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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

We are intrigued about how biology determines size; what genes are important for our height and our brain size?

We have a strong focus in the lab on Meier-Gorlin syndrome (MGS), where disruption of the earliest stages of DNA replication leads to a specific syndrome of short stature, small brain, small ears, and absent kneecaps. The lab investigates the biological roles of both established and novel MGS genes using genomic, cellular and developmental biology approaches. These projects have been supported by the Marsden Fund.

We are also studying the genetics of New Zealanders with microcephaly (reduced brain size). We are undertaking exome sequencing of families in which a child is affected by microcephaly, and will study the mutations using a variety of reporter cells including neural stem cells. We greatly appreciate the support for this project from the Cliff Broad Family Trust, administered through the Neurological Foundation of New Zealand.

An exciting new project, in collaboration with paediatric endocrinologists from around New Zealand, is to study the genetics of short stature in New Zealand children. We will undertake exome sequencing of families where there is a child with unexplained significant short stature, and aim to provide answers for these families about this condition. This project is supported by Cure Kids.

We are grateful for generous support from the Rutherford Discovery Fellowship, the Marsden Fund, HRC, the Neurological Foundation, Cure Kids and the University of Otago.

Clinicians or scientists interested in collaborating are encouraged to email Louise.

Students interested in undertaking a research project should get in touch with Louise.

Email louise.bicknell@otago.ac.nz

Our people

2019 Bicknell lab photo
Back row: Rosie Sullivan, Kendra Ryan, Karen Knapp, Jack Harrison, Matt Reily-Bell. Front row: Serena Bielli, Danielle Jenkins, Louise Bicknell, Rashmi Kumar.

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 Fellow

Karen KnappKaren completed her PhD in the research group of Professor 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. This was 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 out research which focuses on identifying and characterising novel DNA replication components, in which mutations cause the rare Mendelian disorder, Meier-Gorlin syndrome (MGS).

Dr Danielle Jenkins - Assistant Research Fellow

Danielle completed her PhD with Associate Professor Stephen Bunn in the Department of Anatomy and Centre for Neuroendocrinology, University of Otago (2017). During this time, her research focused on interactions between the cytokine interleukin-6 and the adrenal medulla during immune challenge. In 2018, Danielle joined the Bicknell lab as an Assistant Research Fellow where she is investigating genetic mutations associated with microcephaly, and the involvement of these genes in neural development.​

Dr Dario Zimbalatti - Visiting Academic

foto Dario ZimbalattiDario is a registered GP from Milano, Italy and is currently training in his specilisation in Human Genetics through the Universita' degli Studi di Milano. He has a particular interest in genetic research on diseases which are common amongst the general population, such as cancer and neurological disorders. Dario is visiting our lab for his research placement, with a shared interest in autism and neurodevelopmental disorders.

Students

Rashmi Kumar - PhD student

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Rashmi completed her Bachelor of Science in Biotechnology, 1st class, from M G University, Kerala, India in 2016, and her Master’s degree in Biomedical Genetics with Genetic Counselling, 1st class, from Vellore Institute of Technology, Tamil Nadu, India in 2018. During her Master's, she did a six-months' project at the Child Development Center, Government Medical college, Trivandrum, Kerala, India, where she worked on finding genetic causes underlying recurrent pregnancy losses in couples. There she also got the chance to study first hand, the various types of chromosomal and other genetic abnormalities, prevalent among children in India today. She has a special interest in Pediatric and Developmental Genetics. Rashmi joined the Bicknell lab in Feb 2019, and her PhD focuses on identifying and characterising novel gene variants for microcephaly. Rashmi is being co-supervised by Professor Stephen Robertson.

Rosie Sullivan - MSc Genetics student

Rosie completed her Bachelor of Science, majoring in Genetics, at the University of Otago in 2017. Rosie joined the Bicknell Lab in 2018 as a Masters student. Her project is to use CRISPR / Cas9 genome editing to knock-in mutations involved in Meier-Gorlin syndrome into hTERT-RPE1 cells, and to use these cells to look at the cellular consequences of these mutations.

Meghan Mulligan - Summer / Genetics Hons student

Meghan completed her Bachelor of Science, majoring in Genetics, at the University of Otago in 2019. Meghan joined the Bicknell Lab in 2019 as a 2019/2020 Summer Student. Her project focussed on using CRISPR/Cas9 genome editing to disrupt Donson in Xenopus tadpoles to understand what effect disrupting Donson has on the developing brain. For her Honours project, she will be investigating the cellular role of a novel microcephaly-related gene, using RNA-seq analysis and imaging tools.

Suzanne Musgrave - Genetics Hons student

Suzanne completed her Bachelor of Science, majoring in Genetics, at the University of Otago in 2019. Suzanne joined the Bicknell Lab in 2020 for her Honours project, co-supervised by Dr Heather Cunliffe. Her project is on investigating the role of Meier-Gorlin syndrome genes as driver genes in breast cancer.

Collaborators

Alumni

  • Matt Reily-Bell - BSc (Hons) Genetics (1st class), 2017 and MSc (Genetics) Distinction, 2020.
  • Rebecca Dawson - BSc(Hons) Genetics (1st Class) 2016. Winner of 2016 DSM Poster Evening Honours Student Prize. Now undertaking a PhD at Victoria University, Wellington.
  • Isabella Thompson - PGDipSci Genetics (Distinction) 2017. Now undertaking Secondary School Teacher Training at Victoria University, Wellington.

Study forms

PDF packs containing information sheets, consent forms, clinical data forms, and sample sending instructions are available below:

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Publications

Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., … Stuart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics, 49(4), 537-549. doi: 10.1038/ng.3790

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

Journal - Research Article

Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., … Stuart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics, 49(4), 537-549. doi: 10.1038/ng.3790

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., 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

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

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