ISSN 1359-9321 The Galton Institute NEWSLETTER Galtonia candicans Issue Number 83 Winter 2014 - 2015 Contents audience that it was indeed Galton Galton Institute himself who in 1889 introduced the Conference 2014 1 Galton Institute concept of regression to the mediocri- British Society for Population Conference 2014 ty (mean) to become the core of S t u d i e s C o n f e r e n c e 2 0 1 4 7 regression analysis, and also the idea of polygenic inheritance and mathe- B o o k R e v i e w 9 Genetics in Medicine matical relationship between genotype From DNA to Social Minds 10 Held 4 November, 2014 at the Royal and phenotype. Galton used the Society in London example of height, and the genetic European Human advances to date have clearly demon- Behaviour and Evolution strated that over 180 genetic variants Conference 2014 11 are involved in the genetic makeup of Canadian Conference This year’s Galton Institute Annual human height. Conference was dedicated to Genetics o n E p i g e n e t i c s 1 1 in Medicine and covered diverse Integrating the Genome topics, such as genetic testing and with the Phenome 12 gene therapy, as well as the applica- tion of cutting-edge genomic technolo- Genetics, Genomics and gies to cancer and metabolic diseases. Global Health 13 It was an inspiring overview of the Harry Stopes-Roe 14 current application of genetics in clinical care today. Tim Black 15 Anthony Smith 15 The first session, chaired by Profes- sor Dian Donnai, started with an T h e N e w A - L e v e l C u r r i c u l u m 1 5 inspirational talk from Professor Sir Teachers’ Conference 16 John Burn (Newcastle University). He is medical director and head of the Published by: Institute of Human Genetics, and lead The Galton Institute clinician for the National Health 19 Northfields Prospect Service North East. Northfields LONDON SW18 1PE In his lecture, entitled Overview of Professor Sir John Burn Genetic Medicine, Professor Burn Telephone: 020-8874 7257 succeeded in walking us through www.galtoninstitute.org.uk Professor Burn then talked about the genetics, and its transformation and General Secretary: ‘evolution’ into human genetics, then advance in the predictive markers for Mrs Betty Nixon clinical genetics, followed by genetic risks of developing genetic diseases. Newsletter Editor: medicine and more recently into The example of the genotype-driven Dr Geoffrey Vevers genomic medicine. He reminded the anticoagulant Warfarin dosing, where GALTON INSTITUTE NEWSLETTER 1 WINTER 2014—2015 recently published results from a success in neonatal diabetes (NND). former President, Professor Sir randomized trial achieved successful Within NND, 45% of these diagnoses Walter Bodmer, FRS, we heard genotype-guided dosing based on 3 represent a transient form, 45% lectures by two distinguished female individual single nucleotide polymor- permanent diabetes, and 10% are due clinical researchers, Professor phisms (SNPs). to syndromic pancreatic dysplasia. Nazneen Rahman (The Institute of Cancer Research) and Professor Sadaf He envisaged the future of genetic Together with Professor Frances Farooqi (University of Cambridge). medicine and talked about the Ashcroft’s team in Oxford, they were application of nanotechnologies to able to demonstrate that heterozy- DNA testing and presented work gous activating mutations in the gene close to his heart; the development of KCNJ11, encoding the Kir6.2 subunit a Nanowire DNA detection chip, of the ATP-sensitive potassium applying nanowires, (metallic or (KATP) channel cause neonatal semiconducting particles) in pioneer- diabetes. They hypothesized that in ing novel assays for fast, accurate and the patients carrying these activating affordable DNA testing. These excit- mutation, the channel could be closed ing new technological advances will by an ATP-independent mechanism ensure accessibility of genetic testing (e.g. by sulfonylureas) and insulin technologies through the world, not secretion might be restored. Indeed, restricting it to the world’s richest when sulfonylureas in tablet form countries. replaced insulin injections in these patients, they achieved far better glucose control, which also had a Professor Andrew Hattersley, lasting effect. This represents a true FRS (University of Exeter) followed personalized therapy for ~50% of the patients. This also led to change in with his lecture on Using Genetics Professor Nazneen Rahman to improve care in Diabetes, the current guidelines for diabetes presenting his research on the genet- testing for patients <6months of age. Professor Nazneen Rahman, ics of diabetes and translating it into This testing is now offered in >70 talk entitled Genetics in cancer clinical practice. countries. and treatment, presented her work in using science to make a difference Professor Hattersley discussed the for the cancer patients. implications of the fast adoption of genetic diagnostic tests, also leading She described the two types of to new gene discoveries and genetic cancer genes: genes carrying somatic stratification of diabetes. He de- mutation, and the cancer predisposi- scribed the move from a traditional