In chimpanzees, as in humans, the number of mutations in the offspring depends on the age of the father // Alexander Markov Scisne?

Fig. 1. At the close relatives of a person - chimpanzees and bonobos ( on the photo ) - females often mate with several males in a row. This leads to competition between males at the sperm level (“sperm wars”), which, in turn, contributes to the selection of spermatogenesis for an increase in the testes and the intensification of spermatogenesis. Perhaps that is why the number of mutations in sperm cells in chimpanzees increases with the age of the male one and a half times faster than in humans. Photos from

An analysis of the genomes of nine chimpanzees, representing three generations of the same family, showed that the average mutation rate of the closest human relatives is about the same as ours: about 1.2 × 10–8 per nucleotide per generation, which corresponds to about 70 new mutations in each cub. Like people, the number of new mutations in the offspring does not depend on the age of the mother, but strongly depends on the age of the father at the time of conception: each extra year lived by the father adds to his descendants an average of three mutations (in humans - two). This difference is most likely due to the more intensive production of sperm in chimpanzees, in which females mate with many males in a row, which gives rise to "sperm wars."

The rate of mutagenesis is one of the key indicators determining the dynamics of evolutionary changes. Until recently, this value was calculated by indirect signs: for example, they compared the time of appearance of groups, estimated from paleontological data, with the level of differences between their genomes (see Molecular Clock ). In recent years, thanks to the development of powerful new methods for sequencing genomes (see DNA sequencing: Next-generation methods ) it became possible to measure the rate of mutagenesis directly by comparing the genomes of parents and their descendants.

This technology has already been applied to man. So, in 2012, the journal Nature published the results of a full-genome analysis of 78 Icelandic families - “triples”, consisting of a father, mother, and child (A. Kong et al., 2012. Rate of risk of disease ). The study showed that the rate of mutagenesis is about 1.2 × 10–8 per nucleotide per generation. In terms of the entire genome, this means that each child receives on average 74 new mutations from parents.

These figures turned out to be unexpected, since indirect estimates based on phylogenetic reconstructions and paleontological data suggested a twice higher rate of human mutagenesis. The reason for the discrepancy, apparently, is that in the great apes after their separation from other primates there was a significant decrease in the rate of mutation (per one year). The decrease could be associated with an increase in the age of onset of reproduction and with a slowdown in the formation of germ cells. If the new data is correct (and it becomes increasingly difficult to doubt this as new publications become available), then many datings of the key points of anthropogenesis may require revision towards aging. For example, the discrepancy between the lines of humans and chimpanzees, which occurred, according to previous estimates, 6–7 million years ago, can be moved back into the past to 10–13 million years ago. True, there are many subtleties, one of which is that the time of genome divergence, determined by the "molecular clock", due to a number of objective reasons may be deeper in the past than the time of real speciation (separation of populations). For more on this, see article: A. Scally, R. Durbin, 2012. Revising the human evolution rate (PDF, 812 Kb).

Another important result obtained in the course of a full-genome analysis of human families is that the father and the mother make an unequal contribution to the total “mutational burden” received by the child from the parents. Of the total number of new mutations received by the child, he gets about 15 from his mother, and all the rest from his father. At the same time, the number of new mutations in a child almost does not depend on the age of the mother, but very quickly grows with the age of the father. Every extra year of the father’s life adds about two new mutations to the child.

This is explained by the fact that in women, from conception to the formation of a mature egg, only 24 cell divisions and 23 chromosome replication acts take place (chromosomes do not double before the second meiosis division). Replication of chromosomes of the female germ line ends even during fetal development, and during the life of a woman the chromosomes of her germ cells no longer replicate. Accordingly, the number of mutations in them almost does not grow, because the majority of mutations in germ-line cells are replication errors.

In men, the situation is different. Progenitor cells of spermatozoa are divided throughout adult life, undergoing one division every 16 days (23 divisions per year) since reaching puberty. It is believed that the sperm of a 15-year-old man went through about 35 cell divisions, a 20-year-old — 150, a 30-year-old — 380, a 40-year-old — 610, a 50-year-old — 840. Each replication act is a risk of additional mutations, therefore the older man, the more mutations in his sperm (JF Crow, 2000. The origins of human spontaneous mutation ). A. Kondrashov spoke in detail about these facts and studies in an interview published on the Elements (Alexey Kondrashov, Nadezhda Markina. Life without selection: good or danger? ).

And here we finally got the opportunity to compare the parameters of the mutational process of Homo sapiens and our closest relatives - chimpanzees. Genetics from the UK and the Netherlands sequenced and compared the complete genomes of nine chimpanzees from three generations of the same family (Fig. 2).

