Harmful mutations are located in areas rarely recombining chromosome

Fig. 1. An example of chromosomal recombination occurring during the formation of gametes. Prior to recombination the DNA of each chromosome of the pair of homologous chromosomes is doubled, so that both chromosomes are composed of two spirals connected by a special structure – centromere (white ovals). Komplemntarnye spiral from different pairs of chromosomes can exchange areas: in the DNA strand breaks are formed, the DNA fragments are exchanged, and then the resulting hybrid chromosomes stapled.

Canadian researchers studied the distribution of harmful mutations in the chromosomes of man and found that the most likely harmful mutations can be found in areas of the chromosomes, which are rarely recombine. However, this effect was less pronounced in larger populations. It turns out that the more effective population size (the number of people participating in reproduction), the less delayed harmful mutations in the genome.

Sexual reproduction – is not the only way to create new combinations of genes. Bacterium, for example, may transmit another bacterium one or more of its own genes in a small molecule composed of DNA – plasmid. Also genes may be transmitted via viruses, if the assembly of viral particles in their capsid mistakenly fall DNA of the host cell. Finally, thanks to advances in bioengineering person can be added to the genomes of many different organisms, those genes that are deemed appropriate. However, sexual reproduction is one important feature – this recombination sites is exchanged homologous chromosomes, thereby producing not only new combinations of genes and hybrid genes in which a part will be derived from a single chromosome, a part – of another ( Fig. 1).

In somatic cells, organisms that reproduce sexually, all the chromosomes are presented in pairs. Chromosomes pair is not quite identical – they contain the same genes, but some of them may be represented by different variants – alleles. In addition, the chromosomes pair may differ random mutations, which inevitably arise with some frequency. In the formation of sex cells into each of them should get only one chromosome of each pair to the merger with a sexual partner cell embryo was a normal set of chromosomes, instead of twice. But before we disperse to different gametes, chromosomes pair exchanged some areas – this exchange takes place on the stage of meiosis. In males, meiosis begins to go after puberty and may last until his death, with one cell meiosis – sperm precursor is about 70 days. In women, sex cells, meiosis begins during fetal development, and is only completed after fertilization – that is, the female reproductive cell meiosis can last up to 50 years. During this time, the reproductive cells are formed that have a reduced amount twice chromosomes and chromosome germ cells become different from the parent.

Recombination in the formation of sex cells creates a basis for greater variability and helps to quickly weed out bad genetic variants. So, if an individual chromosome is inherited from the harmful mutation, it will be harder to live, it will leave fewer offspring or leave it altogether, resulting in a chromosome with deleterious mutations would be less common in the population. But imagine that on the same chromosome with deleterious mutations, there are beneficial mutations that, on the contrary, give special advantages and compensate the harm of harmful mutations. Because of this harmful mutations will not be discarded, or the selection will be rejected more slowly than it should. However, due to the recombination of the chromosomes are not related to each other forever, and sooner or later have harmful mutations do not prove helpful neighbors in the chromosome and it will be deselected selection. This is one of the reasons that the recombination is so important.

Another reason – Recombination allows you to receive a “good chromosome” (without harmful chromosome mutations) of the two “bad”. For example, if both chromosomes pair have deleterious mutations in different areas, as a result of recombination one may get rid of the mutation and the second receive both. Of course, the other chromosome will be quite harmful, but the first chromosome will return to normal. And if possible to recombine not, chromosome never get rid of a mutation that arose in it.

Thus, Y-chromosome male couple which is very unlike her X chromosome can not recombine with the X chromosome, which is why in the Y-chromosomes are constantly piling up mutations that have already made many of its genes are inoperative, and with time the situation may become worse. For comparison, in the X-chromosome genes in 1400, and in the Y-chromosome – of less than 100, and in fact, these chromosomes once descended from a single precursor. Due to the fact that the Y-chromosome nowhere to throw an unfavorable mutation, it is not possible to “turn back”, restoring the previous version of the chromosome by recombination. If by chance the individual will die a “good» Y-chromosomes, the “good” chromosomes can no longer be restored from fragments bad. Such an irreversible deterioration in the absence of gene recombination is called “Muller’s ratchet.”

Relatively recently it revealed that recombination takes place in different parts of chromosomes with different frequency (S. Myers et al., 2005. A fine-scale map of recombination rates and hotspots across the human genome). It was established by analyzing the distributions SNPs – single nucleotide substitutions of DNA specific to different people. If you put a lot of polymorphisms in the genome map, you can find that somewhere they were “shuffled” often, but somewhere – less. In addition, the frequency of recombination for different parts of the DNA can be measured directly – by comparing the genomes of a large number of parents and their children. If the chromosome of the first child is a parent’s chromosomes, and then part of it to another chromosome – so between these sections recombination has occurred. Many of these events is marked on the map of the genome and see which areas of the chromosomes in recombination occurs more often, and in what – less.

The average frequency of recombination between single polymorphisms – somewhere in one case 2300 meiosis. For “hot spots” where recombination occurs more often, the frequency reaches one case per 80 meiosis. The existence of “hot” and “cold” regions of recombination due to different reasons. Firstly, the recombination does not go to the ends of chromosomes and in the centromere (constrictions that bind the two strands of DNA chromosomes after doubling). DNA in these areas densely folded, so proteins that help chromosomes recombine do not have enough space for action. These proteins are the most preferred free stretches of DNA where proteins found less competition and where DNA easiest approach. In addition, the proteins – assistants are not indifferent to the recombination of DNA sequences and some sequences of nucleotides to them more attractive than others. All this creates an uneven picture of the distribution of recombination sites on the chromosomes where some exchanges occur fairly frequently, but somewhere – less.

Given that regions of chromosomes recombine with varying frequency, scientists from Saint-Justine Hospital at the University of Montreal (Quebec, Canada) suggested that harmful mutations should focus where recombination occurs less frequently, and where the selection of a long time, “lacking.” To do this, scientists otsekvenirovali RNA 1,400 people and are all the mutations found on maps of chromosomes. For each mutation they found out whether it changes the amino acid in the protein (because not all nucleotide substitutions leading to amino acid substitutions in the corresponding protein), can affect the function of the mutation of the protein and whether it is listed in the database of mutations that affect health. It was found that mutations that lead to the substitution of amino acids, often located in regions that are seldom recombined. Those who cause harm, and often located in less recombining regions, and less than recombination occurs at the site of the chromosome, the more likely there is to be found harmful mutations (Fig. 2).

Fig. 2. Enrichment rarely recombining mutations in chromosomal regions of French-speaking Canadians from Quebec (FCQ), European (EUR), Asians (ASN) and the African (AFR). Odds ratio – the ratio of chances to meet certain group of mutations in rare and often recombining recombining regions of chromosomes. The value of this parameter is greater than 1 means that the mutations are more common in areas rarely recombining chromosome. Rare – mutations occur with a frequency of less than 1%, Non synonymous – mutations resulting in an amino acid change in a protein, Damaging – mutations affecting the health of the data base ClinVar, Neutral – mutations that do not cause amino acid substitutions in proteins. Schedule of the article under discussion in Nature Genetics

However, with the increase in the effective size of the population, which belonged to the people, the effect of the accumulation of harmful mutations in the chromosomes recombine slowly become less pronounced. The effective size of the population – is a parameter that reflects the number of breeding animals; It is calculated from data on genetic variability and represents the size of the pool of genes available to the population. The effective population size is higher for Africans than for Europeans and Americans, because, as we now know, the entire population of the Earth occurred in Africa and in the process of resettlement in other areas has experienced repeated to myself the effect of the “bottleneck.” Therefore, compared with Africa, other parts of the population of the Earth was a smaller number of people and its gene pool poorer. Through sexual reproduction, which was attended by more people in the African population to recombine more diverse set of chromosomes. In Africa, much less frequent partner with the same adverse mutations and such mutations will then selected, including less recombining regions of chromosomes.

So, on the one hand, the results of research are cause for optimism, as the world population grows and takes part in the reproduction of an increasing number of people. One would expect that due to the sexual reproduction, eventually harmful mutations will better be discarded from the genome. On the other hand, the population of developed countries is aging and the birth rate is falling in them, so it is difficult to say with certainty whether we will be healthier in the future. Whatever it was, the results are useful to researchers who are looking for mutations in the DNA, leading to disease: it is now clear that such mutations are more likely to settle in areas rarely recombining chromosome, so that their search should be accelerated.

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