Heritable variation underlies variation in human health, and the molecular basis for that variation is largely uncharacterized. Recent results suggest that heritable variation in human disease risk may be shaped by a complex mixture of rare alleles, common alleles of small effect, and alleles of all frequencies whose effects depend on allelic states at other loci. Such complexity is expected for quantitative traits under stabilizing selection, such as human physiology, and the complex architecture of such traits is a major obstacle to their genetic dissection. Knowledge of the genetic variants underlying complex traits is central to methods for ameliorating or predicting disease risk and for developing therapies for treatment. Transcript abundance traits in the nematode C. elegans are a promising model for variation in complex traits under stabilizing selection. These traits are amenable to full genetic dissection using panel of near-isogenic inbred lines of that vary within a small interval of the X chromosome implicated in heritable variation in hundreds of transcript abundance traits. Creation and study of such a permanent mapping resource will permit identification of the causal variants underlying variation in transcript abundances at the resolution of individual sequence variants, generating a catalog of quantitative trait nucleotides. Such a catalog will reveal the types of mutations that contribute to variation in complex traits, their modes of action, their additive and interactive effect sizes, their frequencies in natural populations, and the distribution of their effects across tissues and developmental stages and environments. Quantitative trait nucleotides mapped to single-variant resolution have never been collected for any multicellular organism, and their features will inform efforts to discover the genetic basis of complex disease traits in humans.

Public Health Relevance

Genetic variation explains much of the variation in human disease, but the actual genetic variants that affect traits are exceptionally hard to pinpoint. We will identify the actual genetic variants that affect traits in a model species with the goal of learning rules about what kind of variants influence disease traits and why.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089972-05
Application #
8507755
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$288,677
Indirect Cost
$99,518
Name
New York University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Noble, Luke M; Chelo, Ivo; Guzella, Thiago et al. (2017) Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel. Genetics 207:1663-1685
Bernstein, Max R; Rockman, Matthew V (2016) Fine-Scale Crossover Rate Variation on the Caenorhabditis elegans X Chromosome. G3 (Bethesda) 6:1767-76
Noble, Luke M; Chang, Audrey S; McNelis, Daniel et al. (2015) Natural Variation in plep-1 Causes Male-Male Copulatory Behavior in C. elegans. Curr Biol 25:2730-7
Paaby, Annalise B; White, Amelia G; Riccardi, David D et al. (2015) Wild worm embryogenesis harbors ubiquitous polygenic modifier variation. Elife 4:
Kaur, Taniya; Rockman, Matthew V (2014) Crossover heterogeneity in the absence of hotspots in Caenorhabditis elegans. Genetics 196:137-48
Paaby, Annalise B; Rockman, Matthew V (2014) Cryptic genetic variation: evolution's hidden substrate. Nat Rev Genet 15:247-58
Glater, Elizabeth E; Rockman, Matthew V; Bargmann, Cornelia I (2014) Multigenic natural variation underlies Caenorhabditis elegans olfactory preference for the bacterial pathogen Serratia marcescens. G3 (Bethesda) 4:265-76
Pollard, Daniel A; Rockman, Matthew V (2013) Resistance to germline RNA interference in a Caenorhabditis elegans wild isolate exhibits complexity and nonadditivity. G3 (Bethesda) 3:941-7
Paaby, Annalise B; Rockman, Matthew V (2013) Pleiotropy: what do you mean? Reply to Zhang and Wagner. Trends Genet 29:384
Paaby, Annalise B; Rockman, Matthew V (2013) The many faces of pleiotropy. Trends Genet 29:66-73

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