About

Rachel Brem is a Professor of Plant and Microbial Biology with research interests centered on understanding how and why traits vary in organisms from the wild. Her lab focuses on inventing new applied-statistic and wet-lab approaches to identify DNA sequence variants that underlie traits of interest, particularly as they diverge between strains and species. The research is grounded in classical population and molecular genetics, with projects involving empirical data from fungi and mammalian cells. Trainees in her lab have the opportunity to collaborate closely with experimentalists, working on projects that explore genetic variation and trait divergence in natural populations.

Research topics

• Biology
• Biochemistry
• Cell biology
• Genetics
• Bioinformatics
• Evolutionary biology

Selected publications

• The role of mitotype variation and positive epistasis in trait differences between <i>Saccharomyces</i> species

  Genetics · 2025-10-27

  articleOpen accessSenior author

  Many traits of interest in biology evolved long ago and are fixed in a particular species, distinguishing it from other sister taxa. Elucidating the mechanisms underlying such divergences across reproductive barriers has been a key challenge for evolutionary biologists. The yeast Saccharomyces cerevisiae is unique among its relatives for its ability to thrive at high temperature. The genetic determinants of the trait remain incompletely understood, and we sought to understand the role in its architecture of species variation in mitochondrial DNA. We used mitochondrial transgenesis to show that S. cerevisiae mitotypes were sufficient for a partial boost to thermotolerance and respiration in the Saccharomyces paradoxus background. These mitochondrial alleles worked best when the background also harbored a pro-thermotolerance nuclear genotype, attesting to positive epistasis between the two genomes. The benefits of S. cerevisiae alleles in terms of respiration and growth at high temperature came at the cost of worse performance in cooler conditions. Together, our results establish this system as a case in which mitoalleles drive fitness benefits in a manner compatible with, and fostered by, the nuclear genome.

  PublisherOA PDFDOI

• Evolutionary adaptation under climate change: <i>Aedes</i> sp. demonstrates potential to adapt to warming

  Proceedings of the National Academy of Sciences · 2025-01-07 · 22 citations

  articleOpen access

  Climate warming is expected to shift the distributions of mosquitoes and mosquito-borne diseases, promoting expansions at cool range edges and contractions at warm range edges. However, whether mosquito populations could maintain their warm edges through evolutionary adaptation remains unknown. Here, we investigate the potential for thermal adaptation in Aedes sierrensis , a congener of the major disease vector species that experiences large thermal gradients in its native range, by assaying tolerance to prolonged and acute heat exposure, and its genetic basis in a diverse, field-derived population. We found pervasive evidence of heritable genetic variation in mosquito heat tolerance, and phenotypic trade-offs in tolerance to prolonged versus acute heat exposure. Further, we found genomic variation associated with prolonged heat tolerance was clustered in several regions of the genome, suggesting the presence of larger structural variants such as chromosomal inversions. A simple evolutionary model based on our data estimates that the maximum rate of evolutionary adaptation in mosquito heat tolerance will exceed the projected rate of climate warming, implying the potential for mosquitoes to track warming via genetic adaptation.

  PublisherDOI

• Elevated lysosomal mass and enzyme activity in fibroblasts of the Mediterranean mouse <i>Mus spretus</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-07

  preprintOpen accessSenior authorCorresponding

  Abstract Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have found cases in which challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in species of the genus Mus . We found that fibroblasts from M. spretus , a wild Mediterranean mouse, exhibited elevated lysosomal mass and enzyme activity along with reduced activity of β-galactosidase, a classical marker of cellular senescence, compared to those from M. musculus , a related species adapted to human-associated environments. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately serve as a blueprint for interventions that ameliorate lysosomal dysfunction under conditions of stress and disease.

  PublisherDOI

• eLife assessment: Single-cell eQTL mapping in yeast reveals a tradeoff between growth and reproduction

  2025-03-12

  peer-reviewOpen access1st authorCorresponding

  Using single-cell RNA sequencing, we mapped thousands of expression quantitative trait loci in yeast, including a variant in GPA1 that influences gene expression, cell-cycle occupancy, and mating efficiency.

