Sex Development

Sex Development Research Group

Research Group Head

Professor Vincent Harley is a molecular geneticist whose research combines basic and translational strategies to address three areas of human sexual differentiation where perturbation leads to disease: disorders of sex development (DSD), gender bias in neurological disease susceptibility, and gender dysphoria.

Theme 1 (gonadal sex). There is a need to provide a definitive diagnosis in DSD. First, we will use genome-wide analyses of DSD patients (WES, optical mapping), combined with date from DSD animal models (ChIPseq, RNAseq) to identify candidate DSD genes. Second, the molecular and cellular consequences of perturbing candidate genes and DSD variants will be analyzed using cell culture models, organ cultures, and transgenic, knockin and knockout strategies. This work will position each gene in the emerging network of gene activity during gonadal development. Third, we will continue to share my research data with the clinical community to improve the clinical management of DSD patients. We will also take steps to improve and standardize of the diagnosis of DSD patients and to acquire a more comprehensive patient cohort with which to conduct further genome-wide analyses: a virtuous cycle.

Theme 2 (brain sex). There is no cure for PD and current therapies only treat symptoms. First, we will elucidate the detrimental actions of aberrant brain SRY expression observed in pre-clinical models of Parkinson’s disease (PD). We will also test my patented SRY-based gene therapy for Parkinson’s disease in a Phase I clinical trial, having shown proof-of-principle in three animal models (patents in 2016, 2017). There is no cure for PD and our drug is expected to be disease modifying. Second, we will investigate the genetic basis of gender dysphoria. We will break new ground by identifying genes and pathways associated with this condition using both candidate gene and genome-wide approaches in a very large cohort.

Related Links
http://www.dsdgenetics.org/index.php

Research Projects

Research Group

Selected publications

  • Lee J, Pinares-Garcia P, Loke H, Ham S, Vilain E,Harley V (2019) Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson’s disease. PNAS 116(33):16577-16582.

  • León NY, Reyes AP, Harley VR (2019) A clinical algorithm to diagnose differences of sex development. The Lancet DE 7(7):560-574.

  • Croft B, Ohnesorg T, Hewitt J, Bowles J, Quinn A, Tan J, Corbin V, Pelosi E, van den Bergen J, Sreenivasan R, Knarston I, Robevska G, Vu DC, Hutson J, Harley V, Ayers K, Koopman P, Sinclair A (2018) Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nature communications 9(1): 5319.

  • Bowles J, Feng C-W, Ineson J, Miles K, Spiller CA, Harley VR, Sinclair AH and Koopman P (2018) Retinoic acid antagonises testis development in mice. Cell Rep 24(5):1330-1341.

  • Foreman M, Hare L, York K, Balakrishnan K, Harte F, Erasmus J, Vilain E, Harley V (2018) A genetic link between gender incongruence and sex hormone signalling. J Clin Endocrinol Metab 104(2):390-396.

  • Rahmoun M, Lavery R, Laurent-Chabalier S, Bellora N, Philip G, Rossitto M, Symon A, Pailhoux E, Cammas F, Chung J, Murphy M, Bardwell V, Zarkower D, Boizet-Bonhoure B, Clair P, Harley V, Poulat F (2017) In mammalian foetal testes, SOX9 regulates transcription and splicing of its target genes by binding to genomic regions with conserved signatures. Nucleic Acids Research, 45(12):7191-7211.

  • Bagheri-Fam S, Argentaro A, Svingen T, Combes A, Sinclair A, Koopman P, Harley VR (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Human Molecular Genetics 20:2213-2224.

  • Ono M, Harley V (2013) Disorders of sex development: new genes, new concepts. Nature Reviews Endocrinology 9(2):79-91.