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Interspecific Introgressive Origin of Genomic Diversity in the House Mouse

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Interspecific Introgressive Origin of Genomic Diversity in the House Mouse Interspecific introgressive origin of genomic diversity in the house mouse Kevin J. Liua,1,2, Ethan Steinberga, Alexander Yozzoa, Ying Songb,3, Michael H. Kohnb,1, and Luay Nakhleha,b,1 aDepartment of Computer Science and bBioSciences, Rice University, Houston, TX 77005 Edited by John C. Avise, University of California, Irvine, CA, and approved November 12, 2014 (received for review April 4, 2014) We report on a genome-wide scan for introgression between the introgression from M. spretus into some M. m. domesticus pop- house mouse (Mus musculus domesticus) and the Algerian mouse ulations in the wild, involving the vitamin K epoxide reductase (Mus spretus), using samples from the ranges of sympatry and subcomponent 1 (Vkorc1) gene, which was later shown to be allopatry in Africa and Europe. Our analysis reveals wide variabil- more widespread in Europe, albeit geographically restricted to ity in introgression signatures along the genomes, as well as parts of southwestern and central Europe (11). across the samples. We find that fewer than half of the autosomes Major, unanswered questions arise from these studies. First, is in each genome harbor all detectable introgression, whereas the the vicinity around the Vkorc1 gene an isolated case of adaptive X chromosome has none. Further, European mice carry more introgression in the house mouse genome, or do many other such M. spretus alleles than the sympatric African ones. Using the regions exist? Second, is introgression between M. spretus and length distribution and sharing patterns of introgressed genomic M. m. domesticus common outside the range of sympatry? Third, tracts across the samples, we infer, first, that at least three distinct have there been other hybridization events, and, in particular, hybridization events involving M. spretus have occurred, one of more ancient ones? Fourth, what role do introgressed genes, which is ancient, and the other two are recent (one presumably and, more generally, genomic regions, play? due to warfarin rodenticide selection). Second, several of the To investigate these open questions, we used genome-wide inferred introgressed tracts contain genes that are likely to confer variation data from 20 M. m. domesticus samples (wild and wild- adaptive advantage. Third, introgressed tracts might contain derived) from the ranges of sympatry and allopatry, as well as two driver genes that determine the evolutionary fate of those tracts. M. spretus samples. For detecting introgression, we used PhyloNet- Further, functional analysis revealed introgressed genes that are HMM (12), a newly developed method for statistical inference of essential to fitness, including the Vkorc1 gene, which is implicated introgression in genomes while accounting for other evolutionary in rodenticide resistance, and olfactory receptor genes. Our find- processes, most notably incomplete lineage sorting (ILS). ings highlight the extent and role of introgression in nature and Our analysis provides answers to the questions posed above. call for careful analysis and interpretation of house mouse data First, we find signatures of introgression between M. spretus and in evolutionary and genetic studies. each of the M. m. domesticus samples. The amount of intro- gression varies across the autosomes of each genome, with a few Mus musculus | Mus spretus | hybridization | adaptive introgression | chromosomes harboring all detectable introgression, and most of PhyloNet-HMM Significance lassical laboratory mouse strains, as well as newly established Cwild-derived ones, are widely used by geneticists for answering The mouse has been one of the main mammalian model organ- a diverse array of questions (1). Understanding the genome con- isms used for genetic and biomedical research. Understanding the tents and architecture of these strains is important for studies of evolution of house mouse genomes would shed light not only natural variation and complex traits, as well as evolutionary studies on genetic interactions and their interplay with traits in the Mus spretus Mus musculus in general (2). , a sister species of , mouse but would also have significant implications for human M. musculus impacts the findings in investigations for at least genetics and health. Analysis using a recently developed sta- two reasons. First, it was deliberately interbred with laboratory tistical method shows that the house mouse genome is a mo- M. musculus strains to introduce genetic variation (3). Second, saic that contains previously unrecognized contributions from Mus musculus domesticus is partially sympatric (naturally a different mouse species. We