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Genetics of male infertility
Summary
We are researching the importance of DNA changes, genetic instability and epigenetic imprinting as causes of male infertility. Importantly this research also has consequences for understanding the impact of Assisted Reproduction Technologies (ART) on the health of the next generation.
Description
Poor spermatogenesis is reflected in reduced numbers of motile sperm and/or their inability to fertile an oocyte and initiate normal embryonic development. This heterogeneous group of disorders is the commonest cause of male infertility and the leading single reason for couples resorting to ART.
A genetic basis for many cases is suspected but to date only 10% are explicable on the basis of disorders of chromosomal number or structure, and partial deletions of the long arm of the Y (male) sex chromosome account: the bulk of cases remain unexplained.
As many such couples now utilise ART techniques to have a family. The genetic basis of male infertility, the possible transmission of infertility and other defects to their offspring, and of the de novo appearance of genetic defects are matters of concern to prospective patients and the broader community. We are addressing such issues in collaborative studies with colleagues at Monash University, Monash IVF and with international partners.
Over many years we have developed a repository of genomic DNA and clinical information from over 2000 infertile men, their partners and their ART-conceived children for use in such genetic studies.
Specific research areas include assessment for mutations in genes involved in the DNA repair which in mouse models have been associated with meiotic failure and that may be involved in the human conditions of germ cell arrest at the spermatocyte stage or Sertoli cell only pattern.
More recently in conjunction with our NHMRC Program Grant partners at the University of Newcastle, we have begun examining sperm DNA damage that is common in inferile men. Such damage may reduce sperm fertilising ability and also impact on embryonic development and potential the health of offspring. A better understanding of the mechanism of damage may lead to the development of effective treatments.
Studies on the genetic basis of male infertility may lead to better diagnostic tests and treatment for the infertile couples and is also essential in ensuring couples undertaking ART are fully informed about the likely health of their offspring.
Funding
National Health and Medical Reseach Council
Monash IVF
Outcomes
Description of the relationship between specific genetic deletions and male infertility
Description of the transmission of Y chromosomal defects to IVF offspring
Selected Publications
Aitken RJ, De Iuliis GN, McLachlan RI. Biological and clinical significance of DNA damage in the male germ line. Int J Androl. (2009) Feb;32(1):46-56.
McLachlan RI, Aitken RJ, Cram D, Krausz C, O'Bryan MK (2008). Need for standardization and confirmation of STS deletions on the Y Chromosome. Fertil Steril 90:463-464.
Jamsai D, Reilly A, Smith SJ, Gibbs GM, Baker HW, McLachlan RI, de Kretser DM, O'Bryan MK. (2008). Polymorphisms in the human cysteine-rich secretory protein 2 (CRISP2) gene in Australian men. Hum Reprod. 23:2151-2159.
Cram DS, Osborne E, McLachlan RI. Y chromosome microdeletions: implications for assisted conception. Medical Journal of Australia 2006;185:433-4
Lynch M, Cram DS, Reilly A, O'Bryan MKO, Baker HWG, de Kretser DM, RI McLachlan The Y chromosome gr/gr subdeletion is associated with male infertility. Molecular Human Reproduction 2005, 11:507-512.
Cram DS, Lynch M, O'Bryan MK, Salvado C, McLachlan RI, de Kretser D. Genetic screening of infertile men. Reproduction Fertility & Development 2004, 16: 573-580.