  PublisherDOI

• High-throughput screening reveals mechanisms of environmental control of germination in a fungal thermophile

  mBio · 2025-12-04

  articleOpen accessSenior authorCorresponding

  ABSTRACT Thermothelomyces thermophilus is a filamentous fungus isolated from self-heating compost. Unlike most of the fungal kingdom, this species exhibits a growth optimum at 45°C and is intolerant of temperatures below 30°C. To investigate genetic contributors to temperature-dependent fitness in this system, we implemented a large-scale insertional mutagenesis approach. We generated thousands of T. thermophilus mutants and cultured them at temperature extremes in a standard medium. Phenotyping-by-sequencing identified dozens of disrupted loci representing candidate determinants of thermophilic life history, including several annotated in metal transport. We then validated a subset of screen hits with a directed, single-gene knockout paradigm. The results revealed a temperature-dependent regulatory logic for germination, the developmental decision by which a fungal spore initiates growth. Surprisingly, most mutants germinated far better at 50°C than the wild type in a standard medium and showed markedly slower germination at lower temperatures, consistent with altered germination regulation rather than enhanced intrinsic heat tolerance. We hypothesized that T. thermophilus has evolved sophisticated regulatory machinery to block germination at high temperatures unless environmental conditions are favorable. As a proof of concept, we surveyed media conditions and established that elevated zinc dampened germination of wild-type T. thermophilus at 50°C but promoted it at lower temperatures; mutation experiments made clear that such sensitivity was mediated in part by the zinc transporter zip . We interpret these results under a model in which T. thermophilus integrates temperature and nutrient availability to control the transition from spore dormancy to vegetative growth, a developmental decision that shapes fitness outcomes across temperatures. IMPORTANCE Fungal thermophiles thrive at temperatures that represent the upper limits of eukaryotic life. The regulatory and developmental mechanisms that shape their temperature-dependent fitness remain poorly understood. In this work, we elucidate how Thermothelomyces thermophilus integrates temperature cues with other environmental inputs during germination, a key life-cycle stage for dispersal. Our findings highlight germination regulation as an important contributor to fitness at elevated temperatures in a thermophilic eukaryote. These insights are of basic biological interest and provide a foundation for rational strategies to modulate temperature-dependent performance in industrial strains, with applications for high-temperature bioprocessing.

  PublisherDOI

• “Select and Resequence” Methods Enable a Genome-Wide Association Study of the Dimorphic Human Fungal Pathogen <i>Coccidioides posadasii</i>

  Genome Biology and Evolution · 2025-07-01

  articleOpen access

  Next-generation sequencing has unlocked a wealth of genotype information for wild populations, but interpreting it in the context of phenotypes remains a bottleneck, particularly for nonmodel organisms that are difficult to manipulate. To meet this challenge, we pioneered a method for the mapping of genotype to phenotype in natural populations for the thermally dimorphic pathogenic fungus Coccidioides posadasii, using temperature-responsive growth as a proof of concept. We first sequenced the genomes of 66 natural C. posadasii isolates. We then mixed these strains into pools, competed them in growth assays at 37 °C and room temperature, and sequenced the resulting DNA mixtures. We inferred the abundance of each strain in the pool from the sequence coverage of polymorphisms across their genomes in each competition. Ultimately, we used these abundance measures for genome-wide association tests to find loci predictive of, and potentially causal for, temperature-dependent growth as it varied across strains. Emerging from the top hits were variants in the gene D8B26_001557, which we identified from omics resources as a part of the regulatory network controlled by the thermally responsive dimorphism transcription factor Ryp1. Together, our data underscore the power of pooled strain phenotyping and association mapping as a tool for the genetic dissection of trait variation in nonmodel systems.

  PublisherOA PDFDOI

• Evolutionary adaptation under climate change: <i>Aedes</i> sp. demonstrates potential to adapt to warming

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-24 · 1 citations

  preprintOpen access

  Abstract Climate warming is expected to shift the distributions of mosquitoes and mosquito-borne diseases, facilitating expansions at cool range edges and contractions at warm range edges. However, whether mosquito populations could maintain their warm edges through evolutionary adaptation remains unknown. Here, we investigate the potential for thermal adaptation in Aedes sierrensis , a congener of the major disease vector species that experiences large thermal gradients in its native range, by assaying tolerance to prolonged and acute heat exposure, and its genetic basis in a diverse, field-derived population. We found pervasive evidence of heritable genetic variation in acute heat tolerance, which phenotypically trades off with tolerance to prolonged heat exposure. A simple evolutionary model based on our data shows that the estimated maximum rate of evolutionary adaptation in mosquito heat tolerance typically exceeds that of projected climate warming under idealized conditions. Our findings indicate that natural mosquito populations may have the potential to track projected warming via genetic adaptation. Prior climate-based projections may thus underestimate the range of mosquito and mosquito-borne disease distributions under future climate conditions. Significance Statement Global change may have profound impacts on the distribution of mosquito-borne diseases, which collectively cause nearly one million deaths each year. Accurately predicting these impacts is critical for disease control preparedness, and will depend, in part, on whether mosquitoes can adapt to warming—a key open question. Using experimental and genomic data from a relative of major vector species that already experiences a wide thermal gradient, we find that natural mosquito populations have high levels of genetically-based variation in heat tolerance that could enable adaptation on pace with warming. Incorporating the potential for adaptive responses may therefore be necessary for accurate predictions of mosquito-borne disease distributions under warming, which is critical for preparing mosquito control interventions.

  PublisherOA PDFDOI

• eLife Assessment: Single-cell eQTL mapping in yeast reveals a tradeoff between growth and reproduction

  2024-09-25

  peer-reviewOpen access1st authorCorresponding

  Expression quantitative trait loci (eQTLs) provide a key bridge between noncoding DNA sequence variants and organismal traits. The effects of eQTLs can differ among tissues, cell types, and cellular states, but these differences are obscured by gene expression measurements in bulk populations. We developed a one-pot approach to map eQTLs in Saccharomyces cerevisiae by single-cell RNA sequencing (scRNA-seq) and applied it to over 100,000 single cells from three crosses. We used scRNA-seq data to genotype each cell, measure gene expression, and classify the cells by cell-cycle stage. We mapped thousands of local and distant eQTLs and identified interactions between eQTL effects and cell-cycle stages. We took advantage of single-cell expression information to identify hundreds of genes with allele-specific effects on expression noise. We used cell-cycle stage classification to map 20 loci that influence cell-cycle progression. One of these loci influenced the expression of genes involved in the mating response. We showed that the effects of this locus arise from a common variant (W82R) in the gene GPA1, which encodes a signaling protein that negatively regulates the mating pathway. The 82R allele increases mating efficiency at the cost of slower cell-cycle progression and is associated with a higher rate of outcrossing in nature. Our results provide a more granular picture of the effects of genetic variants on gene expression and downstream traits.

  PublisherDOI

• eLife Assessment: Single-cell eQTL mapping in yeast reveals a tradeoff between growth and reproduction

  2024-04-04

  peer-reviewOpen access1st authorCorresponding

  Expression quantitative trait loci (eQTLs) provide a key bridge between noncoding DNA sequence variants and organismal traits. The effects of eQTLs can differ among tissues, cell types, and cellular states, but these differences are obscured by gene expression measurements in bulk populations. We developed a one-pot approach to map eQTLs in Saccharomyces cerevisiae by single-cell RNA sequencing (scRNA-seq) and applied it to over 100,000 single cells from three crosses. We used scRNA-seq data to genotype each cell, measure gene expression, and classify the cells by cell-cycle stage. We mapped thousands of local and distant eQTLs and identified interactions between eQTL effects and cell-cycle stages. We took advantage of single-cell expression information to identify hundreds of genes with allele-specific effects on expression noise. We used cell-cycle stage classification to map 20 loci that influence cell-cycle progression. One of these loci influenced the expression of genes involved in the mating response. We showed that the effects of this locus arise from a common variant (W82R) in the gene GPA1, which encodes a signaling protein that negatively regulates the mating pathway. The 82R allele increases mating efficiency at the cost of slower cell-cycle progression and is associated with a higher rate of outcrossing in nature. Our results provide a more granular picture of the effects of genetic variants on gene expression and downstream traits.

