# High-resolution, genome-scale mapping of natural variation between reproductively isolated individuals

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $376,355

## Abstract

SUMMARY
One of the primary goals of genetics is to understand how and why naturally varying individuals differ in
phenotype. Mapping the molecular basis of this trait variation can be straightforward, but only in individuals that
can be interbred. We have found that a little-studied worm species, Caenorhabditis latens, has a median
lifespan 50% longer than related nematodes, and we have observed robust, conserved thermotolerance in
Saccharomyces cerevisiae, the only species of its clade that can act as an opportunistic pathogen. In the
current proposal, we dissect these species divergences using a massively parallel version of the reciprocal
hemizygote test. We create a genomic complement of hemizygote mutants, by generating viable, sterile F1
hybrids between species and subjecting them to transposon mutagenesis. We pool the hemizygotes, measure
their longevity and fitness in sequencing-based assays, and test for differences in frequency between clones of
the pool bearing the two parents' alleles of a given gene. The result is a catalog of loci at which variants
between species influence the trait of interest. In our proof of principle using yeast (Aim 1) and worm (Aim 2),
we will uncover alleles that have arisen in wild species to boost healthspan and stress resistance. These
results will stand in contrast to the alleles weakening fitness that are often mapped in intra-specific studies.
Orthologs of our yeast loci will be of immediate interest as candidates for virulence genes in prevalent fungal
pathogens, and orthologs of our worm lifespan factors will be well-suited to analysis for anti-aging effects in
mammals. This effort will be the first-ever comprehensive survey of the genetic architecture and molecular
genetics of trait variation between reproductively isolated individuals. And the methods we pioneer will enable
genetic dissection in any eukaryotic system in which banks of F1 hybrid individuals or their tissues are
available.

## Key facts

- **NIH application ID:** 9880439
- **Project number:** 5R01GM120430-04
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Rachel Beth Brem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,355
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-05-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880439

## Citation

> US National Institutes of Health, RePORTER application 9880439, High-resolution, genome-scale mapping of natural variation between reproductively isolated individuals (5R01GM120430-04). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/9880439. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*