Human Developmental Genetics  


  Annual Report

1. A whole genome approach to characterise the mammalian sex determination pathway

The main focus of the group is the identification of the genetic signaling pathways that regulate mammalian sex determination. How sex is determined has long been of major interest to developmental biologists. Although the Y chromosome linked gene SRYis known to initiate the testis-determining cascade the precise mechanism whereby this occurs and the downstream effectors of SRY action are unknown. The underlying etiology of most patients with anomalies of sex development is unexplained, suggesting that several sex-determining genes are unidentified. Interestingly, some of these patients carry duplications or deletions of chromosomal regions. To delimit these regions and identify the genes involved, we are performing ultra high resolution microarray comparative genome hybridisation (CGH) using both NimbleGen and Affymetrix platforms. These ongoing studies have already identified novel candidate sex-determining genes/loci (figure 1). Using these technologies, we are analysing 300 cases of rare pathologies of sex-determination from our extensive DNA collections. Our data suggest that novel, possibly pathogenic, deletions/duplications are present in about 5-10% of the cases analysed.

2. Genetic and epigenetic control of germ cell specification and differentiation. Our principal goal is to identify genetic and epigenetic factors that are necessary for germ cell development and maintenance. Much of our recent work involved extensive analyses of the human Y chromosome for mutations associated with male infertility. A growing body of evidence suggests that Y chromosome genes may be involved in epigenetic modification during germ cell specification and differentiation. We are determining epigenetic changes in mature sperm from patients using extensive microarray analysis and correlating this data with genetic anomalies. These include Y chromosome mutations that we have characterised in the large collection of patient material available through national and international collaborations with clinical centres.

In parallel, we are using murine embryonic stem (ES) cells as an ex-vivo model to understand the genetic/epigenetic factors involved in the process of specification of primordial germ cells (PGCs) and their differentiation into male germ cells. Stem cell factor (SCF) and its receptor, KIT, play a critical role during PGC proliferation, migration, survival and differentiation bothin vivoandin vitro.We have developed a novel genetically engineered ES cell system that we are using to study this critical signaling pathway (SCF/KIT) during the development of PGCs. Using a pharmacological approach KIT receptor is activated in KIT null ES cells at specific time points during their differentiation into the germ cell lineage. The resulting phenotypes are analysed based on the morphology and gene expression profile using real-time PCR. The global methylation status of the cells at different stages of germ cell differentiation from ES cells is being assayed using a murine whole genome microarray platform. This strategy is envisaged to provide important clues about the role of genetic/epigenetic factors involved and their interaction with each other during the specification of PGCs and their subsequent differentiation into male germ cells.

Keywords: sex determination/germ cell development/embryonic stem cells/male infertility


NimbleGen SignalMap presentation of microarray results of a patient with a lack of testis formation and a Y chromosome deletion of 20 kb immediately 5’ to the SRY gene. The top panel panel indicates window averaging of the signal in 300 bp segments. The middle panel shows normalised signal intensities across chr Y. The lower panel shows transcript positions in the region. The y-axis is an averaged log2 ratio.


Dumic M et al., Report of Fertility in a Woman with a Predominantly 46,XY Karyotype in a Family with Multiple Disorders of Sexual Development. J Clin Endocrinol Metab. 2008 93:182-9. Epub 2007.

Vinci G et al., Association of deletion 9p, 46,XY gonadal dysgenesis and autistic spectrum disorder. Mol Hum Reprod. 2007 13:685-9.

Ravel C et al., Mutations in the protamine 1 gene associated with male infertility. Mol Hum Reprod. 2007 13:461-4.

Ravel C et al. Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26. Mol Hum Reprod. 2006

Palmer CN et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 38:441-6.

More informations on our web site

Activity Reports 2007 - Institut Pasteur
If you have problems with this Web page, please write to