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Approved research

Identification and characterisation of naturally-occurring human gene knockouts.

Principal Investigator: Professor David van Heel
Approved Research ID: 4477
Approval date: June 1st 2016

Lay summary

We will analyse genotypes from the full UK Biobank cohort to identify people with closely related parents. We expect to identify between 2000 and 5000 people, who we will exome sequence to identify rare loss of function genetic variants that cause complete gene knockouts (both gene copies). We expect to find 1000 - 2500 such gene knockouts (pilot data). Gene knockouts tell us a lot about human biology (huge amounts have been learnt from mouse knockouts). They give safety and other information for drug development. We will study the clinical features (if any) of people with gene knockouts. UK Biobank has the aim of improving the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses. 1. Our study will provide important information for drug development. 2. Our study will provide important general information about human biology. Naturally occurring homozygous LoF genotypes for a gene, whilst exceptional in the population, are simply the only way we can directly study the effects of gene inactivation (knockout) in a living human. Step 1: computational analysis of genome-wide genotyped samples will be undertaken by ourselves using UK Biobank generated data. Step 2: exome sequencing is a routine lab technique, and will be performed at the Wellcome Trust Sanger Institute (WTSI) using standard protocols. We have well-developed analysis pipelines for identifying human gene knockouts. Step 3: involves individual by individual analysis of existing UK Biobank data. We cannot completely predict what data will be required without knowing the results of step 2. Step 1: we will analyse all genome-wide genotyped samples from the full cohort. We will look for samples with long runs of homozygosity (autozygosity) using an algorithm we have developed and validated. Step 2: we will request DNA samples and perform whole exome sequencing on an expected 2000 - 5000 individuals with substantial autozygosity (F>0.05 approx). We expect to sequence all individuals with this level of autozygosity with DNA available. Step 3: we will review health records and phenotype data on these 2000-5000 individuals, correlating this the naturally occuring rare variant homozygous gene knockout genotypes.