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Dr Katie Ayers
Dr Katie Ayers is a Team Leader in the Reproductive Development group at the Murdoch Children’s Research Institute (MCRI) in Melbourne, Australia.
In 2004 she completed a BSc. Hons in Genetics at Otago University, NZ. In 2005 she moved to France to study her PhD in Molecular Biology in Nice under a Marie Curie Early Stage Training Fellowship , as part of the InterDeC international PhD program (2005-2010). Following this, she carried out postdoctoral studies in Associate Prof. Craig Smith's lab at MCRI, where she studied the molecular mechanisms underlying sexual differentiation of the gonads using the chicken embryo. This work was carried out under a Poultry Cooperative Research Centre (CRC) grant. In 2015, she moved to work with Prof. Andrew Sinclair (MCRI) on the genetics of human Disorders of Sex Development under an NHMRC program grant. In 2017, she was awarded a team leader position to continue this work and holds an NHMRC project grant (2019-2021).
Katie has an extensive background in genomics and genetics, and significant experience in using animal models (chicken, zebrafish, flies) and cell culture to model disease. She regularly lectures at the University of Melbourne on the genetics of sex development.
University of Melbourne, Department of Paediatrics.
2018. Travel Fellowship. Human Genetics Society of AustralAsia “Flown the Coop” Travel Award.
2015. Travel Fellowship. 7th International Symposium on Vertebrate Sex Determination, Hawaii, USA.
2014. Alan Wilton Award. Genetics Society of AustralAsia.
2013. Co-operative Research Centre (CRC) Travel Grant. Travel to the Gordon Research Conference (developmental biology), Barga, Italy.
2012. Presentation Award. Early-Mid Career Researcher Campus Research Week, MCRI.
2004. Genetics Prize (ranked first in honours class). University of Otago, New Zealand.
2003. Women in Science Scholarship. University of Otago, New Zealand.
Katie Ayers' broad research interests are the genetic and molecular mechanisms underlying gonad development and sexual differentiation, and why aberrations in these cause Disorders of Sex Development (DSD) in humans. DSDs are a broad range of disorders ranging from the common hypospadias (1 in 125 boys), to rare cases of complete sex reversal (1 in 20,000). The causative mutations in these disorders are typically poorly characterised (around 60% of DSDs have an undefined aetiology).
Since 2015, Dr Ayers has led a research team in the Sinclair group including junior post-doctoral researchers, research assistants and PhD students. Our goal is to employ genomic sequencing technologies and functional assays to identify and validate genetic aberrations in patients with DSD. The overarching goal is to improve diagnostic rates for patients with DSD. In 2016 she was equal senior author on a seminal study in Genome Biology showing that a DSD targeted gene panel provided an efficient and robust means to improve diagnosis rates from 13% to 40%. This led to the introduction of this gene panel, covering 68 diagnostic DSD genes, as a clinical diagnostic test at the Victorian Clinical Genetics Services.
Since then, Dr Ayers and her team have published 11 research papers on DSD genetic variants. Their research goals are now to identify novel DSD genes and variants in undiagnosed patients. To study these, she is drawing on her background in genetics and developmental models, including animal models such as the chick embryonic gonad and Drosophila (she has 11 publications in these models in journals such as Dev. Cell, Development and Genome Biology). Finally, she also driving the development of an exciting novel method to differentiate human embryonic gonadal cells from pluripotent stem cells. This will shed light on the earliest events in human gonad development, and allow modelling of how these are disrupted in DSD by using cells carrying novel DSD genetic variants or patient iPS cells.
