Summary
Faculty of Medicine Ambassador for Women 2010-2013 - In this role, I've worked to support women within the Faculty with challenges they may encounter on an individual basis as well as to improve the situation for all through my work with Athena SWAN (http://www.athenaswan.org.uk/).
Research Interests - My research centres on analysis of how human genetic variation affects human health and disease. This work spans the whole range of human genetics, from single gene defects (including my early work on MCAD Deficiency), through genomic disorders, to population-based analyses of complex diseases, such as obesity and type 2 diabetes.
Most recently, my group has concentrated on investigation of genomic integrity – with particular emphasis on the implications of genomic copy number variation (CNV) and telomere length for human health.
I initiated the work on CNVs in 2005 when this type of genomic variation was very newly discovered and together with a range of collaborators have worked to establish new analytical methodologies (both in terms of laboratory investigation and computational analysis of genomics data) and to appy these to the investigation of human disease. In 2007, my group carried out what was at the time the highest resolution genome-wide scan for CNVs, identifying over 1,000 genes affected by previously-undescribed CNVs in normal individuals. We also showed that most small deletions had identical breakpoints in unrelated individuals, commonly in Alu repeats. This gave us new information on how these CNVs originally arose.
Analysis of children with suspected genomic disorders (which are caused by copy number changes in important regions of the genome) has led to the refinement of the minimal region for Prader-Willi syndrome, which causes severe appetite dysregulation leading to obesity. We also identified mirror phenotypes of obesity/leaness resulting from deletion/duplication of a region on chromosome 16p11.2.
Key to our work has been the detailled characterisation of genetic changes individuals with extreme characteristics (such as obesity), followed by exploration of the prevalance and implications of of the same genetic variants in larger population cohorts. For example, much of my group's effort is now directed towards the application of novel methodologies for CNV and inversion prediction to existing large-scale bith cohort datasets in order to investigate the full implications of both rare and common structural variants for human phenotype. Other researchers are concentrating on identifying the consequences of rare single-base sequence variants for health and function.
To complement this work, we are also investigating telomere (protective caps on the ends of chromosome that protect from genomic structural damage) length and telomere damage levels, particularly in regard to childhood growth trajectories and obesity.
To further underpin the work on obesity and diabetes, I have recently established a national and international network of colleagues collecting DNA, tissue biopsies, sequential blood-derived RNA and serum, and faeces samples from obese people before and after bariatric (obesity) surgery. This BRC and MRC-funded research effort is entitled "Personalised Medicine for Morbid Obesity" and includes both investigation of the genetic basis of super-morbid obesity and deep phenotyping (including genomics, metabolomics and metagenomics) during the resolution (or not) of obesity and diabetes following surgical intervention. We are using a range of genomics approaches, including exome sequencing, CNV analysis and RNAseq.
We have also collected psychological and behavioural information on the study participants and aim to integrate this with clinical and genomic information, aiming to identify people who would benefit from particular care programmes (which might include enhanced support to achieve healthier lifestyles, psychological interventions and/or genetic counselling where single-gene forms of obesity are identified). Most recently, we have obtained EPSRC funding to apply smartphone app technology for monitoring of activity patterns and mood in our study participants and hope to develop user-friendly approaches to encourage increased physical activity. Our long-term aim is to improve the targetting and effectiveness of healthcare support for this high-risk patient group.
Google Scholar Profile : http://scholar.google.co.uk/citations?user=ESYKYPEAAAAJ&hl=en
DS_Sequenom -This is an R script designed to improve the accuracy of genotyping in regions of duplication or trisomy. It was developed during a program on heart malformation in Down's syndrome children, carried out by two of my PhD students, Dr Ann Trewick and Julia El Sayed Moustafa. The script carries out SNP genotype assignment in regions where there are three copies of a particular genetic sequence (for example on chromosome 21 in Down's Syndrome, but also could be applied to any area of the genome where there is a duplication) using imbance in allelic ratio in Sequenom MALDI-TOF data. In Down's syndrome subjects, where possible, it also identifies the non-disjoining parent (the parent where the extra chromosome 21 came from) and the stage of meiosis at which non-disjunction occurred. This assignment is carried out using combined data from all of the genotyped SNPs.
If you use this script, please cite: Trewick AL, et al., Accurate single-nucleotide polymorphism allele assignment in trisomic or duplicated regions by using a single base-extension assay with MALDI-TOF mass spectrometry. Clin Chem. 2011 Aug;57(8):1188-95.
Selected Publications
Journal Articles
Alsters SIM, Goldstone AP, Buxton JL, et al., 2015, Truncating homozygous mutation of carboxypeptidase E (CPE) in a morbidly obese female with type 2 diabetes mellitus, intellectual disability and hypogonadotrophic hypogonadism, PLOS One, Vol:10, ISSN:1932-6203