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Across two continents: The genomic basis of environmental adaptation in house mice (Mus musculus domesticus) from the Americas [1]

['Yocelyn T. Gutiérrez-Guerrero', 'Department Of Integrative Biology', 'Museum Of Vertebrate Zoology', 'University Of California', 'Berkeley', 'California', 'United States Of America', 'Megan Phifer-Rixey', 'Department Of Biology', 'Drexel University']

Date: 2024-08

Replicated clines across environmental gradients can be strong evidence of adaptation. House mice (Mus musculus domesticus) were introduced to the Americas by European colonizers and are now widely distributed from Tierra del Fuego to Alaska. Multiple aspects of climate, such as temperature, vary predictably across latitude in the Americas. Past studies of North American populations across latitudinal gradients provided evidence of environmental adaptation in traits related to body size, metabolism, and behavior and identified candidate genes using selection scans. Here, we investigate genomic signals of environmental adaptation on a second continent, South America, and ask whether there is evidence of parallel adaptation across multiple latitudinal transects in the Americas. We first identified loci across the genome showing signatures of selection related to climatic variation in mice sampled across a latitudinal transect in South America, accounting for neutral population structure. Consistent with previous results, most candidate SNPs were in putatively regulatory regions. Genes that contained the most extreme outliers relate to traits such as body weight or size, metabolism, immunity, fat, eye function, and the cardiovascular system. We then compared these results with the results of analyses of published data from two transects in North America. While most candidate genes were unique to individual transects, we found significant overlap among candidate genes identified independently in the three transects. These genes are diverse, with functions relating to metabolism, immunity, cardiac function, and circadian rhythm, among others. We also found parallel shifts in allele frequency in candidate genes across latitudinal gradients. Finally, combining data from all three transects, we identified several genes associated with variation in body weight. Overall, our results provide strong evidence of shared responses to selection and identify genes that likely underlie recent environmental adaptation in house mice across North and South America.

Since their arrival with European colonizers, house mice have successfully spread throughout the Americas. There is strong evidence that populations in North America have adapted in that time, including parallel evolution of phenotypes across latitude (e.g., body size, behavior) as well as significant overlap of genes that show signals of selection. Here, we investigate the genetics of environmental adaptation in South America. We found that populations in South America are genetically distinct from populations in North America. We identified candidate genes for environmental adaptation with links to traits like body size, metabolism, immunity, eye function, thermoregulation and the cardiovascular system. We then bring together data from three transects across two continents to determine if environmental adaptation is predictable, with shared genetic responses. We found that most responses to selection do not involve changes in amino acid sequence and therefore are likely due to changes in gene regulation. We also found that while most candidate genes are unique to individual transects, there was more overlap than expected by chance. In addition, we observed parallel shifts in allele frequency among shared candidate genes, i.e., shifts in the same direction across different latitudinal gradients. These results suggest that there is a shared response to selection and identify a core set of candidate genes that likely contribute to environmental adaptation. Finally, we combine the data from all three transects to identify genes associated with variation in body weight. These findings highlight the value of studying wild populations of this important genetic model system.

Funding: This research was supported by NIH grants to M.W.N. (R01 GM074245, R01 GM127468, and R35 GM149304) and a UC-MEXUS postdoctoral fellowship to Y. T. G. G. This work was also supported by an Extreme Science and Engineering Discovery Environment (XSEDE) allocation to M.W.N. and M.P.R. (MCB130109). XSEDE was supported by National Science Foundation grant number ACI-1548562. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: Exome reads sequencing are available at the Sequence Read Archive (SRA) from NCBI, BioProject accession PRJNA776897. Supplementary Table S1 includes the complete metadata of the samples: locality information, sex, reproductive state, individual body size measures, read sequencing information, and the Museum of Vertebrate Zoology vouchered specimen number and accession. The code and scripts used for the analysis are available from Github ( https://github.com/YocelynG/HouseMouse_EnvAdapt ).

