# Genetic basis of stress tolerance in natural populations of yeast

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $240,368

## Abstract

Complex traits are inherited via the combined effects of quantitative trait loci segregating in a population.
These genetic determinants may have large or small effects, and may combine in a myriad of ways. Despite
over a decade of work on mapping the genetic determinants of complex traits via genome-wide association
studies and other methods, the field has as yet not determined an optimal approach to inferring phenotype
from genotype. We propose to use yeast genetics to learn the underlying genetic architecture of a series of
quantitative traits controlling stress tolerance. The yeast system has superior experimental tools, conserved
biology across eukaryotes, and a growing collection of diverse genome sequences on which to draw. We will
first focus on loci of strong effect, i.e. “Mendelian” traits. These lend themselves to easy genetic mapping and
experimental confirmation via allele swap experiments. Our hypothesis is that genes with strong effect alleles
will also harbor alleles of more quantitative effect across a population. This idea is akin to the “rare variant” 
hypothesis in which low frequency strong effect alleles contribute to high disease risk. We seek to discover
whether these same genes may also be of importance across the population due to lower effect size alleles that
may be more difficult to identify. We will pursue this project in three specific aims as part of an integrated
team with expertise in yeast genetics, genomics, and genome evolution. In Aim 1, we will establish a diallel
pairwise offspring panel to investigate the genetic underpinnings of traits. For this purpose, we will perform
pairwise crosses, generate full meiotic offspring for each cross, and phenotype the parental isolates, hybrids,
and the offspring using high throughput methods. Then, we will estimate the genetic complexity of traits by
analyzing their inheritance patterns. This approach will also clearly identify traits showing simple, Mendelian
inheritance. The second aim is to determine the genetic basis of those phenotypes that segregate as a small
number of large effect loci. To map the causative loci, we will use a bulk segregant mapping method coupled
with deep sequencing, followed by reciprocal hemizygosity and/or allele swap experiments to prove
causation. The third aim is to test whether these same loci are important for phenotypic variation across a large
panel of strains. We will amplify alleles from >1000 genetically diverse isolates, transplant them into multiple
genetic backgrounds, and assay gene function via a pool-based, quantitative, competition assay. Allele
frequency will be measured using deep sequencing. Once we have identified alleles with differential
functional consequences, we will use a novel application of DNA shuffling to map the causative
polymorphisms to single base resolution. This combination of methods will allow us to identify crosses in
which stress tolerance traits segregate in a genetically simple manner, map the caus...

## Key facts

- **NIH application ID:** 9858351
- **Project number:** 5R01GM101091-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Maitreya J Dunham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,368
- **Award type:** 5
- **Project period:** 2012-05-07 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858351

## Citation

> US National Institutes of Health, RePORTER application 9858351, Genetic basis of stress tolerance in natural populations of yeast (5R01GM101091-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9858351. Licensed CC0.

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