traced these contributions to cooccurring) with M. spretus (Fig. 1). ancient and recent interbreeding events. Our findings reveal Recent studies have examined admixture between subspecies the extent of introgression in an important mammalian ge- of house mice (5–8), but have not studied introgression with nome and provide an approach for genome-wide scans of in- M. spretus. In at least one case (5), the introgressive descent of trogression in other eukaryotic genomes. the mouse genome was hidden due to data postprocessing that masked introgressed genomic regions as missing data. In an- Author contributions: K.J.L., M.H.K., and L.N. designed research; K.J.L. performed re- other study reporting whole-genome sequencing of 17 classical search; K.J.L., E.S., A.Y., and Y.S. contributed new reagents/analytic tools; K.J.L., M.H.K., laboratory strains (6), M. spretus was used as an outgroup for and L.N. analyzed data; and K.J.L., M.H.K., and L.N. wrote the paper. phylogenetic analysis. The authors were surprised to find that The authors declare no conflict of interest. 12.1% of loci failed to place M. spretus as an outgroup to the This article is a PNAS Direct Submission. M. musculus clade. The authors concluded that M. spretus was Data deposition: The sequences reported in this paper have been deposited in the GenBank not a reliable outgroup but did not pursue their observation fur- database (accession no. GSE62906). ther. On the other hand, in a 2002 study (9), Orth et al. compiled 1To whom correspondence may be addressed. Email: [email protected], [email protected], or data on allozyme, microsatellite, and mitochondrial variation [email protected]. 2 in house mice from Spain (sympatry) and nearby countries in Present address: Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824. western and central Europe. Interestingly, allele sharing between 3Present address: The State Key Laboratory for Biology of Plant Diseases and Insect Pests the species was observed in the range of sympatry but not outside and Key Laboratory of Weed and Rodent Biology and Management, Institute of Plant in the range of allopatry. The studies demonstrated the possibility Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China. of natural hybridization between these two sister species. Fur- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ther, the study of Song et al. (10) demonstrated a recent adaptive 1073/pnas.1406298111/-/DCSupplemental. 196–201 | PNAS | January 6, 2015 | vol. 112 | no. 1 www.pnas.org/cgi/doi/10.1073/pnas.1406298111 Downloaded by guest on September 26, 2021 on five chromosomes in the sample from La Roca del Vallès, Spain. For all samples, fewer than half the chromosomes of a sample’s genome carried any detected introgression (SI Appendix, Figs. S2–S20). The analysis did not detect any introgression on chromosome X (SI Appendix,Fig.S21). Further, in the two sam- ples from Spain and the six Germany–Hamm samples, one or two chromosomes carried over 50% of all detected introgression. Generally, the percentage of introgressed sites in a genome ranged from about 0.02% in a sample from Tunisia to about 0.8% in samples from Germany (Fig. 2). The large extent of detected in- trogression between M. spretus and M. m. domesticus seen on chromosome 17 in the samples from Spain (see SI Appendix) merits further investigation. The introgressed regions spatially coincide with the known polymorphic recombination-suppressing inversions and t-hapolotypes in house mice (13). The amount of introgression in the genomes of the 20 samples points qualitatively to three groups of samples: Group I, which includes the two samples from Spain and the six Germany– Hamm samples; Group II, which includes the two other Ger- many samples and the Italy and Greece samples; and Group III, Fig. 1. Species ranges and samples used in our study. The species range of which includes the samples from Africa. Variability in the M. spretus is shown in green (4), and the species range of M. m. domesticus amount of introgression across samples within each group is includes the blue regions, the range of M. spretus, and beyond (1). M. m. domesticus and M. spretus samples were obtained from locations marked much smaller than that across groups, as is the amount of sharing with red circles and purple diamonds, respectively. The samples originated of introgressed regions. Further, Group I has the most intro- from within and outside the area of sympatry between the two species. gression, and Group III has the least. Notice that all samples (SI Appendix, Table S1, provides additional details about the samples used in within Group I, except for the one from Spain–Arenal, contain our study.) the introgression with M. spretus that carries Vkorc1 (10). Group II contains all of the allopatric European mice that do not carry Vkorc1,
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