Summary It is known that evolution by selection on new or standing single nucleotide polymorphisms (SNPs) in the vitamin K 2,3-epoxide reductase subcomponent 1 (vkorc1) of house mice (Mus musculus domesticus) can cause resistance to anticoagulant rodenticides such as warfarin [1–3]. Here we report an introgression in European M. m. domesticus spanning as much as ~20.3 megabases (Mb) and including vkorc1, the molecular target of anticoagulants [1–4], that stems from hybridization with the Algerian mouse (M. spretus). We show that in the laboratory the homozygous complete vkorc1 allele of M. spretus confers resistance when introgressed into M. m. domesticus. Consistent with selection on the introgression after the introduction of rodenticides in the 1950s we document historically adaptive population genetics of vkorc1 in M. m. domesticus. Furthermore, we detected adaptive protein evolution of vkorc1 in the M. spretus lineage (Ka/Ks=1.54–1.93) resulting in radical amino-acid substitutions that apparently have anticoagulant tolerance of M. spretus as pleiotropic effect. Thus, positive selection produced an adaptive, divergent and pleiotropic vkorc1 allele in the donor species, M. spretus, which crossed a species barrier where it is expressed as adaptive trait in the recipient species, M. m. domesticus. Resistant house mice originated from selection on new or standing vkorc1 polymorphisms and from selection on vkorc1 polymorphisms acquired by adaptive introgressive hybridization.

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 more M. 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 involving M. 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 the Vkorc1 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.Mus musculus | Mus spretus | hybridization | adaptive introgression | PhyloNet-HMM C lassical 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 of Mus musculus, impacts the findings in M. musculus investigations for at least two reasons. First, it was deliberately interbred with laboratory M. musculus strains to introduce genetic variation (3). Second, Mus musculus domesticus is partially sympatric (naturally cooccurring) with M. spretus (Fig. 1).Recent studies have examined admixture between subspecies of house mice (5-8), but have not studied introgression with M. 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 place M. spretus as an outgroup to the M. musculus clade. The authors concluded that M. 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...

One outcome of interspecific hybridization and subsequent effects of evolutionary forces is introgression, which is the integration of genetic material from one species into the genome of an individual in another species. The evolution of several groups of eukaryotic species has involved hybridization, and cases of adaptation through introgression have been already established. In this work, we report on PhyloNet-HMM—a new comparative genomic framework for detecting introgression in genomes. PhyloNet-HMM combines phylogenetic networks with hidden Markov models (HMMs) to simultaneously capture the (potentially reticulate) evolutionary history of the genomes and dependencies within genomes. A novel aspect of our work is that it also accounts for incomplete lineage sorting and dependence across loci. Application of our model to variation data from chromosome 7 in the mouse (Mus musculus domesticus) genome detected a recently reported adaptive introgression event involving the rodent poison resistance gene Vkorc1, in addition to other newly detected introgressed genomic regions. Based on our analysis, it is estimated that about 9% of all sites within chromosome 7 are of introgressive origin (these cover about 13 Mbp of chromosome 7, and over 300 genes). Further, our model detected no introgression in a negative control data set. We also found that our model accurately detected introgression and other evolutionary processes from synthetic data sets simulated under the coalescent model with recombination, isolation, and migration. Our work provides a powerful framework for systematic analysis of introgression while simultaneously accounting for dependence across sites, point mutations, recombination, and ancestral polymorphism.

The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β-adrenoceptors transduce the signal produced by catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β-adrenoceptors become hyperstimulated. The hyperstimulated β1-adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β2-adrenoceptor-mediated Gi signalling. However, β2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β1-and β2-adrenoceptors and β2-adrenoceptor-mediated β-arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β-adrenoceptor subtype signalling in the failing heart, and conclude that Gi-biased β2-adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2-adrenoceptor-Gs signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs-biased β2-adrenoceptor agonist and a β1-adrenoceptor antagonist in combination. This combination treatment normalizes the β-adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies. LINKED ARTICLES IntroductionCardiovascular disease is the number one cause of death globally (World Health Organization, 2011). Coronary artery disease is the most prevalent form of cardiovascular disease and is the cause of heart attack (myocardial infarction), an acute illness with very high mortality and morbidity. Given that adult cardiomyocytes cannot re-enter the cell cycle, the death of cardiomyocytes as a result of the blockade of a major coronary artery will permanently weaken cardiac performance. The workload of the remaining cardiomyocytes has to increase to maintain a sufficient cardiac output. A series of compensatory responses are usually triggered, which in many cases lead to structural changes in the heart itself. The process once started will progress to a serious chronic illness called heart failure (HF). Thus, survivors of heart attacks are predisposed to HF, a potentially fatal condition manifested by a progressive decline of cardiac function. HF is also a common converging point of various late-stage cardiovascular conditions, such as cardiomyopathy, valvular heart disease and hypertension. Age is an important risk factor for ...