Skip to main content
Grant Details

Grant Number: 5R01CA197139-03 Interpret this number
Primary Investigator: Shendure, Jay
Organization: University Of Washington
Project Title: Integrative Interpretation of the Organismal Consequences of Non-Coding Variation
Fiscal Year: 2017
Back to top


? DESCRIPTION (provided by applicant): Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation, particularly in non-coding regions. To address this challenge, we recently developed a novel framework, Combined Annotation Dependent Depletion (CADD), for estimating the deleteriousness of any genetic variant. CADD defines an objective, data-rich, and quantitative integration of many genomic annotations into a single measure of variant effect at the organismal level. The goals of this R01 proposal are to further develop the CADD framework, to apply it in the context of ongoing genetic studies of both rare and common human diseases, and to experimentally evaluate its predictions. In Specific Aim 1, we will substantially modify CADD in both straightforward and creative ways, with the goal of dramatically improving CADD's ability to annotate non- coding variants, not only to estimate their organismal effects but also to provide insights into molecular mechanisms. In Specific Aim 2, we will apply CADD to a variety of ongoing whole genome sequencing studies of human disease, especially those in which non-coding variants are either known or suspected to be causal. As part of this effort, we will develop new statistical frameworks that directly incorporat CADD into traditional genome-wide discovery approaches. In Specific Aim 3, we will perform a combination of high-throughput (massively parallel reporter assays), medium-throughput (CRISPR/Cas9), and low-throughput (in vivo mouse transgenics) experimental assays for systematic and targeted assessment of CADD predictions. This proposal includes both computational and experimental innovations, and builds on established collaborative relationships between investigators with complementary strengths. The completion of our aims will yield novel methods, data, and resources with which to annotate whole genome sequences, broadly enabling the field to more effectively identify and mechanistically understand non-coding genetic variants that are causally relevant to human disease.

Back to top


Functional characterization of enhancer evolution in the primate lineage.
Authors: Klein J.C. , Keith A. , Agarwal V. , Durham T. , Shendure J. .
Source: Genome Biology, 2018-07-25 00:00:00.0; 19(1), p. 99.
EPub date: 2018-07-25 00:00:00.0.
PMID: 30045748
Related Citations

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.
Authors: Mak A.C.Y. , White M.J. , Eckalbar W.L. , Szpiech Z.A. , Oh S.S. , Pino-Yanes M. , Hu D. , Goddard P. , Huntsman S. , Galanter J. , et al. .
Source: American Journal Of Respiratory And Critical Care Medicine, 2018-06-15 00:00:00.0; 197(12), p. 1552-1564.
PMID: 29509491
Related Citations

Mutations in the fourth ?-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers.
Authors: Sukenik Halevy R. , Chien H.C. , Heinz B. , Bamshad M.J. , Nickerson D.A. , Kircher M. , Ahituv N. .
Source: Human Mutation, 2018-03-10 00:00:00.0; , .
EPub date: 2018-03-10 00:00:00.0.
PMID: 29524275
Related Citations

Variant Interpretation: Functional Assays to the Rescue.
Authors: Starita L.M. , Ahituv N. , Dunham M.J. , Kitzman J.O. , Roth F.P. , Seelig G. , Shendure J. , Fowler D.M. .
Source: American Journal Of Human Genetics, 2017-09-07 00:00:00.0; 101(3), p. 315-325.
PMID: 28886340
Related Citations

Gene Regulatory Elements, Major Drivers of Human Disease.
Authors: Chatterjee S. , Ahituv N. .
Source: Annual Review Of Genomics And Human Genetics, 2017-08-31 00:00:00.0; 18, p. 45-63.
EPub date: 2017-04-07 00:00:00.0.
PMID: 28399667
Related Citations

Use antibiotics in cell culture with caution: genome-wide identification of antibiotic-induced changes in gene expression and regulation.
Authors: Ryu A.H. , Eckalbar W.L. , Kreimer A. , Yosef N. , Ahituv N. .
Source: Scientific Reports, 2017-08-08 00:00:00.0; 7(1), p. 7533.
EPub date: 2017-08-08 00:00:00.0.
PMID: 28790348
Related Citations

CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.
Authors: Gasperini M. , Findlay G.M. , McKenna A. , Milbank J.H. , Lee C. , Zhang M.D. , Cusanovich D.A. , Shendure J. .
Source: American Journal Of Human Genetics, 2017-08-03 00:00:00.0; 101(2), p. 192-205.
EPub date: 2017-07-14 00:00:00.0.
PMID: 28712454
Related Citations

