. 2014 Dec 15;112(1):196–201. doi:10.1073/pnas.1406298111

Interspecific introgressive origin of genomic diversity in the house mouse

Kevin J Liu^a,¹,Ethan Steinberg^a,Alexander Yozzo^a,Ying Song^b,Michael H Kohn^b,¹,Luay Nakhleh^a,^b,¹

^aDepartment of Computer Science and

^bBioSciences, Rice University, Houston, TX 77005

To whom correspondence may be addressed. Email:nakhleh@rice.edu,kjl@msu.edu, orhmkohn@rice.edu.

Edited by John C. Avise, University of California, Irvine, CA, and approved November 12, 2014 (received for review April 4, 2014)

Author contributions: K.J.L., M.H.K., and L.N. designed research; K.J.L. performed research; K.J.L., E.S., A.Y., and Y.S. contributed new reagents/analytic tools; K.J.L., M.H.K., and L.N. analyzed data; and K.J.L., M.H.K., and L.N. wrote the paper.

Issue date 2015 Jan 6.

PMC Copyright notice

PMCID: PMC4291675 PMID:25512534

Significance

The mouse has been one of the main mammalian model organisms used for genetic and biomedical research. Understanding the evolution of house mouse genomes would shed light not only on genetic interactions and their interplay with traits in the mouse but would also have significant implications for human genetics and health. Analysis using a recently developed statistical method shows that the house mouse genome is a mosaic that contains previously unrecognized contributions from a different mouse species. We traced these contributions to ancient and recent interbreeding events. Our findings reveal the extent of introgression in an important mammalian genome and provide an approach for genome-wide scans of introgression in other eukaryotic genomes.

Keywords:Mus musculus,Mus spretus, hybridization, adaptive introgression, PhyloNet-HMM

Abstract

We report on a genome-wide scan for introgression between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus), using samples from the ranges of sympatry and allopatry in Africa and Europe. Our analysis reveals wide variability in introgression signatures along the genomes, as well as across the samples. We find that fewer than half of the autosomes in each genome harbor all detectable introgression, whereas the X chromosome has none. Further, European mice carry moreM. spretus alleles than the sympatric African ones. Using the length distribution and sharing patterns of introgressed genomic tracts across the samples, we infer, first, that at least three distinct hybridization events involvingM. spretus have occurred, one of which is ancient, and the other two are recent (one presumably due to warfarin rodenticide selection). Second, several of the inferred introgressed tracts contain genes that are likely to confer adaptive advantage. Third, introgressed tracts might contain driver genes that determine the evolutionary fate of those tracts. Further, functional analysis revealed introgressed genes that are essential to fitness, including theVkorc1 gene, which is implicated in rodenticide resistance, and olfactory receptor genes. Our findings highlight the extent and role of introgression in nature and call for careful analysis and interpretation of house mouse data in evolutionary and genetic studies.

Classical laboratory mouse strains, as well as newly established wild-derived ones, are widely used by geneticists for answering a diverse array of questions (1). Understanding the genome contents and architecture of these strains is important for studies of natural variation and complex traits, as well as evolutionary studies in general (2).Mus spretus, a sister species ofMus musculus, impacts the findings inM. musculus investigations for at least two reasons. First, it was deliberately interbred with laboratoryM. musculus strains to introduce genetic variation (3). Second,Mus musculus domesticus is partially sympatric (naturally cooccurring) withM. spretus (Fig. 1).

Fig. 1. — Species ranges and samples used in our study. The species range ofM. spretus is shown in green (4), and the species range ofM. m. domesticus includes the blue regions, the range ofM. spretus, and beyond (1).M. m. domesticus andM. spretus samples were obtained from locations marked with red circles and purple diamonds, respectively. The samples originated from within and outside the area of sympatry between the two species. (*SI Appendix*, Table S1, provides additional details about the samples used in our study.)

