Infertility and sex reversal: direct molecular analysis of sex-chromosomal deletions and translocations in sperm

This project ended in 2006; results are currently being written up for publication.

1-2% of men are infertile because of a mutation on the Y chromosome, including interstitial deletions of loci on the long arm, and translocations between X and Y chromosomes causing sex-reversal together with infertility. Little is understood about the details of the molecular mechanisms underlying these processes, since studies to date have relied upon the analysis of individual occurrences in small numbers of patients. We aim to develop PCR-based techniques (building on methods previously established by Alec Jeffreys for the detection of meiotic crossover events and deletions) to detect microdeletions and translocations involving the human sex chromosomes directly in sperm and blood DNA, thus allowing mutation processes to be examined in great detail. Intially we have chosen to analyse two 'genomic disorders', mediated by aberrant recombination between homologous sequences: microdeletions of the AZFa region of the Y, which cause male infertility, and XY translocations involving the genes PRKX and PRKY, which cause sex-reversal (46,XX maleness and 46,XY femaleness).

AZFa deletions: Most AZFa deletions are caused by non-allelic homologous recombination between two HERV retroelements flanking the 750kb AZFa region (1). As well as deletions, duplications also occur (2), though their phenotype is unknown. The principle behind the recovery of AZFa deletion and duplication mutants relies on the ability of PCR to selectively amplify the novel sequence combinations which result from these mutations. Rare deletion and duplication molecules will be recovered from pools of sperm DNA containing 20,000-100,000 amplifiable progenitor molecules.

PRKX/PRKY-mediated translocations: Breakpoint clusters in these translocations lie within the XY-homologous genes PRKX and PRKY, which have an overall homology of 94%. It is known that PRKY exists in two orientations because of a paracentric inversion polymorphism (3). We will use PCR to isolate translocation molecules from sperm DNA, allowing us to investigate the effect of Y haplogroup on PRKX/PRKY translocation mutation rate. We will include males in our experiments who are known from previous work to possess PRKY in both orientations, which should contribute to our understanding of the fundamentals of mutation and genome instability, of the aetiology of infertility and sex-reversal, and of the effects of natural selection on Y-chromosomal diversity.

We will extend these studies to examine microdeletions involving other regions of the Y, such as AZFb and AZFc; however, due to their highly repetitive nature, analysis of these regions may prove difficult. We will also pursue our investigations of rearrangement polymorphisms in normal males (4), which have an influence on the probability of progression to pathogenic mutation.

We will determine the germline and somatic rates of these mutation processes, and the spectra of different mutations. We will examine the breakpoints of the various rearrangements and determine the influence of the length and homogeneity of any sponsoring repeated sequences. We will also ask whether the characteristics of these processes are dependent upon Y-chromosomal lineage, through the different sequence organisations which each carries, and thus whether some lineages are particularly susceptible to mutation. Lineage-specific effects are important in the aetiology and diagnosis of infertility, and because they imply that natural selection can act upon Y chromosomes, affecting the use of the Y as a neutral marker for the history and structure of human populations. Methods and conclusions emerging from these studies should be widely applicable to the study of other genomic disorders affecting loci elsewhere in the genome.


1. Blanco, P., Shlumukova, M., Sargent, C.A., Jobling, M.A., Affara, N. and Hurles, M.E. (2000) Divergent outcomes of intra-chromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism. J. Med. Genet. 37, 752-758.

2. Bosch, E. and Jobling, M.A. (2003) Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility. Hum. Mol. Genet. 12, 341-347.

3. Jobling, M.A., Williams, G., Schiebel, K., Pandya, A., McElreavey, K., Salas, L., Rappold, G.A., Affara, N.A. and Tyler-Smith, C. (1998) A selective difference between human Y-chromosomal DNA haplotypes. Curr. Biol. 8, 1391-1394.

4. Jobling, M.A., Samara, V., Pandya, A., Fretwell, N., Bernasconi, B., Mitchell, R.J., Gerelsaikhan, T., Dashnyam, B., Sajantila, A., Salo, P.J., Nakahori, Y., Disteche, C.M., Thangaraj, K., Singh, L., Crawford, M.H. and Tyler-Smith, C. (1996) Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males.Hum. Mol. Genet. 5, 1767-1775.


This project is funded by the Wellcome Trust.

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Last updated: 6 December, 2002
Mark Jobling
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