The Molecular Genetics of Male Infertility

Project Description

Funding RCSI Rotunda IVF Programme Research Funds/Health Research Board Project Grant.
Principal Investigator Dr David Barton.
Researchers Melissa Rogers, MSc; Dr Tom Barrett (MD Project); Dr David Bailey.
Duration 1997-present.
Collaborators Professor Robert Harrison, Rotunda Hospital and RCSI.


It has been known for many years that there are genes involved in spermatogenesis on the Y chromosome long arm.

Careful study of Yq deletions has allowed mapping of this putative “azoospermia factor” locus (AZF) to an area close to the boundary between the fluorescent and non-fluorescent segemnts of Yq, known as interval 6.

Recent research has identified two genes found to be deleted in a proportion of men with azoospermia or oligospermia, named RBM and DAZ (Deleted in Azoospermia).

Similar studies by other groups have shown that azoospermia can result from deletions which are close to, but do not include the DAZ or RBM loci, indicating that other genes involved in spermatogenesis are located in this region.

IntraCytoplasmic Sperm Injection (ICSI) has made it possible for azoospermic men to become fathers, and has revolutionised the management and prognosis in male-factor infertility. However, the application of ICSI in cases when a Y-chromosome deletion is the underlying cause of the azoospermia risks passing on the deletion to the next generation.

There is a pressing need to assess the frequency of Yq deletions in azoospermia, and to define the critical regions involved. Such studies will have immediate clinical application, and will be an essential prerequisite to attempts to identify the Y-linked genes involved in spermatogenesis.

Project objectives

We have collected DNA from a panel of 850 infertile men attending the Human Assisted Reproduction Unit at the Rotunda Hospital. We have screened these DNAs for micro-deletions in Yq using a consensus panel of six PCR-based probes, or “sequence-tagged sites”.

Our objective is to define the minimal Yq regions necessary for normal spermatogenesis. Testicular biopsies of men from our panel will be examined for expression of candidate spermatogenesis genes, both Y chromosome and autosomal.

The aims of this study are:

  1. To determine what proportion of male-factor infertility in a large cohort of men is due to deletions in interval 6 of the Y chromosome long arm.
  2. To correlate the extent and nature of the spermatogenic defect with the size and position of the deletion, or with the presence or absence of a deletion.
  3. Using these data, to develop a clinical test based on the polymerase chain reaction (PCR) for screening azoospermic men prior to ICSI.


  1. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.
    Rovio A.T, Marchington D.R, Donat S, Schuppe H-C, Abel J, Fritsche E, Elliott D.J, Laippala P, Ahola A.L, McNay D, Harrison R.F, Hughes B, Barrett T, Bailey D.M.D, Mehmet D, Jequier A.M, Hargreave T.B, Kao S-H, Cummins J.M, Barton D.E, Cooke H.J, Wei Y-H, Wichmann L, Poulton J. and Jacobs H.T.
    Nature Genetics 29: 261-262, 2001.
  2. The relationship between Y chromosome DNA haplotypes and Y chromosome deletions leading to male infertility.
    Quintana-Murci L, Krausz C, Heyer E, Gromoll J, Seifer I, Barton D.E, Barrett T, Skakkebaek N.E, Rajpert-Demeyts E, Mitchell M, Lee A.C, Jobling M.A, McElreavey K.
    Human Genetics 108(1):55-58, 2001.