Recent studies have examined admixture between subspecies of house mice (5–8), but have not studied introgression withM. spretus. In at least one case (5), the introgressive descent of the mouse genome was hidden due to data postprocessing that masked introgressed genomic regions as missing data. In another study reporting whole-genome sequencing of 17 classical laboratory strains (6),M. spretus was used as an outgroup for phylogenetic analysis. The authors were surprised to find that 12.1% of loci failed to placeM. spretus as an outgroup to theM. musculus clade. The authors concluded thatM. spretus was not a reliable outgroup but did not pursue their observation further. On the other hand, in a 2002 study (9), Orth et al. compiled data on allozyme, microsatellite, and mitochondrial variation in house mice from Spain (sympatry) and nearby countries in western and central Europe. Interestingly, allele sharing between the species was observed in the range of sympatry but not outside in the range of allopatry. The studies demonstrated the possibility of natural hybridization between these two sister species. Further, the study of Song et al. (10) demonstrated a recent adaptive introgression fromM. spretus into someM. m. domesticus populations in the wild, involving the vitamin K epoxide reductase subcomponent 1 (Vkorc1) gene, which was later shown to be more widespread in Europe, albeit geographically restricted to parts of southwestern and central Europe (11).

Major, unanswered questions arise from these studies. First, is the vicinity around theVkorc1 gene an isolated case of adaptive introgression in the house mouse genome, or do many other such regions exist? Second, is introgression betweenM. spretus andM. m. domesticus common outside the range of sympatry? Third, have there been other hybridization events, and, in particular, more ancient ones? Fourth, what role do introgressed genes, and, more generally, genomic regions, play?

To investigate these open questions, we used genome-wide variation data from 20M. m. domesticus samples (wild and wild-derived) from the ranges of sympatry and allopatry, as well as twoM. spretus samples. For detecting introgression, we used PhyloNet-HMM (12), a newly developed method for statistical inference of introgression in genomes while accounting for other evolutionary processes, most notably incomplete lineage sorting (ILS).

Our analysis provides answers to the questions posed above. First, we find signatures of introgression betweenM. spretus and each of theM. m. domesticus samples. The amount of introgression varies across the autosomes of each genome, with a few chromosomes harboring all detectable introgression, and most of the chromosomes have none. We detected no introgression on the X chromosome. Further, the amount of introgression varied widely across the samples. Our analyses demonstrate introgression outside the range of sympatry. In fact, our results show more signatures of introgression in the genomes of allopatric samples from Europe than in sympatric samples from Africa. For the third question, we used the length distribution and sharing patterns of introgressed regions across the samples to show support for at least three hybridization events: an ancient hybridization event that predates the colonization of Europe byM. m. domesticus and two more recent events, one of which presumably occurred about 50 y ago and is related to warfarin resistance selection (10). For the fourth question, our functional analysis of the introgressed genes shows enrichment for certain categories, most notably olfaction—an essential trait for the fitness of rodents. Understanding the genomic architecture and evolutionary history of the house mouse has broad implications on various aspects of evolutionary, genetic, and biomedical research endeavors that use this model organism. The PhyloNet-HMM method (12) can be used to detect introgression in other eukaryotic species, further broadening the impact of this work.

Results

We now describe our findings of introgression within the individual genomes, as well as across the genomes of the 20M. m. domesticus samples (40 haploid genomes). The four African samples, as well as the two samples from Spain, are sympatric withM. spretus, whereas the other samples are allopatric (Fig. 1).

Genome-Wide Signals of Introgression.

Our analysis detected introgression betweenM. spretus andM. m. domesticus in the genomes of all 20M. m. domesticus samples;Fig. 2 (SI Appendix provides complete scans of introgression of all 20 samples). However, the patterns of introgression varied across the chromosomes within each individual genome, as well as across the genomes. In terms of within-genome variability, a few chromosomes in each genome carried almost all of the introgressed regions. For example, all detected introgressed regions resided 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 samples 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 introgression betweenM. spretus andM. m. domesticus seen on chromosome 17 in the samples from Spain (seeSI 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 Germany samples and the Italy and Greece samples; and Group III, which includes the samples from Africa. Variability in the amount of introgression across samples within each group is much smaller than that across groups, as is the amount of sharing of introgressed regions. Further, Group I has the most introgression, and Group III has the least. Notice that all samples within Group I, except for the one from Spain–Arenal, contain the introgression withM. spretus that carriesVkorc1 (10). Group II contains all of the allopatric European mice that do not carryVkorc1, and Group III contains all of the sympatric African samples. This categorization guides the displays and analyses of our results below. These results answer the first two questions we posed above in the affirmative: there are introgressed genomic regions beyond the region that containsVkorc1, and introgression is present in all 20 samples, pointing to the spread of introgressions beyond the range of sympatry. Quantifying how common such introgressions are outside the range of sympatry, however, requires denser sampling that is beyond the scope of this work.

