Background/Objectives: The colonization history of house mice reflects the maritime history of humans that passively transported them worldwide. We investigated western house mouse colonization in the Atlantic region through studies of mitochondrial D-loop DNA sequences from modern specimens. Methods: We assembled a dataset of 758 haplotypes derived from 2765 mice from 47 countries/oceanic archipelagos (a combination of new and published data). Our maximum likelihood phylogeny recovered five previously identified clades, and we used the haplotype affinities within the phylogeny to infer house mouse colonization history, employing statistical tests and indices. From human history, we predefined four European source areas for mice in the Atlantic region (Northern Europe excluding Scandinavia, Southern Europe, Scandinavia, and Macaronesia) and we investigated the colonization from these source areas to different geographic areas in the Atlantic region. Results: Our inferences suggest mouse colonization of Scandinavia itself from Northern Europe, and Macaronesia from both Southern Europe and Scandinavia/Germany (the latter likely representing the transport of mice by Vikings). Mice on North Atlantic islands apparently derive primarily from Scandinavia, while for South Atlantic islands, North America, and Sub-Saharan Africa, the clearest source is Northern Europe, although mice on South Atlantic islands also had genetic inputs from Macaronesia and Southern Europe (for Tristan da Cunha). Macaronesia was a stopover for Atlantic voyages, creating an opportunity for mouse infestation. Mice in Latin America also apparently had multiple colonization sources, with a strong Southern European signal but also input from Northern Europe and/or Macaronesia. Conclusions: D-loop sequences help discern the broad-scale colonization history of house mice and new perspectives on human history.

A primary function of the skeleton is to resist the loads imparted by body weight. Genetic analyses have identified genomic regions that contribute to differences in skeletal load resistance between laboratory strains of mice, but these studies are usually restricted to 1 or 2 bones and leave open the question of how load resistance evolves in natural populations. To address these challenges, we examined the genetics of bone structure using the largest wild house mice on record, which live on Gough Island (GI). We measured structural traits connected to load resistance in the femur, tibia, scapula, humerus, radius, ulna, and mandible of GI mice, a smaller-bodied reference strain from the mainland, and 760 of their F2s. GI mice have bone geometries indicative of greater load resistance abilities but show no increase in bone mineral density compared to the mainland strain. Across traits and bones, we identified a total of 153 quantitative trait loci (QTL) that span all but one of the autosomes. The breadth of QTL detection ranges from a single bone to all 7 bones. Additive effects of QTL are modest. QTL for bone structure show limited overlap with QTL for bone length and width and QTL for body weight mapped in the same cross, suggesting a distinct genetic architecture for load resistance. Our findings provide a rare genetic portrait of the evolution of load resistance in a natural population with extreme body size.

Some of the most compelling examples of morphological evolution come from island populations. Alterations in the size and shape of the mandible have been repeatedly observed in murid rodents following island colonization. Despite this pattern and the significance of the mandible for dietary adaptation, the genetic basis of island-mainland divergence in mandibular form remains uninvestigated. To fill this gap, we examined mandibular morphology in 609 F2s from a cross between Gough Island mice, the largest wild house mice on record, and mice from a mainland reference strain (WSB). Univariate genetic mapping identifies 3 quantitative trait loci (QTL) for relative length of the temporalis lever arm and 2 distinct QTL for relative condyle length, 2 traits expected to affect mandibular function that differ between Gough Island mice and WSB mice. Multivariate genetic mapping of coordinates from geometric morphometric analyses identifies 27 QTL contributing to overall mandibular shape. Quantitative trait loci show a complex mixture of modest, additive effects dispersed throughout the mandible, with landmarks including the coronoid process and the base of the ascending ramus frequently modulated by QTL. Additive effects of most shape quantitative trait loci do not align with island-mainland divergence, suggesting that directional selection played a limited role in the evolution of mandibular shape. In contrast, Gough Island mouse alleles at QTL for centroid size and QTL for jaw length increase these measures, suggesting selection led to larger mandibles, perhaps as a correlated response to the evolution of larger bodies.

A systematic study into a novel self‐assembling system is presented whereby the small molecule DB921 forms nearly monodisperse nanotubes upon addition of a suitable salt. Small‐angle X‐ray scattering and negative stain transmission electron microscopy are employed as the principal characterization methods to study both the fundamental assembly processes and reaction kinetics. The assembly is found to be hierarchical, culminating with helical winding of intermediate ribbon structures into nanotubes. The driving force for this process is likely the electrostatic interaction between DB921 and salt anions; this aspect can be used to control nanotube assembly and morphology.

