Genetics of Male Fertility

Abstract

Early in embryogenesis, cells that are destined to become germ cells take on a different destiny from other cells in the embryo. The germ cells are not programmed to perform "vital" functions but to perpetuate the species through the transfer of genetic materials to the next generation. To fulfill their destiny, male germ cells undergo meiosis and extensive morphogenesis that transforms the round-shaped cells into freely motile sperm propelled by a beating flagellum to seek out their missing half. Apparently, extra genes and additional regulatory mechanisms are required to achieve all these unique features, and an estimated 11 % of genes are involved in fertility in Drosophila (Hackstein et al., Trends Genet 16(12):565-572, 2000). If comparative numbers of male fertility genes are needed in mammals, extra risks of male fertility problems are associated with disruptive mutations in those genes. Among human male infertility cases, approximately 22 % were classified as "idiopathic," a term used to describe diseases of unknown causes, with idiopathic oligozoospermia being the most common semen abnormality (11.2 %) (Comhaire et al., Int J Androl (Suppl 7):1-53, 1987). "Idiopathic" is a widely used adjective that is used to reflect our lack of understanding of the genetics of male fertility. Fortunately, after more than two decades of phenotypic studies using knockout mice and identifying genes disrupted in spontaneous mutant mice, we have unveiled new and unexpected aspects of crucial gene functions for fertility. Other efforts to categorize genes involved in male fertility in mammals have suggested a total of 1,188 genes (Hermo et al., Microsc Res Tech 73(4):241-494, 2010). Although intracytoplasmic sperm injection (ICSI) can be used to bypass many fertilization obstacles to achieve fertilization with only a few extracted sperm, the widespread use of ICSI without proper knowledge for genetic testing and counseling could still potentially propagate pleiotropic gene mutations associated with male infertility and other genetic diseases (Alukal and Lamb, Urol Clin North Am 35(2):277-288, 2008). In this chapter, we give a brief account of major events during the development of male germ cells and focus on the functions of several crucial genes that have been studied in mutant mouse models and are potential causes of human male infertility.

Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring

“…These genome-wide association studies (GWAS) have been widely used to study complex traits and to identify key genomic regions associated to several diseases. In this context, more than 1000 male infertility-associated genes have been already reported [ 281 ]. However, the transcriptomic, genomic and epigenomic behavior of these genes as well as many single-nucleotide polymorphisms (SNP) during the male reproductive aging is still unknown.…”

“…However, such studies require a proper experimental design and enough number of patients with comparable characteristics which is challenging given the scarcity of the samples and the various aging effects to be assessed [ 169 ]. These suggested data are required to set up functional validation [ 281 ] to demystify the role of each target genes and understand the molecular process of male infertility in its entirety, at a particular stage and over time.…”

Efficient GFP‐labeling and analysis of spermatogenic cells using the IRG transgene and flow cytometry

“…Mouse spermatogenesis is a powerful model system that has provided important insights into molecular mechanisms balancing cell proliferation, differentiation, and apoptosis; DNA repair and recombination; cell–cell communication; adhesion; and stage‐specific transcriptional and post‐transcriptional gene regulation (Licatalosi, ; Lie, Mruk, Lee, & Cheng, ; Song & Wilkinson, ; Youds & Boulton, ). Continued study of spermatogenic cells has the promise to reveal many key aspects of cell biology, infertility, and testicular cancer (Lin & Matzuk, ).…”

Discovering in vitro spermatogenesis stimulating factors

“…Azoospermia is a disorder that currently renders millions of couples infertile due to reduced spermatozoa production. 8 , 9 , 10 Cases of azoospermia, including spermatogenic arrest, are caused by diverse traits that impact various steps in spermatozoa development. 8 , 9 , 10 Highly defined experimental systems are needed to obtain a more detailed understanding on how genetic interactions control spermatozoa development.…”

“… 8 , 9 , 10 Cases of azoospermia, including spermatogenic arrest, are caused by diverse traits that impact various steps in spermatozoa development. 8 , 9 , 10 Highly defined experimental systems are needed to obtain a more detailed understanding on how genetic interactions control spermatozoa development. Once established, chemically defined culture systems supporting spermatogenesis and/or spermiogenesis hold potential to help classify germline-intrinsic and -extrinsic molecular mechanisms controlling distinct steps in spermatozoa development.…”