Despite the small sample (such studies still remain extremely costly and time consuming), the data obtained allowed us to estimate approximately the key quantitative characteristics of mutagenesis in chimpanzees.

The authors calculated new mutations in six individuals, namely those for which the parental genomes were known: D, E, F, G, H, I. In total, they found 204 new mutations in the autosomes and three in the X chromosome. Among the mutations found, a significant proportion (24%) is made up of C substitutions for T (C> T-transitions) in CG dinucleotides (see CpG site ). In humans, such replacements account for 17% of newly arising mutations.

Newly occurring mutations are not quite evenly distributed across the genome: they tend to clusterize. In other words, if a mutation arose in a locus in the course of replication, the likelihood of another occurring somewhere in the same replication act somewhere in the neighborhood increases. Similar patterns have been found in people, the causes of which have yet to be clarified. At the same time, the probability of a new mutation does not depend on the “semantic content” of this DNA segment, whether it is a unique or repeating sequence, a gene or an intergenic gap.

For most of the identified mutations, the authors were able to determine (by the set of polymorphisms in the vicinity of the mutation) whether it was obtained from the father or from the mother. It turned out that in chimpanzees, as in humans, fathers, in comparison with mothers, transfer genomes to their children, which are much stronger than mutations. There were 5.5 times more paternal mutations than maternal mutations (3.9 times in humans).

Like in humans, the number of new mutations in chimpanzees does not depend on the age of the mother (the mother at any age transmits a calf on average 6.7 new mutations), but at the same time it grows rapidly with the age of the father. This dependence even in such a small sample was statistically significant. In humans, every extra year of the father’s life, starting at puberty, adds an average of 1.95 new mutations to descendants, and in chimpanzees, it adds 3.02. The difference is most likely due to the structure of the marriage relationship. In chimpanzee communities, females do not usually have loyalty to one male, which contributes to "sperm wars" and selection for more intensive spermatogenesis (see Fig. 1).

If this assumption is correct, one should expect that gorillas with their harem system, female fidelity, lack of sperm wars and small testes, should increase the number of mutations in sperm cells with the age of the male than in chimpanzees and humans.

To assess the average rate of mutagenesis in chimpanzees, the authors had to take into account the important difference between the studied group of chimpanzees living in captivity and wild relatives. In captivity, chimpanzees usually begin to breed at an earlier age than in nature. This seems to be related to hierarchical, competitive relationships in natural chimpanzee communities where teens are rarely allowed to participate in breeding. Anyway, in the studied chimpanzee family, the average "paternity age" (that is, the average age of males at the moment of conception of the young) is 18.9 years, and the average "age of motherhood" is 15.0 years. For wild chimpanzee populations, it is estimated that these numbers are much higher: 24.3 for males and 26.3 for females. In modern people, the average age of paternity is even higher: about 31.5 years. In other words, in wild chimpanzees, males at the moment of conception of youngsters are, on average, older than in the studied population, which means that their offspring should have more mutations. Taking into account this and a number of other corrections, the authors calculated that the average number of new autosomal mutations in wild chimpanzees should be about 69, and the rate of mutagenesis should be 1.2 × 10–8 per nucleotide per generation (like in humans).

If these estimates are correct (recall that they are based on a very small sample and can be significantly refined in the future) and if the rate of mutagenesis has not undergone significant fluctuations since the time of divergence of ancestors of chimpanzees and humans, then using the method of molecular clocks, you can once again try to evaluate the lifetime of the last common ancestor of man and chimpanzee. The authors did this and got the result: 13 million years ago. Other authors have recently arrived at similar estimates (K. Langergraber et al., 2012. Chimes and gorillas ).

But still the most intriguing result of the research is an indication of the possibility of the influence of the structure of society and marriage relations on the speed of molecular evolution. The influence can be twofold: first, the number of mutations in the offspring depends on the age at which the males begin to participate in breeding, and which, in turn, is determined not only by physiology, but also by social structure and cultural traditions. Secondly, the “sperm wars” characteristic of promiscuous communities contribute to the selection of spermatogenesis for intensification, which can lead to an accelerated increase in the number of mutations in spermatozoa with the age of the male.

Source: Oliver Venn, Isaac Turner, Iain Mathieson, Natasja de Groot, Ronald Bontrop, and Gil McVean. Strong male bias drives germline mutation in chimpanzees // Science . 2014. V. 344. P. 1272–1275.

Alexander Markov

Life without selection: good or danger?