Support for More Than a Single Hybridization Event.

To answer the third question of whether multiple, distinct hybridization events involvingM. spretus andM. m. domesticus have occurred, we focused on two analyses: inspecting the introgressed tract length distribution, where an introgressed tract is defined as a maximally contiguous introgressed region, and inspecting the sharing pattern of introgressed regions across the samples. Repeated back-crossing, recombination, and drift result in fragmentation of introgressed regions, with very long regions pointing to recent hybridization events. On the other hand, selection on adaptively introgressed regions could also maintain them for long periods, confounding the tract length-based analysis of the age of hybridization. However, if a long region is shared across some, but not all, samples from the population, that increases the likelihood of a recent hybridization hypothesis.

For each of the three groups, we plotted the distribution of introgressed tract lengths, where an introgressed tract is defined as a maximally contiguous introgressed region (Fig. 3). The figure shows that Group I contains the only samples that have introgressed tracts of lengths exceeding 4 Mb. All these tracts correspond to the adaptively introgressed region that containsVkorc1 between positions 122 and 132 Mb on chromosome 7 (Fig. 4A). The exclusivity of these very long introgressed tracts to Group I points to a very recent hybridization event involvingM. spretus, in agreement with the assessment of ref.10. Except for this group of introgressed tracts, the three distributions are very similar, with an excess of very short tracts and a smaller number of longer tracts (up to 4 Mb). The very short tracts could be a signal of ancient hybridization or just incorrect inference by the method (detecting very short introgressed regions is very hard due to low signal-to-noise ratio). However, the pattern of sharing of introgressed regions across the samples supports a hypothesis of ancient hybridization, as we now discuss.

Fig. 3. — Distributions of introgressed tract lengths detected in the 40 haploid genomes. (A) Group I: The six Germany–Hamm samples and two Spain samples. (B) Group II: The four Italy, two Greece, and two other Germany samples. (C) Group III: The Algeria, Morocco, and two Tunisia samples. Note thex axis scale difference between panelA and the other two panels. (See main text for the rationale behind the grouping.)

Fig. 4 shows examples of three different patterns of introgression across the samples (full genome-wide scans of all samples can be found in theSI Appendix).Fig. 4A shows introgressed tracts that are shared exclusively among samples in Group I (we hypothesize that the Spain–Arenal sample underwent a secondary loss of the introgressedVkorc1-containing region that it once had). As we discussed above, these point to at least one very recent hybridization event involvingM. spretus.Fig. 4B shows introgressed tracts that are shared across samples from all three groups. This pattern points to an ancient hybridization event involvingM. spretus and that precedes the ancestor of allM. m. domesticus samples in the study. It is important to note here that this pattern could also be a signature of balancing selection on standing variation before the split ofM. musculus andM. spretus. We discuss this possibility in theDiscussion section below.Fig. 4C shows introgressed regions, of considerable length, in the sample from Morocco. This is, again, a signature of a recent hybridization event that is different from that involving the large tracts on chromosome 7 in Group I.

Putting together all of the evidence, the data supports a hypothesis of at least three distinct hybridization events. One hybridization event is ancient, predating the colonization of Europe byM. m. domesticus upward of 2,000 y ago (15). The other two hybridization events are more recent, and one of them presumably occurred about 50 y ago and is related to warfarin resistance selection (10).

Adaptive Signals of Introgression.

Introgressed genomic tracts and the genes they carry are generally assumed to be neutral or deleterious. Further, such tracts would naturally be expected to be present in the genomes of sympatric hybridizing taxa. Consequently, in the samples we considered here, one would expect to find more introgressed tracts, if any, in the sympatric mice (the African and Spanish samples) than in the allopatric ones. However, our results give a very different picture from these expectations. We hypothesize that some of these introgressed tracts have conferred selective advantage on the mice that carry them. For example, the introgressed region on chromosome 7 in Group I contains theVkorc1 gene whose introgression and adaptive role were discussed in the context of warfarin resistance selection in ref.10. To identify whether other introgressed regions of adaptive roles are associated with thatVkorc1-containing region, we applied the selective sweep measure of ref.14 to a comparison of rodenticide-resistant to rodenticide-susceptible wildM. m. domesticus samples, which favors detection of the recent rodenticide-related selective sweep (within the last ∼50 y). Not surprisingly, the selective sweep statistics in theVkorc1-containing region were among the largest of any detected in our study (Fig. 4A) (seeSI Appendix for full results). We also detected selective sweeps outside theVkorc1 region.

