthal alleles? Thanks to the rapid development of paleogenetics and the accumulation of data on the genetic diversity of modern humans, the answers to these questions, at first extremely vague, are becoming clearer and more detailed.

It turned out that for 600 thousand years of separate existence (from the moment of divergence of the ancestors of Sapiens and Neanderthals to hybridization) these two lines managed to accumulate enough genetic differences so that a partial postzygotic reproductive isolation arose between them (see: Genetic incompatibility increases along the parabola, "Elements", 09/26/2010). In other words, mutually incompatible alleles were fixed in their gene pools, which led to a reduced fitness of hybrids (see: There was partial reproductive isolation between Sapiens and Neanderthals, "Elements", 03.02.2014). This, by the way, is a strong argument in favor of the fact that it is more correct to consider Sapiens and Neanderthals as different species, rather than subspecies or varieties.

Neanderthal alleles, which turned out to be harmful (reducing fitness, which is also the efficiency of reproduction) in a sapient genetic context, were gradually cleaned out by selection. As a result, the Neanderthal admixture in the genomes of Europeans decreased from the initial level of about 3% to the current (about 2%). Asians have a little more Neanderthal genes left.

However, from the fact that most of the Neanderthal genes did not benefit our ancestors, it does not follow at all that the indigenous Neanderthal population of Western Eurasia could not pass on some useful genes to people from Africa. After all, Neanderthals lived in this region for hundreds of millennia, which was very different in climate, in the range of available food resources, and in the set of pathogenic viruses, bacteria and other parasites from the African ancestral homeland of Sapiens. Therefore, it would be logical if among the Neanderthal genes that have benefited sapiens, there were genes associated with the immune system, the structure of the skin (its pigmentation, sensitivity to ultraviolet light, etc.), as well as with the assimilation of various nutrients.

These expectations are generally confirmed (see: Our ancestors borrowed important genes from Neanderthals and Denisovans to protect against viruses, "Elements", 07.10.2011). For example, in January 2016, two studies independently showed the role of Neanderthal alleles in strengthening the "first line" of innate immune protection against pathogenic bacteria, fungi and other parasites (M. Dannemann et al., 2016. Introduction of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors; M. Deschamps et al., 2016. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes). It is characteristic that in this case (as, probably, in many others) alleles useful to our Paleolithic ancestors may well be harmful to a modern urban dweller. Enhanced innate immunity can be life-saving for a savage, but in a citizen who comes into contact with a smaller variety of parasites, the main phenotypic manifestation of the same innate feature may be an increased risk of autoimmune diseases. Another example: alleles that increased the efficiency of nutrient absorption or increased food motivation were extremely useful to our ancestors who lived in conditions of constant threat of hunger, but in modern civilized society these same alleles become "obesity genes".

A group of American biologists has conducted a new large-scale study to identify Neanderthal alleles that affect the health of modern Europeans. This work was made possible, on the one hand, thanks to a high-quality reading of Neanderthal genomes (especially the genome of the Neanderthal woman from Denisova Cave, see: There was partial reproductive isolation between Sapiens and Neanderthals, "Elements", 03.02.2014), which made it possible to identify thousands of specific genetic variants (polymorphisms) inherited from Neanderthals in the genomes of modern humans, on the other hand, thanks to the emergence of large databases on medical genetics, in which data on various "medical conditions" are linked to information about the genotype.

The authors used data collected as part of the eMERGE (Electronic Medical Records and Genomics) project, launched in 2007 by the US National Institutes of Health (NIH). Data on the genotypes of 28,416 adult Americans of European descent were taken from this database. For each of them, there is an "electronic medical card" in the database, that is, information about the presence or absence of many phenotypic signs, which in this case are all kinds of diseases and other "medical conditions", such as, for example, bad habits. All these people were genotyped using modern microchips covering most of the known polymorphic loci of the human genome.

The data of "electronic medical records" were compared with the presence or absence of Neanderthal alleles in humans. In order to obtain statistically reliable results, the authors considered only those phenotypes and those Neanderthal alleles that occur quite often in the studied sample.

First, a general assessment was made of the influence of 1,495 common (with a frequency >1%) Neanderthal single-nucleotide polymorphisms on the risk of developing 46 common pathologies. To do this, we looked at how much similarity between people in a set of Neanderthal alleles correlates with similarity in phenotype, that is, in the presence of pathologies (see Genome-wide Complex Trait Analysis). This technique is designed to identify the complex effect of multiple alleles on multigenic traits. It turned out that Neanderthal alleles do affect the likelihood of a number of medical conditions. The most significant results were obtained for depression, other affective disorders, as well as for actinic keratosis (see Actinic keratosis). With slightly less certainty, Neanderthal genes affect the risk of other keratoses, corns, obesity, atherosclerosis, myocardial infarction. All these influences are not very strong: for depression, affective disorders and actinic keratosis, Neanderthal alleles explain 1-2% of risk variability, for other disorders – less than 1%.

Among the Neanderthal polymorphisms affecting these ailments, some increase the likelihood of pathology, others decrease, and the number of both is approximately the same.

