Why are pygmies not afraid of sleeping sickness?
Our genome is more diverse than it seems
Alexander Sokolov, XX2 century
Even now, in the 21st century, our knowledge of the human genome is very incomplete. The reference genome GRCh38 is a reference DNA reference, a database of nucleotide sequences made up of DNA from 13 anonymous volunteers from Buffalo, New York (with 66% of the reference sequence coming from one man). Any human genetic sequences are compared with this standard.
Obviously, the genomes of different people differ from the reference one, but how big are these differences and what do they affect? The simplest case of differences is single–nucleotide polymorphism, and in simple terms, the replacement of one letter of the genetic alphabet with another. Such differences are evaluated most often when studying human diversity, but there are a large number of other kinds of changes: deletions (loss of a DNA section), insertions (a piece of another is embedded in the genetic sequence), duplications (part of the sequence is doubled), inversions (the section turns "backwards") and so on. Such changes are called structural variations. They are more difficult to catch, but it is obvious that they sometimes have a very significant effect on the work of our genes. It is important to know about such things, first of all, from a medical point of view – for example, how effective the treatment will be depends on the characteristics of the immunity of a particular person.
In a new study, the results of which are published in the journal Cell (Almarri et al., Population Structure, Stratification, and Introduction of Human Structural Variation), experts analyzed 911 qualitatively read genomes from the Human Genome Diversity Project (HGDP) database belonging to 54 human populations from all over our planet. As a result, it was possible to detect 126,018 (!) new structural variations of the human genome, each of which affects at least 50 pairs of nucleotides. 78% of the variants found were previously unknown. One would expect that these are some kind of rare mutations, but among them there are many variants that are very common in individual populations and even within continents.
The evolution of different human groups can be traced by the spread of structural variations. For example, according to the set of deletions, African mbuti, bayaka and koisans, known for their specificity, differ markedly from other populations of Africa. Similarly, the inhabitants of Oceania occupy a special place. There are also differences within individual populations. The aborigines of Papua are indicative in this regard. Lowland Papuans have a high frequency (86%) deletion in the hemoglobin A2 (HBA2) gene, which is believed to increase resistance to malaria. Mountain Papuans do not have this feature, which is logical, since malaria does not occur in the mountains, but is common in the lowlands of Papua.
Another example, well explained from the standpoint of natural selection, is the multiplication of the number of copies of the HPR gene, which affects resistance to sleeping sickness. The largest number of copies of the gene (9) is found in the genomes of the indigenous inhabitants of Central and West Africa, that is, exactly where the tsetse fly terrifies people.
There are also strange, hard-to-explain examples. Such oddities include deletion of a site of 14 thousand nucleotide pairs in the regulatory region of the MGAM gene. This variant occurs with a frequency of 40% in the Brazilian Caritiana people. This is a small ethnic group – there are only 320 Karitians left, most of whom live in one remote village and have little contact with the outside world. What is surprising about the deletion in the MGAM gene? The fact is that it encodes an enzyme involved in the breakdown of starch. It is known that Andean farmers have spread changes in this gene, "sharpened" for a diet rich in cereals. MGAM has evolved in a similar way even in dogs, which, when domesticated, began to consume more starchy food. Deletion, on the contrary, broke the gene – and this is among the people traditionally engaged in agriculture. Moreover, in some representatives of Karithian, the mutation occurs in a homozygous form. With the assimilation of starch, these people must have serious problems. Scientists explain this oddity by gene drift, in other words, a fatal accident. A typical negative effect of a sharp decline in numbers: a harmful mutation turned out to be in one of the few survivors of Karitian, and since there is very low genetic diversity in the population, and there are no contacts with the outside world, natural selection has not yet helped these people get rid of the harmful allele.
I wonder which of the identified variations were inherited by our ancestors from Neanderthals and Denisovans? Of course, the researchers did not ignore this issue. They found a number of common variants found both in archaic hominins and in people outside Africa. Some mutations are located near or inside genes, so they can affect their work. Many Denisov variants are specific to the population of Oceania.
For example, duplication on the 16th chromosome is clearly of Denisovan origin occurs only in Oceania, and with a very high frequency of 82%. So far, the functional role of deletion is unclear. The researchers only point out that it is unlikely to be malaria – in this case, the variant is equally frequent in both lowland and mountain Papuans.
A number of other archaic variants that occur with high frequency in the population of Oceania are associated with the work of immunity. Presumably affects immunity and deletion in the MS4A1 gene, apparently of Neanderthal origin, which is very common in American Indians Surui and Pima.
All these data confirm the idea that medical techniques developed for some human populations, without knowledge of the genetic background, may be less effective for others. It is necessary to replenish the reference sequence with new findings! The researchers counted 1,643 inserts on all chromosomes, occupying a total of 1.9 MB and missing from the reference genome. A number of these inserts seem to affect the work of genes related to immunity, glucose regulation, and tumor suppression. And although many inserts are rare, 290 of them are found in at least half of the studied samples. Why, then, are they absent from the reference genome? Apparently, the people from whose genetic sequences the reference genome was assembled had rare deletions in these places.
The South African Bushman (san) had the most inserts. After all, the Khoisans confirm their special evolutionary path again and again.
To find out when the open structural variations occurred, the researchers conducted a comparison with the genomes of great apes. It turned out that our closest relatives also have many inserts (62% in chimpanzees, 59% in gorillas, 35% in orangutans). Thus, a significant part of the open sequences is ancient, and was still present in the common ancestor of humans and chimpanzees.
It is obvious that only a small part of human populations participated in the study. Many structural variations of the human genome remain unknown.
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