Professor Andrew Sinclair

Biography:

Professor Andrew Sinclair is Deputy Director of the Murdoch Children’s Research Institute and a Professor in the Department of Paediatrics at The University of Melbourne. In these roles and as Executive Director of the Victorian Clinical Genetics Service at the Royal Children’s Hospital, Melbourne he is using genomic information to improve healthcare for children and their families.

At a national level Professor Sinclair co-leads the Australian Genomic Health Alliance, a network of over 40 organisations, that aim to integrate genomics into the Australian health care system. He is also on the Executive Management Committee of Melbourne Genomics which is implementing genomic medicine into routine care in Victoria. In addition, he leads an NHMRC research Program (2004-2019) focusing on disorders of sex development; genomics and diagnosis to inform clinical care. His contributions have been fundamental to the advancement of the field, including the identification and characterization of the human testis determining gene (SRY) and other genes critical for gonad development. He has also implemented new, accurate, rapid and comprehensive diagnostic procedures to improve outcomes for patients with DSD.

While President of the Australian Society for Medical Research in 2004 he led national advocacy efforts to increase Federal Government funding for health and medical research. He has served on numerous government committees including: the Australian Biotechnology Advisory Council (2005-2006) and been a member and chair of the NHMRC Grant Review Panel for Genetics (2007-2008), NHMRC Human Genetics Advisory Committee (2009-2015), NHMRC Assigners Academy (2011-2013) and a member and chair of the NHMRC Research Fellowships peer review panel (2014-2017). He is an editorial board member of several international journals. Professor Sinclair has received numerous national and international awards including the 2009 Sutherland Award for contributions to Human Genetics, the 2010 Emil Steinberger Memorial Award from the American Society of Andrology and in 2015 was elected a Fellow of the Australian Academy of Health and Medical Sciences.

Awards:

1987: Smith-White Award, Genetics Society of Australia

1988: Imperial Cancer Research Fellowship award, UK

1990: Outstanding Research Award, Royal Society, UK

1993: NHMRC RD Wright Award

1995: NHMRC Senior Research Fellowship

1998: Distinguished Alumni Award LaTrobe University for outstanding professional achievement and leadership

2000: NHMRC Principal Research Fellowship

2000: Sutherland Award for contributions to Human Genetics (HGSA)

2010: Emil Steinberger Award and Lecturer, American Society for Andrology

2010: David Danks Oration, Deans Lecture Series, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne

Research:

One of the most fundamental influences on our lives is our sex. Whether we are born as male or female has a lifelong impact on our behavioral patterns, personality, reproductive options, disease susceptibility and life expectancy. Not surprisingly, the sex of a newborn child is often the first question asked. When no clear answer can be given, a family and medical emergency follow.

Disorders of Sex Development (DSDs – also known as intersex disorders) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. They are surprisingly common and represent a significant healthcare burden due to the direct clinical management of these conditions and also their common association with gonadal cancer and infertility. Uncertainty about a child's gender is extremely traumatic for the individual, parents and other family members, and carries profound psychological and reproductive consequences for the patient. The cause of these problems is most often a breakdown of the complex network of gene regulation responsible for proper development of testes or ovaries in the embryo. Studies have identified a small number of genes that play critical roles in testis and ovary development, but efforts to assemble these into a regulatory network have failed, most likely because key pieces of the puzzle are missing.

Professor Andrew Sinclair's research is aimed at identifying the molecular and cellular basis of gonad development and the genetic causes underlying disorders of sex development (DSDs), and applying this knowledge to the diagnosis and clinical management of DSD to improve outcomes for affected children.

Projects:

Disorders of Sex Development: Genetics, Diagnosis, Informing Clinical Care
Identification and analysis of regulatory regions associated with Disorders of Sex Development

Western, P.S., Miles, D., van den Bergen, J.A., Burton, M. and Sinclair, A.H. (2008) Dynamic regulation of mitotic arrest in fetal male germ cells. Stem Cells 26:339-347.

Smith, C.A. Roeszler, K. Ohnesorg, T. Farlie, P. and Sinclair, A.H. (2009) The conserved avian Z-linked gene, DMRT1, is required for male sex determination in the chicken. Nature 461:267-271

Western, P.S., van den Bergen, J., Miles, D.C., Sinclair, A.H. (2010) Male fetal germ cell differentiation involves complex repression of the regulatory network controlling pluripotency. FASEB J 24(8):3026-35

Pearlman, A., Loke, J., Le Caignec, C., White, S., Chin, L., Friedman, A., Willan, J., Warr, N., Brauer, D., Brooks, E., Oddoux, C., Riley, B., Shajahan, S., Camerino, G., Homfray, T., Crosby, A., Couper, J., David, A., Greenfield, A., Sinclair, A.H., and Ostrer, H. (2010) Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis development. Am J Hum Genet 87: 898- 904

Bagheri-Fam S, Argentaro A, Svingen T, Combes A, Sinclair AH, Koopman P, Harley V (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome Human Molecular Genetics 20(11): 2213-2224

Sutton, E., Hughes, J., White, S., Tan, J., Rogers, N., Sekido, R., Knower, K., Rowley, L., Eyre, H., Rizzoti, K., Goncalves, J., Slee, J., Turbitt, E., Arboleda, V., Bruno, D., Bengtsson, H., Harley, V., Vilain, E., Sinclair, A.H., Lovell-Badge, R., and Thomas, P. (2011) Identification of Sox3/SOX3 as a XX male sex reversal gene in mice and humans. J Clin Invest 121:328-41

White S, Hewitt J, Turbitt E, Zwan Y, Hersmus R, Drop S, Harley V, Cools M, Looijenga L, Sinclair AH. (2011) A multi-exon deletion within WWOX is associated with a 46,XY Disorders of Sex Development. Eur. J. Hum. Genet. 20(3): 348-351.

White, S., Daggag, H., Ohnesorg, T., Notini, A., Roeszler, K., Turbitt, E., Hewitt, J., Smith, C., Gustin, S., van den Bergen, J., Miles, D., Western, P., Arbodela, V., Gordon, L., Bell, K., Bengtsson, H., Speed, T., Hutson, J., Warne, G., Goncalves, J., Harley, V., Koopman, P., Vilain, E., and Sinclair, A.H. (2011) Copy number variation in patients with disorders of sex development due to gonadal dysgenesis. PLoS One 6(3):e17793

Ayers KL, Davidson NM, Demiyah D, Roeszler KN, Grutzner F, Sinclair AH, Oshlack A, and Smith CA. (2013). RNA sequencing reveals sexually dimorphic gene expression before gonadal differentiation in chicken embryos and allows comprehensive annotation of W-chromosome genes. Genome Biol. 2013 Mar 25;14(3):R26. PMID: 23531366

Eggers, S. Smith, KR. Bahlo, M. Looijenga,L.H.J. Drop,SLS. Juniarto, ZA. Harley, V. Koopman, P. Faradz, SMH. Sinclair AH. (2014) “Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1" Eur. J. Hum. Genet doi: 10.1038/ejhg.2014.130

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Funding: