Biology subjects

Ballinger, M. A.

Publications and source records attributed to Ballinger, M. A..

5 recordsLinked to original sources

bioRxiv2023

Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory code NachJ.

genetics↗

bioRxiv2023

Tissue-specific and cis-regulatory changes underlie parallel, adaptive gene expression evolution in house mice

Changes in gene regulation have long been appreciated as a driving force of adaptive evolution, however the relative contributions of cis- and trans-acting changes to gene regulation over short evolutionary timescales remain unclear. Instances of recent, parallel phenotypic evolution provide an opportunity to assess whether parallel patterns are seen at the level of gene expression, and to assess the relative contribution of cis- and trans-changes to gene regulation in the early stages of divergence. Here, we studied gene expression in liver and brown adipose tissue in two wild-derived strains of house mice that independently adapted to cold, northern environments, and we compared them to a strain of house mice from a warm, southern environment. To investigate gene regulatory evolution, we studied expression in parents and allele-specific expression in F1 hybrids of crosses between warm-adapted and cold-adapted strains. First, we found that the different cold-adapted mice showed both unique and shared changes in expression, but that the proportion of shared changes (i.e. parallelism) was greater than expected by chance. Second, we discovered that expression evolution occurred largely at tissue-specific and cis-regulated genes, and that these genes were over-represented in parallel cases of evolution. Finally, we integrated the expression data with scans for selection in natural populations and found substantial parallelism in the two northern populations for genes under selection. Furthermore, selection outliers were associated with cis-regulated genes more than expected by chance; cis-regulated genes under selection influenced phenotypes such as body size, fat content, immune functioning, and skeletal morphology. These results demonstrate that parallel patterns of gene expression in mice that have independently adapted to cold environments are driven largely by tissue-specific and cis-regulatory changes, providing insight into the mechanisms of adaptive gene regulatory evolution at the earliest stages of divergence. Author summaryThe parallel movement of organisms into novel environments provides an opportunity to understand the molecular basis of adaptation and the repeatability of this process. Mutations affecting the expression of genes are known to underlie much of adaptive evolution. Such mutations can arise in cis-(near the gene of interest) or in trans-(at a distant locus), but the relative contribution of these different kinds of changes to adaptation is poorly understood, especially during very recent divergence. Here, we compared evolved gene expression differences between a warm-adapted house mouse strain and two different cold-adapted strains that have independently evolved similar phenotypic traits, such as increased body size and decreased extremity length during the last few hundred years. Using crosses between warm-adapted and cold-adapted mice, we found that mutations acting in a context specific manner (cis-regulatory and tissue-specific changes) predominate expression divergence and are more likely to be involved in parallel evolution. We used population level selection scans in wild animals to identify regions of the genome under selection and combined these findings with the gene expression data to identify candidate genes underlying adaptation to novel environments. Together, our work describes the gene regulatory dynamics of rapid environmental adaptation, and the repeatability of these patterns over multiple instances of adaptation.

evolutionary biology↗

bioRxiv2023

Tuberculosis susceptibility in genetically diverse mice reveals functional diversity of neutrophils

Tuberculosis (TB) is a heterogenous disease in humans with individuals exhibiting a wide range of susceptibility. This heterogeneity is not captured by standard laboratory mouse lines. We used a new collection of 19 wild-derived inbred mouse lines collected from diverse geographic sites to identify novel phenotypes during Mycobacterium tuberculosis (Mtb) infection. Wild derived mice have heterogenous immune responses to infection that result in differential ability to control disease at early timepoints. Correlation analysis with multiple parameters including sex, weight, and cellular immune responses in the lungs revealed that enhanced control of infection is associated with increased numbers of CD4 T cells, CD8 T cells and B cells. Surprisingly, we did not observe strong correlations between IFN-{gamma} production and control of infection. Although in most lines high neutrophils were associated with susceptibility, we identified a mouse line that harbors high neutrophils numbers yet controls infection. Using single-cell RNA sequencing, we identified a novel neutrophil signature associated with failure to control infection.

immunology↗

bioRxiv2022

Environmentally robust cis-regulatory changes underlie rapid climatic adaptation

Changes in gene expression are proposed to play a major role in adaptive evolution. While it is known that gene expression is highly sensitive to the environment, very few studies have determined the influence of genetic and environmental effects on adaptive gene regulation in natural populations. Here, we utilize allele-specific expression to characterize cis and trans gene regulatory divergence in temperate and tropical house mice in two metabolic tissues under two thermal conditions. First, we show that gene expression divergence is pervasive between populations and across thermal conditions, with roughly 5-10% of genes exhibiting genotype-by-environment interactions. Second, we found that most expression divergence was due to cis-regulatory changes that were stable across temperatures. In contrast, patterns of expression plasticity were largely attributable to trans-effects, which showed greater sensitivity to temperature. Nonetheless, we discovered a small subset of temperature-dependent cis-regulatory changes, thereby identifying loci underlying expression plasticity. Finally, we performed scans for selection in wild house mice to identify genomic signatures of rapid adaptation. Genomic outliers were enriched in genes with evidence for cis-regulatory divergence. Notably, these genes were associated with phenotypes that affected body weight and metabolism, suggesting that cis-regulatory changes are a possible mechanism for adaptive body size evolution between populations. Our results show that gene expression plasticity, largely controlled in trans, may facilitate the colonization of new environments, but that evolved changes in gene expression are largely controlled in cis, illustrating the genetic and non-genetic mechanisms underlying the establishment of populations in new environments. Significance StatementGene expression variation is shaped by both genetic and environmental effects, yet these two factors are rarely considered together in the context of adaptive evolution. We studied environmental influences on gene regulatory evolution in temperate and tropical house mice in cold and warm laboratory environments. We discovered that genetic effects in the form of cis-regulatory divergence were pervasive and largely insensitive to the environment. Many of these genetic effects are under selection and are associated with genes that affect body size, suggesting cis-regulatory changes as a possible mechanism for adaptive body size evolution. We also discovered many trans-effects controlling expression plasticity, demonstrating the importance of both genetic and non-genetic changes associated with adaptation over short timescales (a few hundred generations).

evolutionary biology↗

bioRxiv2021

The contribution of genetic and environmental effects to Bergmanns rule and Allens rule in house mice

Distinguishing between genetic, environmental, and genotype-by-environment effects is central to understanding geographic variation in phenotypic clines. Two of the best-documented phenotypic clines are Bergmanns rule and Allens rule, which describe larger body sizes and shortened extremities in colder climates, respectively. Although numerous studies have found inter- and intraspecific evidence for both ecogeographic patterns, we still have a poor understanding of the extent to which these patterns are driven by genetics, environment, or both. Here, we measured the genetic and environmental contributions to Bergmanns rule and Allens rule across introduced populations of house mice (Mus musculus domesticus) in the Americas. First, we documented clines for body mass, tail length, and ear length in natural populations, and found that these conform to both Bergmanns rule and Allens rule. We then raised descendants of wild-caught mice in the lab and showed that these differences persisted in a common environment and are heritable, indicating that they have a genetic basis. Finally, using a full-sib design, we reared mice under warm and cold conditions. We found very little plasticity associated with body size, suggesting that Bergmanns rule has been shaped by strong directional selection in house mice. However, extremities showed considerable plasticity, as both tails and ears grew shorter in cold environments. These results indicate that adaptive phenotypic plasticity as well as genetic changes underlie major patterns of clinal variation in house mice and likely facilitated their rapid expansion into new environments across the Americas.

evolutionary biology↗