To assess the potential adaptive benefit of other introgressed regions, we used the frequencies of the introgressed regions, as reflected by the sharing patterns. For example, the shared introgressed regions across sympatric and allopatric samples on chromosome 1 and 7, as shown inFig. 4B, point to a hypothesis of adaptive roles of parts of these regions. To further zoom in on these shared regions, we analyzed the sharing patterns of genes across the introgressed regions in all samples.Fig. 5 shows the Venn diagram of the sets of introgressed genes in Groups I, II, and III.

Fig. 5 shows that the two European groups have 399 introgressed genes in common, almost twice the number of introgressed genes that are in common between either of them and the African group. We hypothesize that the set of 157 genes that are shared across all three groups contain a subset that we call “driver genes”—those that have driven the maintenance of those introgressed regions for a long time across the samples. In our proposed classification, driver genes would be beneficial upon introgression and would be subject to selection. Genes that are introgressed in one group, but not the others, are potential neutral, linked “passenger” genes. Although passenger genes would be expected to be neutral, they could also introduce new polymorphisms intoM. m. domesticus genomes and could become subject to selection at some point during its sojourn time.

Individual driver genes on introgressed tracts are not expected to result in functional enrichment scores. For example, the introgressed region that containsVkorc1 on chromosome 7 has many other genes, yet is not enriched for any functional categories. On the other hand, introgressed tracts with an abundance of genes from a given family tend to result in significant enrichment scores of the tracts. We illustrate this with two examples related to olfaction, a multigenic trait known to be essential for the fitness of rodents (full lists of the genes in introgressed regions and their Gene Ontology functional enrichment are given in theSI Appendix). The introgressed tract on chromosome 1 that is shared by mice from Africa and Europe, including allopatric mice, is significantly enriched [P = 5.9E-8 after Benjamini and Hochberg (16) correction] for genes involved in olfactory transduction and encodes olfactory receptor genes (13 out of 36 genes) located on the contiguous tracts (Fig. 4B). It is conceivable that this group of genes, or a subset of these, may have acted as a driver for this introgressed fragment carrying at least another set of 23 passenger genes. Similarly, the region on chromosome 7 shared by the African samples is highly enriched (P = 3.6E-6) for genes involved in olfactory transduction and encodes at least 15 olfactory receptors among at least 62 genes situated on this tract. Evidently, large tracts have become polymorphic for introgressed and native repertoires of olfactory receptor alleles.

Discussion

The biological significance of hybridization and introgression in the evolution of new traits in natural eukaryotic populations has ignited much research into these two processes (17). Introgressed genetic material can be neutral and go unnoticed in terms of phenotypes but can also be adaptive and affect phenotypes (10,18). Notably, these processes have played a crucial role in the domestication of plants and animals and appear to be common in natural populations of plants (17). Additionally, the importance of introgression has become a central discussion point when reconstructing the evolution of primates, including humans (19). Further, it has now become clear that the genomes of model organisms before their adoption as laboratory models by humans have been shaped by hybridization and introgression in their natural ancestral populations, such as in mice and macaques (9,20,21). Such influx of genetic variation of intersubspecific or interspecific origins is expected to continue, as wild-derived strains of mice will contribute to the Collaborative Cross in laboratory mice (22), and primate research centers continue to rely on imports of macaques from Asia.