Copyright: © 2024 Gutiérrez-Guerrero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Here, we explore genomic signatures of environmental adaptation in house mice from South America across a latitudinal transect from equatorial Brazil (~3° S) to southern Argentina (~ 55° S) using exome capture data of wild-caught individuals. We combined the data generated in this study with published data from eastern and western North America. We address five main questions. First, do house mice in South America derive from the same subspecies (M. m. domesticus) as house mice in North America? House mice are comprised of three major subspecies which diverged ~150,000–500,000 years ago and have distinct ranges: M. m. musculus is found in Eastern Europe and northern Asia, M. m. domesticus is found in Western Europe and the Mediterranean region, and M. m. castaneus is found throughout South and Southeastern Asia [ 45 – 48 ]. M. m. domesticus is the presumed source population for the Americas [ 30 , 49 – 51 ], although the subspecific origin of house mice across most of South America has never been explored. Second, are house mice in South America genetically distinct from populations in North America? If so, this would provide an opportunity to study the repeatability of evolution, including shared signals of selection and parallel evolution. Third, which genes show signatures of selection in house mice from South America? Fourth, to what extent are signatures of selection shared in comparisons among mice from three different latitudinal transects: South America (SA), eastern North America (ENA), and western North America (WNA)? Previous work showed that mice in eastern and western North America form two clades [ 38 ], providing an opportunity here to compare three phylogenetically independent transects. Finally, what genes underlie variation in body size and are they associated with signals of selection? We found that mice in South America are of M. m. domesticus origin and that they are more closely related to each other than to any populations in North America. We found signatures of selection across the genome among mice from South America across climatic gradients and we found significant overlap among candidate genes for all three transects, providing evidence of shared responses to selection. We also found that shifts in allele frequency at SNPs within overlapping candidate genes were typically in the same direction, suggesting that shared signals result from parallel evolution. Finally, a genome-wide association study (GWAS) identified eight genes associated with differences in body weight, all but one of which also showed signatures of selection.

Less is known about genetic variation in South American populations. Previous studies of altitudinal adaptation [ 41 , 42 ] and cytogenetics [ 43 ] provided evidence that house mice in South America derive from the same subspecies (M. m. domesticus) as mice in North America. However, sampling was limited, and it is not known whether there may be introgression from other subspecies. Patterns of genetic diversity and differentiation across the continent are also largely unknown as are the relationships to populations in North America. Importantly, some aspects of the environment, such as temperature, vary similarly across latitude in North and South America [ 44 ] providing an opportunity for an investigation of parallel rapid environmental adaptation across two continents.

House mice (Mus musculus domesticus) provide an opportunity to study the genomic basis of environmental adaptation using natural replicates. Native to Western Europe, house mice have spread opportunistically around the world in association with humans during the last five hundred years [ 30 – 34 ]. In this short time, they have successfully colonized both North and South America, from Tierra del Fuego (55°S) to Alaska (61°N), spanning an enormous range of habitats and climates. Previous studies have found that house mice exhibit clinal variation in body size, with size increasing with distance from the equator in South America and North America, consistent with Bergmann’s Rule [ 35 – 39 ]. House mice also show clines in ear length and tail length across North and South America, with length decreasing with increasing distance from the equator, consistent with Allen’s Rule [ 39 ]. These observations conform to well-known ecogeographic patterns in mammals and are thought to reflect thermoregulatory adaptations for animals living in cold or warm environments. These differences persist in a common laboratory environment for multiple generations, indicating that they have a genetic basis [ 36 , 38 , 39 ]. Genomic surveys have identified candidate genes using covariation between environmental variables and genetic variation in two clines across latitude in North America [ 36 , 38 , 40 ] in tandem with phenotype and gene expression data [ 36 , 40 ]. Furthermore, comparison of the two latitudinal transects in North America identified significant overlap in signals of selection, including several genes related to heat sensing (e.g., Trpm2) and body weight (e.g., Mc3r and Mtx3), suggesting some shared response to selection [ 38 ].

Characterizing phenotypic variation in wild populations can be difficult, and biologically important phenotypes contributing to adaptation may go undetected. Even when there are known clines in phenotypes, many of the traits of interest may be polygenic and influenced by the environment. Detecting signatures of selection on complex traits and connecting those changes to phenotypes remains challenging [ 25 – 29 ]. However, signals of selection that are shared among clines can help identify genes and traits that contribute to adaptation. Moreover, because genome scans are agnostic with respect to phenotype, this kind of comparative approach can also point to previously unnoticed traits that may be important to adaptation.