Identification of novel genes and genetic variants underlying Disorders of Sex Development in Humans:
Disorders of sex development (DSD) represent a broad group of genetic conditions characterised by ambiguous external genitalia or atypical sexual development that manifests at birth or puberty, respectively. DSDs affect up to 1% of the population and are also associated with over 200 complex syndromes. Receiving an accurate genetic diagnosis early in life is empowering to patients with DSD and their family, and is vital when discussing sex assignment, gonad/genital surgery or the reproductive and cancer complications of these disorders. Furthermore, an early genetic diagnosis can reduce health care costs, especially for complex childhood disorders. Research from my team has significantly improved genetic diagnosis rates from 13% to ~ 40% and we have driven the implementation of our DSD-specific targeted sequencing panel as a clinical diagnostic test at the Victorian Clinical Genetics Service. This is the most comprehensive DSD gene test internationally. Despite these improvements, 60% of patients will still be negative in genetic testing. This research project uses genomic sequencing technologies of large patient cohorts with advanced functional analysis to identify and validate new DSD causing genes to fill these diagnostic gaps. This includes neglected DSDs such as the poorly understood Müllerian duct agenesis disorders and complex disorders combining DSD with neurological phenotypes. This research will increase diagnosis and improve health and wellbeing outcomes for patients born with neglected DSDs.
Modelling gonad disorders in a dish using patient derived stem cells:
Genomic sequencing allowing swift identification of novel candidate disease genes in undiagnosed patients. Yet, to move these genes from “candidate” to “diagnostic” is a huge challenge, requiring multiple affected patients with the same gene/variant and functional analysis to validate pathogenicity. In DSD this is especially difficult due to the rarity of severe DSD, the derth of appropriate cell models and the near impossibility of obtaining human embryonic gonad tissue. Thus, we have an urgent need for novel high-throughput functional models of DSD. To address this, I have been working closely with Prof. Melissa Little (MCRI) to develop an innovative differentiation protocol for human embryonic gonadal cells derived from pluripotent stem cells, including induced patient stem (iPS) cells. This innovative model will allow us to understanding how new genes and genetic variants cause DSD in humans.
Ayers KL# van den Bergen J Robevska G et al. Functional analysis of novel Desert Hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46XY Differences of Sex Development (In press) Journal Med. Genetics
Bouty A et al. Ayers KL* Sinclair AH* (2018) Identification and Functional Characterisation of Two New Variants in ihe Bmp7 Prodomain in Two Pairs of Monozygotic Twins with Hypospadias Journal of the Endocrine Society (In press)
Knarston IM et al. Ayers KL*# and Andrew H Sinclair* (2018) NR5A1 gene variants repress the ovarian-specific WNT signalling pathway in 46XX Disorders of Sex Development patients Human Mutation 40: 207-216
Backhouse B et al. Sinclair A Ayers K* Tan T* (2018) Identification of candidate genes for Mayer-Rokitansky-Kuster-Hauser Syndrome using genomic approaches Sexual Dev.
Croft B* Ohnesorg T* Hewitt J Bowles J Quinn A Tan J Corbin V Pelosi E van den Bergen J Sreenivisan R Knarston I Robevska G Vu DC Hutson J Harley V Ayers KL Koopman P and A Sinclair (2018) Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9 Nature Comms. 9(1): p5319-5329
Rothacker KM Ayers KL et al. (2018) A novel homozygous mutation in desert hedgehog (DHH) in a 46 XY patient with dysgenetic testes presenting with primary amenorrhoea International Journal of Pediatric Endocrinology 2: doi:101186/s13633-018-0056-3
Robevska G et al. Ayers KL*# Sinclair AH* (2018) Functional characterisation of novel NR5A1 variants reveal the complexities of its role in Disorders of Sex Development Human Mutation 39: 124-139
Hirst CE Major AT Ayers KL Brown RJ Mariette M Grayson P Sackton T Edwards SV and CA Smith (2017) Sex reversal and comparative data undermine the W chromosome and support Z-linked DMRT1 as the master switch for gonadal sex differentiation in birds Endocrinology 158: 2970–2987