Currently approved immune checkpoint inhibitor (ICI) therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, the majority of patients across cancer types still fail to respond. Addressing alternative pathways that mediate immune suppression could enhance ICI efficacy. One such mechanism is the increase in sialic acid-containing proteins and lipids (sialoglycans) in malignancy, which recently has been shown to inhibit immune cell activation through multiple mechanisms including Siglec receptor binding, and therefore represents a targetable glyco-immune checkpoint. Here, we report the design of a trastuzumab- sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells in vivo. In a syngeneic orthotopic HER2+ breast cancer model, targeted desialylation delayed tumor growth and enhanced immune cell infiltration and activation, leading to prolonged survival of mice with trastuzumab-resistant breast cancer. Thus, antibody-sialidase conjugates represent a promising modality for cancer immune therapy.

Since their arrival approximately 200 years ago, the house mice (Mus musculus) on Gough Island (GI) rapidly increased in size to become the largest wild house mice on record. Along with this extreme increase in body size, GI mice adopted a predatory diet, consuming significant quantities of seabird chicks and eggs. We studied this natural experiment to determine how evolution of extreme size and a novel diet impacted masticatory apparatus performance and functional morphology in these mice. We measured maximum bite force and jaw opening (i.e., gape) along with several musculoskeletal dimensions functionally linked to these performance measurements to test the hypotheses that GI mice evolved larger bite forces and jaw gapes as part of their extreme increase in size and/or novel diet. GI mice can bite more forcefully and open their jaws wider than a representative mainland strain of house mice. Similarly, GI mice have musculoskeletal features of the masticatory apparatus that are absolutely larger than WSB mice. However, when considered relative to body size or jaw length, as a relevant mechanical standard, GI mice show reduced performance, suggesting a size-related decrease in these abilities. Correspondingly, most musculoskeletal features are not relatively larger in GI mice. Incisor biting leverage and condylar dimensions are exceptions, suggesting relative increases in biting efficiency and condylar rotation in GI mice. Based on these results, we hypothesize that evolutionary enhancements in masticatory performance are correlated with the extreme increase in body size and associated musculoskeletal phenotypes in Gough Island mice. Anat Rec, 2019. © 2018 American Association for Anatomy.

Recombination rate is a heritable trait that varies among individuals. Despite the major impact of recombination rate on patterns of genetic diversity and the efficacy of selection, natural variation in this phenotype remains poorly characterized. We present a comparison of genetic maps, sampling 1212 meioses, from a unique population of wild house mice (Mus musculus domesticus) that recently colonized remote Gough Island. Crosses to a mainland reference strain (WSB/EiJ) reveal pervasive variation in recombination rate among Gough Island mice, including subchromosomal intervals spanning up to 28% of the genome. In spite of this high level of polymorphism, the genomewide recombination rate does not significantly vary. In general, we find that recombination rate varies more when measured in smaller genomic intervals. Using the current standard genetic map of the laboratory mouse to polarize intervals with divergent recombination rates, we infer that the majority of evolutionary change occurred in one of the two tested lines of Gough Island mice. Our results confirm that natural populations harbour a high level of recombination rate polymorphism and highlight the disparities in recombination rate evolution across genomic scales.

Organisms on islands often undergo rapid morphological evolution, providing a platform for understanding mechanisms of phenotypic change. Many examples of evolution on islands involve the vertebrate skeleton. Although the genetic basis of skeletal variation has been studied in laboratory strains, especially in the house mouse Mus musculus domesticus, the genetic determinants of skeletal evolution in natural populations remain poorly understood. We used house mice living on the remote Gough Island—the largest wild house mice on record—to understand the genetics of rapid skeletal evolution in nature. Compared to a mainland reference strain from the same subspecies (WSB/EiJ), the skeleton of Gough Island mice is considerably larger, with notable expansions of the pelvis and limbs. The Gough Island mouse skeleton also displays changes in shape, including elongations of the skull and the proximal vs. distal elements in the limbs. Quantitative trait locus (QTL) mapping in a large F2 intercross between Gough Island mice and WSB/EiJ reveals hundreds of QTL that control skeletal dimensions measured at 5, 10, and/or 16 weeks of age. QTL exhibit modest, mostly additive effects, and Gough Island alleles are associated with larger skeletal size at most QTL. The QTL with the largest effects are found on a few chromosomes and affect suites of skeletal traits. Many of these loci also colocalize with QTL for body weight. The high degree of QTL colocalization is consistent with an important contribution of pleiotropy to skeletal evolution. Our results provide a rare portrait of the genetic basis of skeletal evolution in an island population and position the Gough Island mouse as a model system for understanding mechanisms of rapid evolution in nature.

