Surveying disease-associated genetic variants in the 100,000 Genomes Project
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Project Title
Project Lead Project DateResearch projects for Population genomics
Genetic and environmental factors affecting de-novo germline mutation
Analysis of differences in cancer across ethnic groups
Effects of endogamy versus consanguinity on risk of rare disorders
Identifying genes associated with severe COVID-19 clinical course
Disentangling the genetic ancestry predisposition to COVID-19 from socioeconomic stratification using population genetics
The prevalence of nuclear mitochondrial segments (NUMTs) in the population
Diagnosis rates across ancestral population groups
Oligogenic model for rare disorders
Export of ethnically-defined allele frequency data from the Research Environment
The burden of Neanderthal introgression in rare diseases and cancers
The genetic ancestry of the 100,000 Genomes Project participants and its association with chemotherapeutic toxicities
De novo SNV and indel detection
Genetic analysis of renal disease.
We aim to identify new genetic causes of renal disease with the ultimate goal of identifying novel targets for therapeutic intervention. We will approach this research in two ways: first by collecting data from a group of individuals with renal disease and determining whether any particular genes in this population have a higher frequency of mutations compared to a control group; second, by starting with a list of candidate genes and determining whether individuals with mutations in these genes have a higher likelihood of exhibiting renal phenotypes than a control group. Specifically, we are interested to investigate polycystic kidney disease and kidney stone cohorts among others.
We aim to identify new genetic causes of renal disease with the ultimate goal of identifying novel targets for therapeutic intervention. We will approach this research in two ways: first by collecting data from a group of individuals with renal disease and determining whether any particular genes in this population have a higher frequency of mutations compared to a control group; second, by starting with a list of candidate genes and determining whether individuals with mutations in these genes have a higher likelihood of exhibiting renal phenotypes than a control group. Specifically, we are interested to investigate polycystic kidney disease and kidney stone cohorts among others.
Factors affecting mutation rate in somatic tissues and the germline
Changes in the DNA occur in every cell in our bodies, including the eggs and sperm which give rise to children. Every child inherits and average of ~60 new mutations (DNA changes) which were not present in either parent. The number of these mutations increases with the age of the parents, but it also seems to differ between families for reasons we do not yet understand. We will take ~10,000 families in GEL that consist of two sequenced parents plus their child, to study whether variants in the DNA of the parents (which they inherited from their own parents) affect the rate and patterns of new mutations in their blood and sperm/eggs. We will also look in their health records to extract factors that might impact this (such as smoking and history of chemotherapy).
Changes in the DNA occur in every cell in our bodies, including the eggs and sperm which give rise to children. Every child inherits and average of ~60 new mutations (DNA changes) which were not present in either parent. The number of these mutations increases with the age of the parents, but it also seems to differ between families for reasons we do not yet understand. We will take ~10,000 families in GEL that consist of two sequenced parents plus their child, to study whether variants in the DNA of the parents (which they inherited from their own parents) affect the rate and patterns of new mutations in their blood and sperm/eggs. We will also look in their health records to extract factors that might impact this (such as smoking and history of chemotherapy).
The effects of common genetic variation and polygenic risk in cardiomyopathy
Cardiomyopathy is an uncommon condition resulting from heart muscle disease, and is an important cause of death and need for heart transplantation. Genetic differences are partially responsible for the risk of cardiomyopathy. Although a substantial proportion of people with cardiomyopathy have rare genetic mutations that cause the disease, over half of people have no known genetic cause for their disease. This project aims to analyse genetic data from people with and without cardiomyopathy in the hopes of expanding our understanding on why cardiomyopathy develops in people more broadly. We hope to generate genetic risk scores that can be used to tailor treatments and disease screening to those who are at higher genetic risk.
Cardiomyopathy is an uncommon condition resulting from heart muscle disease, and is an important cause of death and need for heart transplantation. Genetic differences are partially responsible for the risk of cardiomyopathy. Although a substantial proportion of people with cardiomyopathy have rare genetic mutations that cause the disease, over half of people have no known genetic cause for their disease. This project aims to analyse genetic data from people with and without cardiomyopathy in the hopes of expanding our understanding on why cardiomyopathy develops in people more broadly. We hope to generate genetic risk scores that can be used to tailor treatments and disease screening to those who are at higher genetic risk.
High resolution profiling of 3D genome folding links disease variants to causal target genes
Mutations in genes produce non-functional genes that can lead to various diseases. There is however another mechanism that can cause disease even when the genes themselves are intact. This is because for normal development and health, it is crucially important when during development, and where in the human body, a gene is active. This is determined by so-called enhancers which act like molecular switches to turn genes on. When these enhancers are mutated (non-functional enhancers), genes are either not expressed, or they are expressed at the wrong time or in the wrong tissues, and this can lead directly to a range of diseases. The mechanisms that underpin these forms of disease predisposition and progression are much less well understood, compared to the disease-causing mutations in genes themselves. This is mainly because enhancers can be located far away from the genes they switch on; therefore, it is very challenging to identify which enhancer regulates which gene. We have developed a method that can link the enhancers with the genes they control in the entire human genome through our pioneering technology. This allows us to identify potential novel causal disease genes that cannot be identified using other approaches. Establishing these enhancer-gene links is therefore a crucial step to better understand diseases, and represents a highly promising avenue for the development of novel drugs to target causal disease genes, and for treatments to ameliorate diseases.
Mutations in genes produce non-functional genes that can lead to various diseases. There is however another mechanism that can cause disease even when the genes themselves are intact. This is because for normal development and health, it is crucially important when during development, and where in the human body, a gene is active. This is determined by so-called enhancers which act like molecular switches to turn genes on. When these enhancers are mutated (non-functional enhancers), genes are either not expressed, or they are expressed at the wrong time or in the wrong tissues, and this can lead directly to a range of diseases. The mechanisms that underpin these forms of disease predisposition and progression are much less well understood, compared to the disease-causing mutations in genes themselves. This is mainly because enhancers can be located far away from the genes they switch on; therefore, it is very challenging to identify which enhancer regulates which gene. We have developed a method that can link the enhancers with the genes they control in the entire human genome through our pioneering technology. This allows us to identify potential novel causal disease genes that cannot be identified using other approaches. Establishing these enhancer-gene links is therefore a crucial step to better understand diseases, and represents a highly promising avenue for the development of novel drugs to target causal disease genes, and for treatments to ameliorate diseases.
Population genomics research plan
Full details of the research proposed by this domain