Evolution and male fertility: lessons from the insulin-like factor 6 gene (Insl6).

Male factor still accounts for at least half of all cases of human infertility, suggesting that something like one in 20 of all men might be affected, and andrological analysis still indicates that greater than 50% of such cases are idiopathic (1). In about 15% of male infertility patients, genetic abnormalities may be detected, including chromosome rearrangements and single gene mutations. There is mounting evidence that infertility is a complex trait affected by many genes and the environment and may also involve polymorphisms as risk factors. At a time when assisted reproductive technology (ART) has now been used for 30 yr with over 1 million births, it may seem less important to understand completely the molecular basis of infertility, particularly where intracytoplasmic sperm injection (ICSI) is used to resolve the male factor. On the contrary, nowthatweknowthat ICSI canpassonagenetic defect from father to son (2), a better understanding of the genetic and epigenetic aspects of male infertility is urgently needed for both a better diagnosis as well as for counseling in regard to the passing on of genetic defects or infertility predisposition to the next generation. In humans, the identification of genes and mutations leading to male infertility is haphazard, and the mouse model has been our most powerful tool to systematically identify genes with a direct role in spermatogenesis with over 200 mouse mutants generated with an infertility phenotype (3). The description and thorough analysis of an Insl6 knockout mouse reported by Burnicka-Turek and colleagues (4) in this issue adds a new gene to the list of factors required for male spermatogenesis. More importantly, it is a gene coding for a member of the well-known family of relaxin-like peptides that include genes that have been conserved over hundreds of millions of years as well as genes that emerged only recently on the genomic landscape of placental mammals. The evolutionary history, enigmatic signal transduction, and a phenotype that depends on genetic background additionally illuminate a number of important aspects that go beyond the simple description of a new gene required for male fertility. The development and maturation of sperm is a complicated and unique process of differentiation, which generates haploid and functional spermatozoa from diploid stem cells (spermatogonia) in the testes. This process continues from puberty throughout life, taking (in humans) roughly 72 d for the full differentiation of mature sperm to be completed. At the heart of sexual reproduction is the meiotic cell division, which involves chromosome pairing and recombination followed by segregation into the haploid spermatocytes. Meiosis and packaging of the genome into sperm also involves dramatic changes in terms of genome organization, epigenetic make-up, and chromatin composition, with specific gene transcription both before and after meiosis (5). This culminates in the wholesale repackaging of almost the entire genome from histone-dominated chromatin to a protamine-compacted pseudocrystalline structure, with the chromosomes organized in a specific nonrandom fashion inside the sperm head (6, 7). All of this is required to achieve the highly specialized and evolutionarily variable morphology of the spermatozoon, with its unique ability to mature and function while in the reproductive tract of another individual. Every individual sperm must retain the capacity to decondense and reorganize its chromatin in a recipient oocyte (8) and provide a full and intact single-copy genome with which to create a new individual. This is a much more complicated process than that undergone by oocytes, although these may be