Large-scale efforts have been made to decode the genetic background of most commonly used laboratory mouse strains, including inbred and wild-derived strains ofM. m. domesticus, and of other subspecies of the laboratory mouse, includingM. m. musculus andM. m. castaneus (2). Among the numerous insights of the evolutionary genomic analyses of the laboratory mouse and its wild relatives were that intersubspecific introgression between strains has been common (2). In addition to understanding the ancestry and mosaic structure of laboratory mouse genomes, detecting introgression is also of biomedical significance. In a recent study (10), the authors discovered in a mouse model resistance to the commonly used anticoagulant warfarin (23) through the acquisition of a mutated version of a key enzyme of the vitamin K cycle,Vkorc1, that is targeted by warfarin. Whereas previous genome-wide studies in mice focused on polymorphism and introgression within theM. musculus group (2,5), we focused here on introgression involving genomic material ofM. spretus and the genomes of severalM. m. domesticus samples from the regions of sympatry and allopatry in Africa and Europe. These analyses are now enabled by our recently developed method for statistical inference of introgression in the presence of other evolutionary events, most notably incomplete lineage sorting (12).

In terms of the debate surrounding the importance of introgression in animal evolution, an important result of our genome-wide study is that it is not only a recent strong and potentially human-driven selection (warfarin rodenticide andVkorc1) that has promoted introgression in natural populations of mice. In fact, hybridization and introgression betweenM. spretus andM. m. domesticus appear to be natural processes spanning at least several thousand years. Nevertheless, even from a rather dense genome-wide survey such as ours it is difficult to discern how frequently introgression occurs. This is because most hybridization does not lead to introgression, as drift and selection tend to remove introgressed regions. However, here we infer at least three hybridization events, one in the distant past and two of more recent timing (including the introgression ofVkorc1). We suspect that this is an underestimate of the frequency of hybridization and introgression betweenM. spretus andM. m. domesticus in the wild because the species have established secondary contact a few thousand years ago when house mice reached the Mediterranean Basin on their westward spread into northern Africa and Europe.

In terms of a role of selection on introgressed tracts, our genome-wide scan revealed informative patterns. First, introgression is limited to a few autosomes and absent from the X chromosome. This is consistent with a strong role of purifying selection and drift in the removal of introgressed material. We find it noteworthy that tracts are very frequently found in the homozygous state, which indicates that introgressed variants can be recessive as well as dominant. The sharing of tracts across samples is consistent with positive selection on introgressed material (adaptive introgression). Such tract sharing is observed over long time scales, such as for chromosome 1, as well as over shorter time scales and locally, as is suggested by tract sharing by subsets of samples from presumably local populations, such as Hamm in Germany or African samples. Finally, it is common to infer that introgressed regions are adaptive if these are found outside the area of sympatry. As we observed numerous introgressed tracts, both presumably old and young, as judged by their tract lengths, it is reasonable to assume that selection might have favored the spread of some of these variants into the allopatric range of house mice. It is important to note here that more sampling from the two species and, potentially, subspecies ofM. musculus, would be necessary to determine, with more certainty, the directionality of the introgression between the two species’ genomes.

Selection could have confounding effects on our analyses and inferences. Specifically, it is important to note that various evolutionary events could give rise to genomic patterns and signals that resemble those created by introgression, including ILS, convergence, and ancestral polymorphism coupled with balancing selection (24). Indeed, all of these processes could confound the detection of introgression (25). The introgression detection method (12) that we use here accounts for ILS (hence, ancestral polymorphism that is not under balancing selection) and employs finite-site models in a statistical inference framework, which helps account for convergence at the nucleotide level. Currently, methods that automatically distinguish introgression from balancing selection do not, however, exist. For example, recent studies of adaptive introgression (26,27) focused solely on introgression. Two studies have recently reported on signatures of balancing selection in house mouse genomes (28,29). However, each of the studies reported on a single, very short region that was shared across all of the samples, including from the various subspecies considered. Our current analysis of multipleM. m. domesticus from the ranges of sympatry and allopatry in Africa and Europe mostly point to a very polymorphic signal of introgression across these samples, which, consequently, decreases the likelihood that ancestral polymorphism with balancing selection acting on it could explain the patterns we see in the data. We also scanned genomes of samples fromM. m. musculus, which is a sister subspecies ofM. m. domesticus (SI Appendix, Fig. S23). As the figure shows, no introgression was detected in theM. m. musculus sample (a similar result to that shown in ref.12), which further weakens the plausibility of balancing selection acting from the most recent common ancestor ofM. musculus andM. spretus until the present day. Furthermore, many of the introgressed regions we detect are much longer than regions with balancing selection signatures reported in previous studies. For example, in humans, DeGiorgio et al. (30) reported that the maximum contiguous genomic region with balancing selection signal was of length ∼40 kb (near theFANK1 gene) and which “surprised” them because it was “abnormally large for balancing selection” (ref.29, p. 11). Introgressed tract lengths on the order of megabases would require much stronger balancing selection than have been previously reported in the literature. Still, for some of the shared introgressed regions, we cannot rule out the possibility of balancing selection, as an alternative to introgression. Whereas our method for detecting introgression can be confounded by balancing selection, a similar issue might arise for methods that detect balancing selection. For example, DeGiorgio et al. noted recently that gene flow is very likely to confound their test for balancing selection (30). New methods need to be developed to account for the two processes simultaneously, as detecting balancing selection could shed light on the evolution of species (31).

