Understanding the genetic basis of complex traits is critical for advancing medicine, evolutionary biology, and agriculture. A central problem limiting progress in this area is that genetic variants can interact in complicated ways, making their effects difficult to detect in standard genetic mapping studies. In particular, recent research suggests that 'higher-order' genetic interactions involving three or more loci commonly contribute to trait variation. Little is known about these complex genetic effects that appear to b surprisingly important. Determining how higher-order interactions arise at the molecular level and contribute to traits may prove vital to solving the 'missing heritability' problem in humans and other species. Our goal in this proposal is to fully characterize the molecular bases and phenotypic effects of multiple higher-order interactions. We have identified three traits in Saccharomyces cerevisiae crosses that are specified by sets of interacting loci and can each provide unique insights into how higher-order interactions contribute to phenotypic variation. We will comprehensively dissect a discrete morphological trait (Aim 1), an environmentally sensitive growth defect (Aim 2), and a quantitative drug sensitivity phenotype (Aim 3) using the power of the yeast model system. By completing our work, we will provide some of the first direct, mechanistic insights into higher-order interactions. Relevance: Elucidating the connection between genotype and phenotype is critical to achieving new heights in medicine, evolutionary biology, and agriculture. However, for many phenotypes of interest, genome-wide association and linkage studies have only identified a small fraction of the traits' genetic bases. The missing heritability that remains in these studies is arguably the primary barrier to a new era of personalized medicine and genome sequence-informed biology. Higher-order genetic interactions involving three or more loci could represent a significant source of missing heritability, as they may not be detected in standard genetic mapping studies. We are among a small number of research groups that have found compelling evidence that higher-order interactions can result in major, unexpected phenotypic effects. In this proposal, our goal is to understand the functional mechanisms that underlie higher-order interactions. Completion of our work should provide crucial insights into the potential contribution of higher-order interactions t the missing heritability of complex traits in humans and other species.

Public Health Relevance

Genetic interactions contribute to trait variation in many species, but remain incompletely understood. In particular, how higher-order genetic interactions involving three or more loci arise at the molecular level is largely unknown. We will fully characterize the molecular bases of three higher-order interactions that occur in crosses of budding yeast strains, thereby providing some of the first direct, mechanistic insights into genetically complex forms of epistasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM110255-02
Application #
8850465
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Mullis, Martin N; Matsui, Takeshi; Schell, Rachel et al. (2018) The complex underpinnings of genetic background effects. Nat Commun 9:3548
Linder, Robert A; Greco, John P; Seidl, Fabian et al. (2017) The Stress-Inducible Peroxidase TSA2 Underlies a Conditionally Beneficial Chromosomal Duplication in Saccharomyces cerevisiae. G3 (Bethesda) 7:3177-3184
Ehrenreich, Ian M; Magwene, Paul M (2017) Genetic Dissection of Heritable Traits in Yeast Using Bulk Segregant Analysis. Cold Spring Harb Protoc 2017:pdb.prot088989
Ehrenreich, Ian M; Magwene, Paul M (2017) Genetic Analysis of Complex Traits in Saccharomyces cerevisiae. Cold Spring Harb Protoc 2017:pdb.top077602
Matsui, Takeshi; Lee, Jonathan T; Ehrenreich, Ian M (2017) Genetic suppression: Extending our knowledge from lab experiments to natural populations. Bioessays 39:
Ehrenreich, Ian M (2017) Epistasis: Searching for Interacting Genetic Variants Using Crosses. G3 (Bethesda) 7:1619-1622
Ehrenreich, Ian M (2017) Epistasis: Searching for Interacting Genetic Variants Using Crosses. Genetics 206:531-535
Taylor, Matthew B; Phan, Joann; Lee, Jonathan T et al. (2016) Diverse genetic architectures lead to the same cryptic phenotype in a yeast cross. Nat Commun 7:11669
Lee, Jonathan T; Taylor, Matthew B; Shen, Amy et al. (2016) Multi-locus Genotypes Underlying Temperature Sensitivity in a Mutationally Induced Trait. PLoS Genet 12:e1005929
Matsui, Takeshi; Ehrenreich, Ian M (2016) Gene-Environment Interactions in Stress Response Contribute Additively to a Genotype-Environment Interaction. PLoS Genet 12:e1006158

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