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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Eckstrand, Irene A
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New York University
Schools of Arts and Sciences
New York
United States
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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) The many faces of pleiotropy. Trends Genet 29:66-73
Paaby, Annalise B; Rockman, Matthew V (2013) Pleiotropy: what do you mean? Reply to Zhang and Wagner. Trends Genet 29:384
Rockman, Matthew V (2012) The QTN program and the alleles that matter for evolution: all that's gold does not glitter. Evolution 66:1-17
Bendesky, Andres; Tsunozaki, Makoto; Rockman, Matthew V et al. (2011) Catecholamine receptor polymorphisms affect decision-making in C. elegans. Nature 472:313-8
Seidel, Hannah S; Ailion, Michael; Li, Jialing et al. (2011) A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans. PLoS Biol 9:e1001115
Kiontke, Karin C; Felix, Marie-Anne; Ailion, Michael et al. (2011) A phylogeny and molecular barcodes for Caenorhabditis, with numerous new species from rotting fruits. BMC Evol Biol 11:339

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