Stage proposé par Ken McELREAVEY
« Fonction et Organisme d’appartenance »
Nom et adresse du Laboratoire : Reproduction, Fertility and Populations
Téléphone : 01 45 68 89 20
Mail : kenmce@pasteur.fr
Directeur du Laboratoire : Ken McElreavey
Titre : Chip analysis of genetic and epigenetic modifications associated with male infertility and
reduced sperm counts
Projet de stage : : situation du sujet, objectif du stage, approches expérimentales
(une dizaine de lignes maximum)
Genetic (or epigenetic) causes of male infertility are poorly understood. Cytogenetically detectable
chromosomal rearrangements, Y chromosome microdeletions and mutations in genes involved in
spermatogenesis account for spermatogenic failure in a small percentage of cases. There is also
considerable evidence for a decline in sperm counts in some European countries suggesting that
environmental factors may be acting. The project consists of two parallel genetic and epigenetic
approaches to understand male spermatogenic failure associated global decline in sperm counts. The
former consists of applying ultra-high resolution oligoarray comparative genomic hybridization to
detect gene copy number changes at a whole genome level (resolution 50 Kb) in azoospermic men.
The epigenetic analyses consists of measuring global changes of methylation status at 35,000 CpG
islands in sperm from men with reduced sperm counts or normospermic men using 100K mapping
arrays from affymetrix.
Techniques mises en œuvre par le stagiaire : DNA isolation and purification, PCR, PCR-RFLP,
SNP analysis, sequencing, preparation of DNA for CGH and methylation analysis, analysis of CGH
and methylation array data. Bioinformatic analyses.
Publications du responsable de stage au cours des 5 dernières années : (12 selected from a total
of 50)
1. Ravel et al. Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin
protease USP26. Mol Hum Reprod. 2006 Aug 3
2. Palmer et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major
predisposing factor for atopic dermatitis. Nature Genetics 2006 38:441-6.
3. McElreavey et al. Y chromosome variants and male reproductive function. Int J Androl. 2006
29:298-303
4. Barreiro et al. Promoter variation in the DC-SIGN-encoding gene CD209 is associated with
tuberculosis. PLoS Med. 2006 3:e20.
5. Patsalis et al. Identification of high frequency of Y chromosome deletions in patients with sex
chromosome mosaicism and correlation with the clinical phenotype and Y-chromosome instability. Am
J Med Genet A. 2005 135:145-9.
6. Vinci et al. A deletion of a novel heat shock gene on the Y chromosome associated with
azoospermia. Mol Hum Reprod. 2005 11:295-8.
7. Quintana-Murci et al. Where west meets east: the complex mtDNA landscape of the southwest and
Central Asian corridor. Am J Hum Genet. 2004 74:827-45.
8. Quintana-Murci et al. Y chromosome haplotypes and testicular cancer in the English population. J
Med Genet. 2003 40:e20.
9. Patsalis et al. Effects of transmission of Y chromosome AZFc deletions. Lancet. 2002 360:1222-4.
10. Gorlov et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet. 2002 11:230918.
11. Ottolenghi et al. Novel paralogy relations among human chromosomes support a link between the
phylogeny of doublesex-related genes and the evolution of sex determination. Genomics. 2002
79:333-43.
12. Krausz et al. Identification of a Y chromosome haplogroup associated with reduced sperm counts.
Hum Mol Genet. 2001 10:1873-7.