Genomic diagnosis for children with intellectual disability and/or developmental delay.
Authors: Bowling K.M. , Thompson M.L. , Amaral M.D. , Finnila C.R. , Hiatt S.M. , Engel K.L. , Cochran J.N. , Brothers K.B. , East K.M. , Gray D.E. , et al. .
Source: Genome Medicine, 2017-05-30 00:00:00.0; 9(1), p. 43.
EPub date: 2017-05-30 00:00:00.0.
PMID: 28554332
Related Citations

Mutations In Ebf3 Disturb Transcriptional Profiles And Cause Intellectual Disability, Ataxia, And Facial Dysmorphism
Authors: Harms F.L. , Girisha K.M. , Hardigan A.A. , Kortüm F. , Shukla A. , Alawi M. , Dalal A. , Brady L. , Tarnopolsky M. , Bird L.M. , et al. .
Source: American Journal Of Human Genetics, 2017-01-05 00:00:00.0; 100(1), p. 117-127.
PMID: 28017373
Related Citations

A Systematic Comparison Reveals Substantial Differences In Chromosomal Versus Episomal Encoding Of Enhancer Activity
Authors: Inoue F. , Kircher M. , Martin B. , Cooper G.M. , Witten D.M. , McManus M.T. , Ahituv N. , Shendure J. .
Source: Genome Research, 2017 Jan; 27(1), p. 38-52.
PMID: 27831498
Related Citations

Transcriptomic And Epigenomic Characterization Of The Developing Bat Wing
Authors: Eckalbar W.L. , Schlebusch S.A. , Mason M.K. , Gill Z. , Parker A.V. , Booker B.M. , Nishizaki S. , Muswamba-Nday C. , Terhune E. , Nevonen K.A. , et al. .
Source: Nature Genetics, 2016-03-28 00:00:00.0; , .
PMID: 27019111
Related Citations

Bat Accelerated Regions Identify A Bat Forelimb Specific Enhancer In The Hoxd Locus
Authors: Booker B.M. , Friedrich T. , Mason M.K. , VanderMeer J.E. , Zhao J. , Eckalbar W.L. , Logan M. , Illing N. , Pollard K.S. , Ahituv N. .
Source: Plos Genetics, 2016 Mar; 12(3), p. e1005738.
PMID: 27019019
Related Citations

Exonic Enhancers: Proceed With Caution In Exome And Genome Sequencing Studies
Authors: Ahituv N. .
Source: Genome Medicine, 2016; 8(1), p. 14.
PMID: 26856702
Related Citations

Minor Loops in Major Folds: Enhancer-Promoter Looping, Chromatin Restructuring, and Their Association with Transcriptional Regulation and Disease.
Authors: Matharu N. , Ahituv N. .
Source: Plos Genetics, 2015 Dec; 11(12), p. e1005640.
PMID: 26632825
Related Citations

Uncovering drug-responsive regulatory elements.
Authors: Luizon M.R. , Ahituv N. .
Source: Pharmacogenomics, 2015 Nov; 16(16), p. 1829-41.
PMID: 26555224
Related Citations

Parlez-vous Vus?
Authors: Cooper G.M. .
Source: Genome Research, 2015 Oct; 25(10), p. 1423-6.
PMID: 26430151
Related Citations

Decoding Enhancers Using Massively Parallel Reporter Assays
Authors: Inoue F. , Ahituv N. .
Source: Genomics, 2015 Sep; 106(3), p. 159-64.
PMID: 26072433
Related Citations

A Genome-wide Association Study Identifies Four Novel Susceptibility Loci Underlying Inguinal Hernia
Authors: Jorgenson E. , Makki N. , Shen L. , Chen D.C. , Tian C. , Eckalbar W.L. , Hinds D. , Ahituv N. , Avins A. .
Source: Nature Communications, 2015; 6, p. 10130.
PMID: 26686553
Related Citations

Genome-wide distribution of Auts2 binding localizes with active neurodevelopmental genes.
Authors: Oksenberg N. , Haliburton G.D. , Eckalbar W.L. , Oren I. , Nishizaki S. , Murphy K. , Pollard K.S. , Birnbaum R.Y. , Ahituv N. .
Source: Translational Psychiatry, 2014-09-02 00:00:00.0; 4, p. e431.
EPub date: 2014-09-02 00:00:00.0.
PMID: 25180570
Related Citations

Limb development: a paradigm of gene regulation.
Authors: Petit F. , Sears K.E. , Ahituv N. .
Source: Nature Reviews. Genetics, 2017 04; 18(4), p. 245-258.
EPub date: 2017-02-06 00:00:00.0.
PMID: 28163321
Related Citations

Back to Top