Adaptive introgressive hybridization may be an important source for novel functional genetic variants, and combinations thereof, that encode novel traits upon which selection could act. Here, one objective of the study is to discern whether multiple introgressed genes encode the previously reported warfarin resistance trait. Our functional annotation of the introgressed tract did not reveal any discernible enrichment for genes that clearly modulate warfarin resistance. Moreover, we did not observe a pattern where all mice that carry theVkorc1 introgression share introgressed tracks of comparable length. We therefore conclude that, until further samples are analyzed and tracts are annotated in terms of function more comprehensively, the adaptive introgressive hybridization leading to warfarin resistance in house mice requires the introgression of onlyVkorc1. Whether the introgressedVkorc1 interacts with the native genes in pathways resulting in warfarin resistance cannot be deduced from our analysis at this time.

We observed that the raw material for a complex trait known to be important to rodent life history could be introgressed. We noticed the large numbers of olfactory receptor genes for which now polymorphic and divergent copies segregate in the populations of house mice (32). It is known that both minor nucleotide differences, as well as larger scale differences in the olfactory receptor repertoire, have measurable phenotypic consequences in mice (32). Thus, we hypothesize that wild mice from Europe that have experienced gene flow, such as seen for chromosome 1 which is enriched for olfactory receptor clusters, may indeed be the subject of natural selection.

Materials and Methods

Our study used twoM. spretus samples and twentyM. m. domesticus samples from the ranges of sympatry and allopatry that were either newly sampled or from previous publications. The work relied on tissue sharing and was exempted by Rice University's institutional review board. For details on the samples, compiling the sequence data, genotyping and phasing it, as well as single nucleotide polymorphism (SNP) calling, see theSI Appendix. We used PhyloNet-HMM (12) to scanM. musculus genomes for segments with introgressed origin fromM. spretus. For every haploidM. m. domesticus genome, we analyzed it along with theM. spretus genomes and detected introgression. See theSI Appendix for full details on how the analysis was done. We used XP-CLR (14) version 1.0 to scan for selective sweep patterns. The method was run using its default settings. See theSI Appendix for the set of samples used in these scans.

Supplementary Material

Supplementary File

pnas.1406298111.sapp.pdf^{(23.4MB, pdf)}

Acknowledgments

We thank Yun Yu for help with the PhyloNet-HMM software and Stefan Endepols for sharing mouse tissues. The work was partially supported by R01-HL091007-01A1 (to M.H.K.) from the National Institutes of Health, National Heart, Lung and Blood Institute, and by startup funds from Rice University (to M.H.K.). L.N. was supported in part by National Science Foundation Grants DBI-1062463 and CCF-1302179 and Grant R01LM009494 from the National Library of Medicine (NLM). K.J.L. was partially supported by a training fellowship from the Keck Center of the Gulf Coast Consortia, on the NLM Training Program in Biomedical Informatics, NLM T15LM007093.

Footnotes

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession no.GSE62906).

²Present address: Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824.

³Present address: The State Key Laboratory for Biology of Plant Diseases and Insect Pests and Key Laboratory of Weed and Rodent Biology and Management, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.1073/pnas.1406298111/-/DCSupplemental.

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Interspecific introgressive origin of genomic diversity in the house mouse

Kevin J Liu

Ethan Steinberg

Alexander Yozzo

Ying Song

Michael H Kohn

Luay Nakhleh

Significance

Abstract

Fig. 1.