Understanding the genetic details of how species adapt to new environments is a key goal of evolutionary biology. One approach to investigating the genetic basis of environmental adaptation is to look for covariation between allele frequencies and environmental variables [ 1 , 2 ]. Such clines can result from neutral processes, but statistical methods can be used to account for neutral population structure [e.g., 3 , 4 ], and this approach has been applied successfully to a wide range of organisms [ 5 – 9 ]. An extension of this approach is to compare patterns of genetic variation across multiple independent environmental gradients [e.g., 9 – 14 ]. For example, comparisons of Drosophila melanogaster populations in the northern and southern hemispheres have identified shared responses to selection [ 13 , 15 , 16 ]. When neutral population structure is accounted for, shared responses to selection and parallel clines, in particular, can provide strong evidence that particular genes and traits contribute to adaptation even when the specific mechanism is unknown. “Parallel evolution” is used to refer to a range of related patterns including similar shifts in phenotypes or alleles as well reuse of the same genes and/or pathways over independent gradients [e.g., 17 – 21 ]. For clarity, we refer to overlapping candidate genes as “shared” responses to selection, and we refer to shifts in allele frequencies or phenotypes in the same direction over an environmental gradient as “parallel” changes [e.g., 22 – 24 ].

Results

Mus musculus domesticus ancestry in the Americas We sequenced the complete exomes of 86 wild house mice sampled from 10 populations along a latitudinal transect from central Mexico to the southern tip of South America (Fig 1A and S1 Table). To analyze patterns of admixture, we combined these data with previously published data from populations in eastern (n = 50) and western (n = 50) North America [36,38] and published data from each of the three major Mus musculus subspecies [52] (S2 Table). Specifying K = 3 genetic clusters, we found that house mice in the sampled populations of the Americas are of M. m. domesticus origin, apart from one population in Tucson which is mostly of M. m. domesticus origin but also shows some limited admixture with M. m. castaneus (Fig 1B), as previously reported [38]. These results provide strong evidence that house mice in Mexico and South America are M. m. domesticus with no evidence of significant introgression from the other subspecies. PPT PowerPoint slide

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TIFF original image Download: Fig 1. a) Map of mean annual temperature across the Americas (Map generated in R, using the WorldClim database information for Bio1- Mean Annual Temperature). Populations of wild house mice sampled across a latitudinal transect in Mexico and South America are shown with large circles. Populations included in previously published surveys in North America [36,38] are shown with small circles. b) Admixture plot including representatives from all three primary subspecies of house mouse as well as mice from sampled populations in the Americas. c) Phylogenetic reconstruction of Mus musculus domesticus populations across the Americas, with M. spretus as the outgroup. https://doi.org/10.1371/journal.pgen.1011036.g001

Phylogenetic relationships among transects in the Americas We constructed a maximum likelihood phylogenetic tree using RAxML [53] with M. spretus as an outgroup (Fig 1C and S2 Table). For this analysis, we pruned the dataset to only include autosomal sites for which 80% of the individuals were covered, resulting in 895,333 sites. This analysis identified three major clades: populations from western North America, populations from eastern North America, and populations from Mexico and South America, each with 100% bootstrap support (Fig 1C). Within South America, mice formed two reciprocally monophyletic groups, each with 100% bootstrap support, largely corresponding to a northern clade (Manaus, Porto Velho, Brasilia, and Maringa) and a southern clade (Uruguaina, Tandil, Gaiman, and Ushuaia). In North America, mice formed two reciprocally monophyletic groups, each with 100% bootstrap support, corresponding to the eastern and western transects as previously reported [38]. Thus, these analyses indicate that mice within each transect are more closely related to each other than they are to mice in the other transects. This conclusion does not address whether selection has acted on new mutations, shared ancestral variation, or alleles introduced by rare long-distance migrants. House mice in the Americas derive from house mice in Western Europe within the last 500 years. Given the recency of this history, it is likely that selection acted mainly on ancestral shared variation or perhaps on alleles introduced through rare long-distance migration. However, the phylogenetic grouping of populations suggests that the response to selection occurred separately in each transect. For example, Fig 1C is inconsistent with the hypothesis that large-bodied mice far from the equator in the northern and southern hemispheres share a more recent common ancestor with each other than with the small-bodied mice closer to the equator within their transects.

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[1] Url: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011036

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