Identifying Pathogenic Variants for Rare Diseases from Whole Genome Sequencing data

Project Overview

Whole genome sequencing (WGS) is increasingly being used in a clinical setting to provide a molecular diagnosis for patients with a broad spectrum of rare inherited genetic diseases.  Identifying the pathogenic variant in an individual, from the millions that occur in any genome, requires applying a series of genetic filters which take into account the deleteriousness of the variant, its frequency, inheritance pattern and the biological context. The challenge then is to demonstrate pathogenicity of the candidate gene through replication in genetics databases and through complementary functional studies.  These may be very diverse, depending on the gene in question, but will undoubtedly require molecular biology tools such as expression in cell systems via transient or stable transfection or gene editing of induced pluripotent stem cells using CRISPR techniques and appropriate downstream assays.

Oxford has been at the forefront of applying WGS for clinical applications; 500 rare disease (RD) and cancer genomes were sequenced as part of the WGS500 project, and this has been followed by a further 800 genomes as part of a Health innovation Challenge Fund grant. Whilst many of these cases have been solved, some remain unsolved and for some cases, lead candidates have been identified that need to be functionally validated.

The aim of this DPhil project will be to combine bioinformatics analysis and functional biology to solve some of these cases.  A range of commercial software tools and custom bioinformatics pipelines are available in our group to underpin the analysis of WGS data enabling applicants both with, or without, a bioinformatics background to analyse these WGS datasets. Candidates will also have the opportunity to undertake functional analysis of the variants they identify through CRISPR based approaches and relevant biological assays according to the gene being investigated.

Training Opportunities

The primary research area is in WGS analysis and functional biology. 


Genetics & Genomics


Project reference number: 1021

Funding and admissions information


Name Department Institution Country Email
Professor Jenny Taylor Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine GBR
Prof Andrew OM Wilkie FRS FMedSci FRCP Nuffield Division of Clinical Laboratory Sciences Oxford University, Weatherall Institute of Molecular Medicine GBR

There are no publications listed for this DPhil project.