Shankara Narayana N Kean A-M Ewans L Ohnesorg T Ayers KL Watson G Vasilaras A Sinclair AH Twigg SM and DJ Handelsman (2017) Painful Ovulation in a 46XX Sry-ve Adult Male with SOX9 Duplication: Case Report & Literature Review Endocrinology Diabetes Metabolism Case Reports doi: 101530
Hirst CE Serralbo O Ayers KL Roeszler KN and C A Smith (2017) Genetic manipulation of the avian urogenital system using in ovo electroporation Methods in Molecular Biology – Avian and Reptilian Dev. Biol.1650: 177-190
Ohnesorg T* van den Bergen* J Belluoccio D Shankara-Narayana N Kean A-M Ewans L Ayers K L Sinclair A H (2017) A duplication in a patient with 46XX ovo-testicular Disorder of Sex Development refines the SOX9 testis–specific regulatory region to 24 kilobases Clinical Genetics 92: 347-349
Ayers KL et al. (2017) Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46XY under-virilised boys. Hum. Genomics 11:1
Eggers S et al KL Ayers* Sinclair A* (2016) Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort Genome Biol. 17:243
Lambeth L Ayers KL et al. Smith C (2016) Over-expression of Anti-Müllerian Hormone disrupts gonadal sex differentiation blocks sex hormone synthesis and supports cell autonomous sex development in the chicken Endocrinology 157:1258
Ayers KL et al. (2015) Identification of candidate gonadal sex differentiation genes in the chicken embryo using RNA-seq BMC Genomics 16:704
Ayers KL et al. (2015) DMRT1 is required for Müllerian duct formation in the chicken embryo Developmental Biology 400:224
Lambeth L Ayers KL et al. (2015) Anti-Müllerian hormone is required for chicken embryonic urogenital system growth but not sexual differentiation Biol. of Repro. 93:138
Cutting A Ayers KL et al. (2014) Identification expression and regulation of Anti-Müllerian Hormone type-II receptor in the embryonic chicken gonad Biol. of Repro.: 90:1
Ayers K* Davidson N* et al. (2013) RNA sequencing reveals sexually dimorphic gene expression before gonadal differentiation in chicken and allows comprehensive annotation of the W-chromosome. Genome Biol. 14:R26
Ayers KL et al. (2012) Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling Dev. 139:3168
Johnson J et al. Ayers K et al (2012) Scube activity is necessary for Hedgehog signal transduction in vivo Dev. Biol. 368:193
Ayers KL* Gallet A* Thérond P (2010) The Long Range activity of Hedgehog Is Regulated in the Apical Extracellular Space by the Glypican Dally and the Hydrolase Notum Dev. Cell 18:605 *Equal
Ayers KL* Rodriguez R* et al. (2009) Tow a novel repressor of the Hedgehog pathway Developmental Biology 329:280
Roly ZY et al. Ayers KL Major A Smith C (2018) Evolution and Development of the Müllerian duct Review WIRES Developmental Biology 7:e310
Croft B Ayers KL et al (2016) “Disorders of Sex Development: The evolving role of genomics in diagnosis and gene discovery” Invited review Birth Defects Res. C Emb. Today 108:337
Knarston I Ayers KL Sinclair A (2016) Molecular mechanisms associated with 46XX Disorders of Sex Development Review Clin. Sci. 130:421
Bouty A* Ayers KL* et al. (2015) The Genetic and Environmental Factors Underlying Hypospadias Review Sex. Dev. 9:239
Ayers KL et al. (2013) The molecular genetics of avian sex determination and its manipulation Review Genesis 51:325
Ayers KL and P Therond (2010) Evaluating Smoothened as a G-protein coupled receptor for Hedgehog Signalling Review Trends in Cell Biol. 20:287
*Equal authorship # Corresponding author
2017. MCRI Strategic pilot projects in stem cell and genomic medicine. Ayers, K., Knarston, I., Combes, A., Little, M., and A Sinclair. Title: Growing testis in a dish: A novel in vitro tool to study Disorders of Sex Development.$46,000
2016. Cell Biology Grant, MCRI. Ayers, K., Knarston, I., Combes, A., Little, M., and A Sinclair. Title: Induction of a gonadal cell fate in human iPS cells: Towards the creation of "testis in a dish". $10,000
2015. Cell Biology Grant, MCRI. Bouty, A., Ayers, K. and A. Sinclair. Title: DNA methylation profiling in patients with Hypospadias. $14,000.
2015. MCRI Cell biology grant for stem cell work. Ayers, K. and A. Sinclair. Title: Creation of a Sertoli cell line. $6000
2009. L’Association pour la Recherche sur le Cancer (ARC) fellowship. Fellowship for 4th year of doctorate studies.
2005 – 2008. Marie Curie early stage training fellowship - International PhD Program in Developmental and Cellular Decisions (InterDec). 3 years fully funded doctorate studies.