Genetic factors in male infertility

Male infertility is one of the most crucial problems in Fertility Science. In accordance with modern data, 20—30% of infertility cases are caused by male factor alone, 20—35% – by female factor alone, 25—40% – by a combination of both factors and in 10—20% of cases infertility is of uncertain genesis [ESHRE statistics, http://www.eshre.eu/guidelines-and-legal/art-fact-sheet.aspx]. According to ASRM [http://www.asrm.org/detail.aspx?id=2322], in 40% of infertile couples a strong male factor is observed.

Male infertility can be caused by a whole range of reasons including varicocele, oncologic diseases, infections, sexual problems etc. Out of these, up to 30% of all cases are associated, according to some assessments, with genetic factors including chromosomal rearrangements, deletions in the AZF region on the Y chromosome and CFTR gene mutations. The total number of genes involved in male reproductive function nears 3000. Hence checking if there are genetic factors of infertility in a given man by screening all these genes is at the moment technically impossible [J.H. Hackstein, R. Hochstenbach, P.L. Pearson; M.M. Matzuk, D.J. Lamb].

However, even by the most optimistic assessments, the total number of men with genetically conditioned problems in the reproductive system does not exceed 2-5%. Why so few?

Mutations in genes responsible for reproduction must be very harshly eliminated from the population: in nature, individuals with such problems have practically no chance of reproduction, hence there is practically no possibility for any such mutation to be handed down to further generations. The complete set of mutations present in population should appear each time de novo, and since mutations are random, the number of such «problematic» individuals should be small.

This concept has two shortcomings:

As is, it is not applicable to sex chromosomes and genes active only in one sex.

Such genes experience the pressure of natural selection only in individuals of one sex (the one where they are active). In individuals of the opposite sex these genes are «dormant» and thus cannot be sorted out by natural selection. The opposite sex is a potential carrier of mutations in such genes, and this carriage significantly increases the background level of mutations [Gershoni & Pietrokovski, 2014];

Can the occurrence of mutations always be deemed purely random? Is the probability of occurrence the same for different mutations?

Well, these ones are questions for significantly more complex studies.
As it is known, the rate of new mutations – i.e. disruptions of the nucleotide sequence in DNA – depends on the condition of the DNA itself (package density), the work of the systems of replication (DNA duplication) and reparation (the reconstruction of damaged regions). Under certain conditions, one or another genomic region may show “hypersensitivity” to external mutagenic influences leading to an abnormally high number of mutations in this very region. This concept came to be called a “phenotypic window of genome” [http://www.evolbiol.ru/labas.htm].