The sequencing of individual human genomes may soon be routine in certain clinical contexts - for example, to diagnose suspected Mendelian disorders in pediatric patients, or to guide therapeutic decisions in cancer treatment. However, even as its cost plummets to $1,000 or less, the value of a "personal genome" will remain highly constrained by the poor interpretability of individual genetic variants. For example, although BRCA1 and BRCA2 are clinically actionable when loss-of-function mutations are present, and although both genes have been sequenced in >50,000 patients over the past decade, the result returned to patients is often still "variant of uncertain significance". This challenge will profoudly deepen as clinical sequencing accelerates and as the list of clinically actionable genes grows. To address this, we propose to develop a novel approach for experimentally measuring the functional consequences of such "variants of uncertain significance" at an unprecedented scale, as well as innovative computational approaches for estimating the relative pathogenicity of any possible variant in the entire human genome. For clinically relevant genes, we will exploit massively parallel technologies for nucleic acid synthesis and sequencing towards a new paradigm for dissecting function at saturating resolution. The application of this paradigm will yield experimentally grounded predictions for the functional consequences of all possible single residue variants, thereby informing the interpretation of variants newly observed in patients. For the remainder of the human genome, we will develop a framework for integrating a proliferating diversity of coding and non-coding annotations to a single metric. We will then calculate this metric of relative pathogenicity for all possible single nucleotide variants in the human genome. We anticipate that these methods and the resulting "pre-computations" of pathogenicity will broadly enable the interpretatio

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1HG007811-01
Application #
8563280
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Brooks, Lisa
Project Start
2013-09-23
Project End
2018-07-31
Budget Start
2013-09-23
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$772,500
Indirect Cost
$272,500
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kircher, Martin; Witten, Daniela M; Jain, Preti et al. (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310-5
Findlay, Gregory M; Boyle, Evan A; Hause, Ronald J et al. (2014) Saturation editing of genomic regions by multiplex homology-directed repair. Nature 513:120-3