Previously, it has been suggested that Neanderthal impurities in the genomes of modern humans can affect depression and other psychological disorders (as well as lipid metabolism, digestion, immunity, hair and skin properties), because the proportion of Neanderthal DNA fragments is increased in the vicinity of genes associated with the corresponding functions. A new study confirmed these assumptions, showing that many Neanderthal polymorphisms located in these parts of the genome really correlate with the listed pathologies. For example, Neanderthal polymorphisms that affect the risk of actinic keratosis are associated with genes involved in the differentiation of keratinocytes and in some immune processes, and many genetic variants of Neanderthal origin that affect the likelihood of depression are associated with genes that were previously known that changes in their work affect mood.

In addition, several Neanderthal polymorphisms that increase the likelihood of depression are located in the vicinity of genes associated with the regulation of circadian rhythms. There is a logic in this: it is known that the risk of depression is affected by the mode of illumination, and Sapiens and Neanderthals lived in different latitudes. Therefore, their circadian rhythms had to be tuned differently.

Of course, this does not mean that Neanderthals suffered from severe depressions and we inherited this property from them. Rather, it means that alleles borrowed from Neanderthals that affect adaptation to the change of day and night were initially useful to sapiens who settled from their tropical ancestral homeland to higher latitudes. But then, with the development of civilization and artificial lighting, something from the Neanderthal heritage could turn from useful to harmful.

It is important to understand that, since the authors studied the influence of only those Neanderthal alleles that occur quite often in modern Europeans, those alleles that were very harmful to our ancestors from the very beginning could not get into the sample. Such alleles have either been cleared out by selection long ago, or have been preserved as rare variants and therefore remained outside the scope of the study.

Additional information was obtained by comparing individually each of the 1,495 Neanderthal alleles with 1,152 "phenotypes" (pathologies) from eMERGE electronic medical records (phenotypes represented in the database by less than 20 cases were not considered). This approach allowed us to catch 4 more Neanderthal alleles that significantly affect the health of modern people.

The first of them is the rs3917862 polymorphism, which occurs in Europeans with a frequency of 6.5%. Such a high frequency indicates that this genetic variant was supported by selection from our ancestors. This polymorphism marks the Neanderthal DNA region (haplotype), which includes several genes involved in blood clotting. Its presence significantly correlates with increased clotting (see Thrombophilia). Apparently, this was useful in the Stone Age, when there were no other ways to stop bleeding after injury or childbirth, and few people lived to old age anyway. For a modern citizen, however, this is a harmful sign.

The second polymorphism, rs12049593, occurs in Europeans with a frequency of 5% (and, therefore, was also useful to the ancestors) and is associated with the gene responsible for the transport of thiamine (vitamin B1). The presence of this Neanderthal genetic variant in humans correlates with the symptoms of protein-energy deficiency (see Protein–energy malnutrition). Thiamine is a mandatory participant in carbohydrate metabolism, and the Neanderthal allele seems to reduce its entry into cells. It is quite possible that the sapiens used the Neanderthal gene when they settled in cold Europe, where they had to eat a completely different food than in hot Africa, and had to adjust the metabolism to a new diet. But with the development of agriculture, the amount of thiamine in food has decreased, and the proportion of simple carbohydrates has increased. Theoretically, this could lead to the fact that a useful Neanderthal gene in the past became harmful.

The third allele, rs11030043, occurs in Europeans with a frequency of 9%. This is a Neanderthal variant of the STIM1 gene involved in intracellular signaling using calcium ions (see Calcium signaling). People with this Neanderthal gene have decreased STIM1 expression in the caudate nucleus, a part of the brain responsible, among other things, for the functioning of the bladder. The presence of this allele slightly increases the risk of urinary incontinence and other disorders of the urinary tract. The authors refrain from speculating why this could be necessary for Paleolithic sapiens. But there had to be some benefit, otherwise the gene would not have reached such a high frequency in the European gene pool.

Finally, the fourth allele, rs901033, occurs in Europeans with a frequency of 0.5% (which means it could have been harmful for a long time). This Neanderthal gene increases the risk of nicotine addiction. The rs901033 polymorphism is located in the intron of the SLC6A11 gene responsible for the reverse transport of the inhibitory neurotransmitter GABA in brain synapses. There is logic in this, because nicotine addiction disrupts the transmission of signals using GABA and reduces the expression of SLC6A11.

Thus, the study showed that the admixture of Neanderthal genes obtained by the ancestors of non-African humanity as a result of episodic hybridization 47-65 thousand years ago significantly affects the health of modern Europeans.

The authors focused on "medical conditions" not because they were not interested in all other human signs, but because too little genetic data has been collected for such an analysis for other signs. Further development of science should give an answer to the question of what role the Neanderthal heritage plays in the variability of non-African sapiens in all other interesting signs, and not only in medical ones.

Source: Simonti et al., The phenotypic legacy of admixture between modern humans and Neanderthals // Science. 2016. V. 351. P. 737–741.

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