  PublisherDOI

• Inferring the composition of a mixed culture of natural microbial isolates by deep sequencing

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-05

  preprintOpen accessCorresponding

  Abstract Next generation sequencing has unlocked a wealth of genotype information for microbial populations, but phenotyping remains a bottleneck for exploiting this information, particularly for pathogens that are difficult to manipulate. Here, we establish a method for high-throughput phenotyping of mixed cultures, in which the pattern of naturally occurring single-nucleotide polymorphisms in each isolate is used as intrinsic barcodes which can be read out by sequencing. We demonstrate that our method can correctly deconvolute strain proportions in simulated mixed-strain pools. As an experimental test of our method, we perform whole genome sequencing of 66 natural isolates of the thermally dimorphic pathogenic fungus Coccidioides posadasii and infer the strain compositions for large mixed pools of these strains after competition at 37°C and room temperature. We validate the results of these selection experiments by recapitulating the temperature-specific enrichment results in smaller pools. Additionally, we demonstrate that strain fitness estimated by our method can be used as a quantitative trait for genome-wide association studies. We anticipate that our method will be broadly applicable to natural populations of microbes and allow high-throughput phenotyping to match the rate of genomic data acquisition. Author summary The diversity of the gene pool in natural populations encodes a wealth of information about its molecular biology. This is an especially valuable resource for non-model organisms, from humans to many microbial pathogens, lacking traditional genetic approaches. An effective method for reading out this population genetic information is a genome wide association study (GWAS) which searches for genotypes correlated with a phenotype of interest. With the advent of cheap genotyping, high throughput phenotyping is the primary bottleneck for GWAS, particularly for microbes that are difficult to manipulate. Here, we take advantage of the fact that the naturally occurring genetic variation within each individual strain can be used as an intrinsic barcode, which can be used to read out relative abundance of each strain as a quantitative phenotype from a mixed culture. Coccidioides posadasii , the causative agent of Valley Fever, is a fungal pathogen that must be manipulated under biosafety level 3 conditions, precluding many high-throughput phenotyping approaches. We apply our method to pooled competitions of C. posadasii strains at environmental and host temperatures. We identify robustly growing and temperature-sensitive strains, confirm these inferences in validation pooled growth experiments, and successfully demonstrate their use in GWAS.

  PublisherOA PDFDOI

Recent grants

• The role of natural genetic variants in nutrient-dependent changes in healthspan using D. melanogaster

  NIH · $825k · 2017–2021

• Mapping deep evolutionary divergences in cellular models of stress response

  NIH · $3.9M · 2017–2027

• NIH Grant R56NS098097

  NIH · $425k · 2019

• NIH Grant R21NS077224

  NIH · $415k · 2014

• NIH Grant F32GM064268

  NIH · $32k

Frequent coauthors

• Jennifer L. Garrison

  Buck Institute for Research on Aging

  128 shared

• Wenke Wang

  Taipei Medical University

  79 shared

• Andrew T. Rodriguez

  Buck Institute for Research on Aging

  67 shared

• Anna G. Flury

  City University of New York

  59 shared

• Pankaj Kapahi

  Park University

  51 shared

• Kenneth A. Wilson

  Buck Institute for Research on Aging

  37 shared

• Carly Weiss

  28 shared

• Jeffrey M. Skerker

  University of California, Berkeley

  27 shared

Labs

• Center for Computational BiologyPI

Education

• Ph.D., Graduate Group in Biophysics

  UC San Francisco

  2000

• B.S., Biochemistry

  Brown University

  1994