Ontcijferen van de rol van Y-chromosomale genen bij falende spermatogenese: een benadering langs de weg van genomics en transcriptomics
01 / 2005 - 01 / 2008
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Research into the genetic causes of spermatogenic failure has focused on the human Y chromosome, which contains many multicopy genes expressed specifically or predominantly in testis. Thus far, six common Y-chromosome deletions have been described that cause spermatogenic failure. Of these six common deletions, the three most frequent deletions (AZFc, gr/gr and b2/b3) co-localize in a ~4 Mb, highly repetitive region in distal Yq. The AZFc deletion removes eight gene families completely, while the gr/gr and b2/b3 deletion both only reduce the copy number of these gene families. Interestingly, the gr/gr and b2/b3 deletion remove a similar set of genes but have variable phenotypes. Men with gr/gr deletions are at increased risk for spermatogenic failure while most men with b2/b3 deletions appear to have no spermatogenic failure phenotype. The basis for this variable phenotype of these genetically similar deletions is currently unknown. We propose to investigate the variable phenotypes associated with these deletions using a genomic and transcriptomic approach. First, we will investigate whether the gene copies that remain after the gr/gr and b2/b3 deletions are functionally equivalent. We will focus on the DAZ genes, which have previously been shown to have variable numbers of DAZ repeats and RNA recognition motifs. Secondly, we will determine with the use of SAGE whether there are differences in expression levels of AZFc genes or downstream targets of such genes, in men with gr/gr or b2/b3 deletions. We hypothesize that differences in DAZ-gene structure and/or in AZFc gene expression level form the basis of the variable phenotype in men with gr/gr or b2/b3 deletions. The proposed research will shed new light on the functional and transcriptional differences of AZFc genes between men with similar genomic deletions. The results will contribute to our understanding of the complex process of spermatogenesis and the genetic aberrations that can disturb this process and lead to infertility.