The Human Genetics Programme seeks to bring genomics to population-scale studies (in the UK, and in diverse populations); progress beyond locus discovery and mapping, to causal variant and pathway identification; provide mechanistic insights into how individual variants impact health and disease; and gain knowledge of variable phenotypic expressivity, and assess reversibility of developmental phenotypes, which may yield important therapeutic insights.
The Human Genetics Programme will:
use genetic and genomic approaches to improve understanding of the aetiology of rare and complex inherited disease, to characterise healthy variation in humans of different ancestry and to advance knowledge of human population evolution, demography and history.
study cohorts of 10,000s - 100,000s healthy participants from the UK population for 100s to 1000s of quantitative traits, relating these to cardiometabolic and other diseases; and identify thousands of homozygously null genes compatible with human life.
begin studies using electronic health records for patient recruitment (e.g. in patients with drug-induced liver injury), endophenotyping (e.g. in patients with osteoarthritis) and provision of detailed medical information for apparently healthy individuals carriers of homozygous loss-of-function mutations in lipid metabolism genes.
leverage diverse human populations (African, isolated European and cosmopolitan European) to elucidate the genetic architecture of cardiometabolic diseases and traits; and with the study of ancient DNAs gain insights into human evolution, history and diversity.
use a multidimensional functional genomics approach (including rare genetic variation studies, studies of intestinal microbiota, studies of gene effects in subsets of immune cells) to understand consequences of disease-associated variants on genome regulation, focusing on disorders of inflammation and immunity; and understand the effect of genetic variation on normal immune response (e.g. variation in response to immune stimulation through studies of vaccinated individuals).
continue to search for mutated genes causing rare developmental and metabolic disorders, model these disease phenotypes in engineered mice, and with use of mouse models examine the possibility that some phenotypic elements of these conditions may be reversible.
begin to explore the cell biology underlying variability in organism-level phenotypic expression of genetic abnormalities.
The main areas of research of the Human Genetics Programme can be summarised as:
Genomics of UK biomedical resources
We are facilitating powered population-scale genetic studies in medically relevant traits, by aligning genomic approaches to samples from individuals with existing electronic health records (eHRs) in established cohorts and registries.
Complex traits in diverse populations
We are studying diverse human populations with different LD (linkage disequilibrium) structures to elucidate the genetic architecture of cardiometabolic and infectious diseases and traits, and inform population genetic studies. By combining whole-genome sequencing and genotyping approaches in thousands of people (>100,000) we are carrying out powered association analysis to delve further into human history and evolution.
Integrated genomics of inflammation and immunity
We are employing post-GWAS (genome-wide association study) multidimensional functional genomic analyses to understand the consequences of disease-associated variant on genome regulation, focusing on disorders of inflammation and immunity.
Causes, mechanisms and reversibility of rare diseases
We seek to extensively characterise the genetic architecture of rare metabolic and developmental disorders through whole-genome sequencing approaches (in partnership with Genomics England); to integrate investigations (including functional genomics) in cells and mice to support inferences of causality; and provide insights into disease mechanism.
Parts of our research build on our ability to characterise human genetic variation globally, in isolated (Finnish, Greek and Italian isolates) and cosmopolitan populations (1000 Genomes Project, UK10K, African Genome Variation Project), to harness information pertaining to human population diversity and evolution. While other elements seek to provide new resources and foundations for worldwide research, for example we are working with our network of partners in Africa to jointly undertake GWAS on 100,000 participants from Africa, across a range of cardiometabolic and infectious traits. This will bring these studies to a scale equivalent to that obtained in European cohorts.
Our work will also continue to focus on a core set of traits and phenotypes with significant impact on morbidity and mortality: haematological, cardiometabolic, inflammation and immunity and developmental disorders. And in all of these areas we aspire to understand the impact of rare and very rare variation in these diseases and traits.
The African Partnership for Chronic Disease Research (APCDR) is an international network of research groups which work together to facilitate and promote collaborative research of chronic diseases across Africa.
The BLUEPRINT Project is a five-year project to further the understanding of how genes are activated and repressed in healthy and diseased human blood cells and their precursors. The BLUEPRINT Consortium is made up of 42 leading European universities, research institutes and industry entrepreneurs, and ran from October 2011 to September 2016.
DECIPHER is an interactive web-based database which incorporates a suite of tools designed to aid the interpretation of genomic variants. DECIPHER enhances clinical diagnosis by retrieving information from a variety of bioinformatics resources relevant to the variant found in the patient. The patient’s variant is displayed in the context of both normal variation and pathogenic variation reported at that locus thereby facilitating interpretation.
The aim of the Deciphering Developmental Disorders (DDD) Study is to advance clinical genetic practice for children with developmental disorders by the systematic application of the latest microarray and sequencing methods while addressing the new ethical challenges raised.
The MRC Uganda Medical Informatics Centre (UMIC) is a UK Medical Research Council (MRC) funded initiative to build and operate a high-throughput medical bioinformatics data centre in sub-saharan Africa.
The PAGE study is striving to gain a better understanding of genetic variants causing developmental problems during pregnancy. The ultimate aim is to improve prenatal diagnostics, allowing better genetics-derived prognoses and more informed parental counselling in the future.
The UK10K project enabled researchers in the UK and beyond to better understand the link between low-frequency and rare genetic changes, and human disease caused by harmful changes to the proteins the body makes.
We are a multidisciplinary team that combines large-scale genetic and genomic approaches, and studies in model organisms, to understand the aetiology of various metabolic diseases. We are also actively engaged in developing partnerships with collaborators in Africa focused on applying genomic approaches to study diseases of relevance to Africa and its peoples.The knowledge of genetic predisposition is important to help those at high risk for these disorders to develop healthier lifestyles and to avoid risky behaviours (such as high fat diets). It can also lead to the development of better drugs that work in each affected individual.
The Genome Reference Informatics Team analyses genome assemblies to reveal and correct quality issues and to identify and add variation. It forms the Sanger division of the Genome Reference Consortium and the Vertebrate Genomes Project.
Human Genetics Informatics (HGI) supports the scientific aims of the Human Genetics programme by developing and operating computational analysis workflows, managing shared storage, and providing bioinformatics software tools for the use of researchers across all Human Genetics faculty groups.
We are interested in all aspects of gene regulation by non-coding RNA. Current research themes include: miRNA biology and pathology, miRNA mechanism, piRNA biology and the germline, endo-siRNAs in epigenetic inheritance and evironmental conditioning, small RNA evolution and the role of RNAi in host pathogen interaction.
Our research focuses on the application of large-scale genomic analysis to unravel the spectrum of human genetic variation associated with cardiometabolic diseases, and its interaction with non-genetic and environmental cues.
We study variation in the DNA of people from different parts of the world, and also in related species such as chimpanzees and gorillas. This tells us about the evolutionary history of human populations and also allows us to compare the different species.
We analyse large-scale genetic and electronic health record data from populations in which parental relatedness (consanguinity) is common, to explore fine-scale structure, its impact on disease risk, and the genetic architecture of both rare and complex diseases.
We developed algorithms and technologies that enable researchers to discover and share genetic variation using next-generation sequencing technologies. We were part of the Global Alliance for Genomics and Health consortium (GA4GH), an international, not-for-profit alliance formed to help accelerate the potential of genomic medicine to advance human health.
This group consists of manual annotators and software developers. The HAVANA team provides the manual annotation of human, mouse, zebrafish and other vertebrate genomes that appear in the Vega browser. Our software is written and developed by the Annosoft team.
Genetic study reveals possible new routes to treating osteoarthritis