Most populations harbor enormous numbers of low-frequency recessive alleles, rarely exposed as homozygotes, creating great statistical challenges for efforts to understand their effects. The problem calls for an experimentally tractable model of segregating recessive variation. The model should include rare alleles shifted to more tractable frequencies, completely sequenced genomes, and highly replicable diploid genotypes that vary in the location and extent of their homozygosity. This proposal answers that call by dissecting the genetic basis of deleterious recessive variation in a sample of genomes extracted from a natural population of Caenorhabditis sp. 29, obligate outcrossing nematodes closely related to the hermaphroditic laboratory model C. elegans. These nematodes share with C. elegans exceptional virtues for genetic study, including a compact genome, a short generation time, high fecundity, and the capacity for cryopreservation. Unlike C. elegans, this species harbors a substantial load of segregating recessive variation.
The aims of this proposal involve the creation of a permanent resource for mapping the deleterious recessive alleles, the phenotyping of reproductive fitness across a range of homozygosities, and the construction of predictive models that connect the phenotypic effects of homozygosity to specific molecular features of the segregating alleles. A more precise molecular characterization of low-frequency recessive alleles will be of great value in inferring genetic risk from sequence-defined variants. It will be particularly valuable in individual phenotypic prediction, a key goal for genetic medicine.
Recessive mutations of modest effect cumulatively represent a major source of genetic burden on health, but their characteristics make them extremely difficult to study in human populations. Creation of an experimentally tractable animal model for analysis of this class of mutations will facilitate the discovery of rules that will guide interpretation of genomic data.
|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|