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Bicknell Laboratory: Human Genetics

Overview

Bicknell DNA replication figureDr Louise Bicknell's laboratory focuses on understanding how the genetic variation present in our genomes can shape or influence genetic conditions. The lab harnesses the power of mutations underlying Mendelian disorders to gain biological insight into our development and lifetime health.

The laboratory has two main themes:

  • identifying the causes of rare Mendelian disorders using exome / genome sequencing and learning about the biology connecting the causative gene with the clinical syndromes.
  • investigating how additional genetic variation in our genomes can influence the clinical consequence of a genetic mutation to explain differences between patients with the same genetic condition.

A particular focus of the lab is on Meier-Gorlin syndrome (MGS), where disruption of the earliest stages of DNA replication leads to a specific syndrome of short stature, small ears and absent kneecaps. The lab investigates the biological roles of both established and novel MGS genes using cellular and developmental biology approaches, including utilising CRISPR in Xenopus laevis to model disease mutations (in collaboration with Dr Caroline Beck, Department of Zoology).

Dr Bicknell's laboratory is supported by a Rutherford Discovery Fellowship, the Marsden Fund and the University of Otago.

Clinicians or scientists interested in collaborating are encouraged to email Louise: louise.bicknell@otago.ac.nz

Students interested in undertaking a research project should get in touch with Louise: louise.bicknell@otago.ac.nz

Our key people

Dr Louise Bicknell - Principal Investigator, Rutherford Discovery Fellow

Louise BicknellLouise completed her PhD with Professor Stephen Robertson, University in Otago (2007), examining the genetic contributors to joint dislocation in children. She undertook a postdoctoral fellowship with Professor Andrew Jackson, University of Edinburgh (2008-2015), the last three years of which were personally supported by Medical Research Scotland. This research focused on characterising novel causes of microcephalic primordial dwarfism, a rare genetic disorder of extreme global growth failure.

Amongst her successes, she successfully identified five novel genes underlying Meier-Gorlin syndrome, a disorder of short stature, small ears and absent kneecaps (Bicknell et al., 2011a, Nature Genetics; Bicknell et al., 2011b, Nature Genetics) and has continued this interest at Otago.

The clinical differences seen in children with the same genetic syndrome piqued her curosity, and she now also investigates the role that additional background genetic variation may play in shaping disease development and progression.

Dr Karen Knapp - Postdoctoral Research FellowKaren Knapp

Karen completed her PhD in the research group of Prof. Norbert Sträter at Leipzig University, Germany (2010), carrying out research involving the biochemical and structural characterization of a cancer drug target (CD73). She went on to carry out postdoctoral research within the Biochemistry Department, at the University of Otago (2010-2013), involving the structural characterization of viral and host protein complexes, followed by further postdoctoral research at the North West Cancer Research Institute, Bangor University, UK (2013-2015), investigating DNA repair mechanisms and their role in cancer. In 2016 Karen joined the Bicknell Lab as a postdoctoral research fellow, and is carrying our research which focuses on identifying and characterising novel DNA replication components, in which mutations cause the rare Mendelian disorder, Meier-Gorlin syndrome (MGS).

Dr Amy Taylor - Postdoctoral Research Fellow

Amy completed her PhD with Dr Caroline Beck, Department of Zoology, University of Otago in 2013, providing some of the first evidence that epigenetic mechanisms distinguish whole structure regeneration from normal embryonic development. From 2014-2016 Amy worked in the Department of Medicine, University of Otago as an Assistant Research Fellow and Departmental Lab Manager. In 2016 Amy joined the Bicknell lab as a Postdoctoral Research Fellow to develop CRISPR/Cas9 genome editing techniques in Xenopus laevis, to serve as a model for DNA replication associated disorders.

Students

Isabella Thompson - MSc Genetics Student

Isabella completed her Bachelor of Biomedical Science at Victoria University of Wellington in 2016, majoring in Humans Genetics and Molecular Pathology. In 2017 Isabella joined the Bicknell lab as a Masters student and is currently working on characterising the novel genetic cause of a family with a Meier-Gorlin-like syndrome, using genetic and cellular techniques.

Matthew Reily-Bell - BSc(Hons) Genetics Student

Matt completed his Bachelor of Science, majoring in Genetics, at the University of Otago in 2016. He then undertook a summer research project in the Virus Research Unit, Department of Microbiology, University of Otago, investigating ORFV’s ability to manipulate host cell genes to bypass the hosts own defence system. In collaboration with Associate Professor Caroline Beck, Matt’s Honours project is to utilise CRISPR / Cas9 in Xenopus laevis to disrupt cdt1, a replication licensing factor and a common disease gene associated with Meier-Gorlin syndrome.

Collaborators

Dr Caroline Beck, Department of Zoology, University of Otago

Professor Andrew Jackson, University of Edinburgh, UK

Professor Andrew Wilkie, University of Oxford, UK

Professor Wojciech Niedzwiedz, University of Oxford, UK

Dr Ernie Bongers, Radboud University Nijmegen Medical Centre, the Netherlands

Alumni

Rebecca Dawson - BSc(Hons) Genetics student 2016. Winner of 2016 DSM Poster Evening Honours Student Prize. Now undertaking a PhD at Victoria University, Wellington.

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Publications

Fenwick, A. L., Kliszczak, M., Cooper, F., Murray, J., Sanchez-Pulido, L., Twigg, S. R. F., … Bicknell, L. S. (2016). Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. American Journal of Human Genetics, 99(1), 125-138. doi: 10.1016/j.ajhg.2016.05.019

Murray, J. E., van der Burg, M., IJspeert, H., Carroll, P., Wu, Q., Ochi, T., … Bicknell, L. S. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. American Journal of Human Genetics, 96(3), 412-424. doi: 10.1016/j.ajhg.2015.01.013

Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379. doi: 10.1038/nature12517

Bicknell, L. S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., … Jeggo, P. A. (2011). Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics, 43(4), 350-356. doi: 10.1038/ng.776

Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., … Jackson, A. P. (2011). Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genetics, 43(4), 356-360. doi: 10.1038/ng.775

Journal - Research Article

Fenwick, A. L., Kliszczak, M., Cooper, F., Murray, J., Sanchez-Pulido, L., Twigg, S. R. F., … Bicknell, L. S. (2016). Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. American Journal of Human Genetics, 99(1), 125-138. doi: 10.1016/j.ajhg.2016.05.019

Murray, J. E., van der Burg, M., IJspeert, H., Carroll, P., Wu, Q., Ochi, T., … Bicknell, L. S. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. American Journal of Human Genetics, 96(3), 412-424. doi: 10.1016/j.ajhg.2015.01.013

Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379. doi: 10.1038/nature12517

Bicknell, L. S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., … Jeggo, P. A. (2011). Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics, 43(4), 350-356. doi: 10.1038/ng.776

Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., … Jackson, A. P. (2011). Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genetics, 43(4), 356-360. doi: 10.1038/ng.775

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