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 interpretation of human genome sequences in diverse clinical and research settings.

Public Health Relevance

As we enter an era of personalized medicine, the sequencing of individual human genomes will be increasingly important to public health, contributing towards the unraveling of the genetic basis of human disease and serving a growing role in patient care. However, the interpretation of genetic variants of uncertain significance represents a fundamental obstacle for the field. This project will develop several innovative approaches for estimating the consequences of all possible genetic variants of clinically relevant genes. The resulting pre-computations of pathogenicity will broadly enable the interpretation of human genome sequences in diverse clinical and research settings.

National Institute of Health (NIH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZRG1)
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Brooks, Lisa
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University of Washington
Schools of Medicine
United States
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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