tion genes, where germline mutations scenario, where selective late testing confer highly or moderately increased of individuals genes based on clinical risks of cancer. There are over 100 features is being replaced by an early cancer predisposition genes (CPGs), non-selective investigation, involving explaining 2-3% of cancers, and they comprehensive genetic analysis of have clear clinical utility, including multiple genes by next-generation improved diagnostics, familial cancer sequencing (NGS). This change in the prevention, and optimized tailored paradigm for genetic testing is therapies. In the UK, the National already bearing fruits as novel genetic Health Service only tests for half of discoveries further the mechanistic these genes, and access is restricted. insights into diabetes and pancreatic In 2013 a research programme, called function. Professor Andrew Hattersley, FRS Mainstream Cancer genetics (MCG) programme, generously funded by He began by talking about work In the second scientific session, the Wellcome Trust and directed by from his laboratory on gene discovery chaired by the Galton Institute Professor Rahman, was initiated to WINTER 2014—2015 2 GALTON INSTITUTE NEWSLETTER lay the foundations for an accessible economic benefits of Predictive cally and interventionally). genetic testing for anyone with Genetic testing in healthy individuals cancer. compared to Medical Genetic testing Historically, the first studies to in diseased individuals, and how this point to the brain regions controlling This initiative is a joint venture changing paradigm is dependent on body weight, the hypothalamus and between The Institute of Cancer successful and timely integration of the brainstem, have been performed Research, The Royal Marsden Hospi- multiple expertises to apply techno- in rodent models. Also in experi- tal, the Wellcome Trust Centre for logical advances into mainstream mental animals, it was discovered Human Genetics (Oxford) and oncology services. that fat acts as an endocrine organ, Illumina. and nutritional signals from the gut Professor Sadaf Farooqi are also transmitted in to the brain. The major aims are identification followed, presenting her talk on Professor Farooqi and Professor of the CPGs in an accredited NGS Genetics and Obesity. Starting Stephen O’Rahilly, through the testing laboratory setting, making the with a reminder that obesity seen in discovery of gene mutations in genomic medicine in cancer genetics population is largely environmentally patients with obesity, demonstrated a reality. The current gene panel tests driven, but with an underlying that Leptin, a hormone secreted by 97 genes, 260 Genome-wide associa- importance of genetic factors. Her white adipose tissue is a pivotal tion (GWAS) SNPs and 24 finger- laboratory studies the extreme regulator of energy balance in hu- printing SNPs. Professor Rahman phenotype of severe childhood onset mans. In the brain, leptin modulates took us through the sequencing and obesity in a cohort of >5,000 pa- the function of regions, involved in analytical challenges that the pro- tients, Genetics of Obesity Study food reward as shown by fMRI gramme is facing and its attempts in (GOOS, www.goos.org.uk). Using the imaging of patients. These studies setting a high standard for such tractable approach of studying the illuminate the biological basis of food initiatives. The genetic interpretation extremes of body weight in humans, reward with complex behavioural of the detected genetic variants is they have been successful in assign- regulation. The commonest highly particularly complicated, and all ing roles for multiple genes in the penetrant obesity gene is MC4R, variants should be considered inno- energy homeostasis, achieving encoding the melanocortin receptor cent until proven guilty and deemed insights into mechanism of disease, 4, accounting for approximately 5% pathogenic mutation. In order to which lead to drug discovery and of the genetic mutations in GOOS. In increase the confidence of the results, benefits to patients (both diagnostic addition to their severe obesity, these the programme has generated whole patients paradoxically also have low exome sequencing data on 1000 blood pressure, disproportionate to people from the 1958 British Birth their level of obesity. Cohort, which has been made publi- cally available (www.icr.ac.uk/genetic Recently, the team was able to show -resources). Making the causal that it was indeed Leptin, which is the relationship between a genetic key link to blood pressure regulation. variant and disease is the next hurdle The gene discovery program, com- in interpreting the functional signifi- bined with data from animal models cance of a variant. Interpretation is now building a picture of the brain goals for genetic testing are to make control of energy balance, where the processes automated, evidence- these processes are regulated by based and dynamic, where variants molecules acting in several hypotha- are triaged into clear clinical manage- lamic areas, the arcuate and the ment categories. Custom-made paraventricular nuclei in particular.