PROJECTABSTRACT Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among individuals who carry it. We propose to study a specific type of modified penetrance caused by genetic interactionorepistasisinhumans,wherearegulatoryvariantincismodifiesthepenetranceofcodingvariants ofthetargetgene.Wecallthisphenomenonhaplotypeepistasis.Wewillstudythisphenomenonusinggenetic dataofthegeneralhumanpopulationandofdiseaseswithdifferentgeneticarchitectures.First,wewillstudy signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant epistatic effects. This will shed light on the modes and prevalence of haplotype epistasis, and the role of epistatic selection in shaping the spectrum of genetic variation in humans. Second, haplotype epistasis has beenshowntoaffectgeneticdiseaseriskinsomespecificexamples,butthismechanismisrarelyconsidered in genetic studies that typically analyze genetic variants one-by-one.
We aim to characterize haplotype epistasisasapotentiallyimportantphenomenoninrarevariantscontributingtoautismrisk,commonvariants predisposingtodiversetraitsmappedbygenome-wideassociationstudies,andgermlinemodifiersofsomatic cancerdrivermutations.Furthermore,wewillvalidate5-10examplesofepistasisbygenomeeditingofhuman celllines,followedbycellularphenotyping.Insummary,ourstudyintegratesmanydomainsinhumangenetics that are usually studied in isolation. It is the first systematic characterization of haplotype epistasis and has potentialtobringforwardanimportantparadigmofepistaticfunctionaleffectsofgeneticvariants.

Public Health Relevance

Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among individuals who carry it. We propose to study a specific type of modified penetrance where a genetic variant thataffectsgeneregulationalsoaffectshowsevereanaffectanothervariantinsidethegenewillhave.Wewill studytheimplicationsofthisphenomenoninhumanevolutionanddisease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM122924-01
Application #
9285926
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2017-05-01
Project End
2022-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York Genome Center
Department
Type
DUNS #
078473711
City
New York
State
NY
Country
United States
Zip Code
10013