Organisms on islands provide a revealing window into the process of adaptation. Populations that colonize islands often evolve substantial differences in body size from their mainland relatives. Although the ecological drivers of this phenomenon have received considerable attention, its genetic basis remains poorly understood. We use house mice (subspecies: Mus musculus domesticus) from remote Gough Island to provide a genetic portrait of rapid and extreme size evolution. In just a few hundred generations, Gough Island mice evolved the largest body size among wild house mice from around the world. Through comparisons with a smaller-bodied wild-derived strain from the same subspecies (WSB/EiJ), we demonstrate that Gough Island mice achieve their exceptional body weight primarily by growing faster during the 6 weeks after birth. We use genetic mapping in large F-2 intercrosses between Gough Island mice and WSB/EiJ to identify 19 quantitative trait loci (QTL) responsible for the evolution of 16-week weight trajectories: 8 QTL for body weight and 11 QTL for growth rate. QTL exhibit modest effects that are mostly additive. We conclude that body size evolution on islands can be genetically complex, even when substantial size changes occur rapidly. In comparisons to published studies of laboratory strains of mice that were artificially selected for divergent body sizes, we discover that the overall genetic profile of size evolution in nature and in the laboratory is similar, but many contributing loci are distinct. Our results underscore the power of genetically characterizing the entire growth trajectory in wild populations and lay the foundation necessary for identifying the mutations responsible for extreme body size evolution in nature.

Island populations provide natural laboratories for studying key contributors to evolutionary change, including natural selection, population size and the colonization of new environments. The demographic histories of island populations can be reconstructed from patterns of genetic diversity. House mice (Mus musculus) inhabit islands throughout the globe, making them an attractive system for studying island colonization from a genetic perspective. Gough Island, in the central South Atlantic Ocean, is one of the remotest islands in the world. House mice were introduced to Gough Island by sealers during the 19th century and display unusual phenotypes, including exceptionally large body size and carnivorous feeding behaviour. We describe genetic variation in Gough Island mice using mitochondrial sequences, nuclear sequences and microsatellites. Phylogenetic analysis of mitochondrial sequences suggested that Gough Island mice belong to Mus musculus domesticus, with the maternal lineage possibly originating in England or France. Cluster analyses of microsatellites revealed genetic membership for Gough Island mice in multiple coastal populations in Western Europe, suggesting admixed ancestry. Gough Island mice showed substantial reductions in mitochondrial and nuclear sequence variation and weak reductions in microsatellite diversity compared with Western European populations, consistent with a population bottleneck. Approximate Bayesian computation (ABC) estimated that mice recently colonized Gough Island (~100 years ago) and experienced a 98% reduction in population size followed by a rapid expansion. Our results indicate that the unusual phenotypes of Gough Island mice evolved rapidly, positioning these mice as useful models for understanding rapid phenotypic evolution.

We incorporated radio-telemetry data with genetic analysis of bat-eared foxes (Otocyon megalotis) from individuals in 32 different groups to examine relatedness and spatial organization in two populations in South Africa that differed in density, home-range sizes, and group sizes. Kin clustering occurred only for female dyads in the high-density population. Relatedness was negatively correlated with distance only for female dyads in the high-density population, and for male and mixed-sex dyads in the low-density population. Home-range overlap of neighboring female dyads was significantly greater in the high compared to low-density population, whereas overlap within other dyads was similar between populations. Amount of home-range overlap between neighbors was positively correlated with genetic relatedness for all dyad-site combinations, except for female and male dyads in the low-density population. Foxes from all age and sex classes dispersed, although females (mostly adults) dispersed farther than males. Yearlings dispersed later in the high-density population, and overall exhibited a male-biased dispersal pattern. Our results indicated that genetic structure within populations of bat-eared foxes was sex-biased, and was interrelated to density and group sizes, as well as sex-biases in philopatry and dispersal distances. We conclude that a combination of male-biased dispersal rates, adult dispersals, and sex-biased dispersal distances likely helped to facilitate inbreeding avoidance in this evolutionarily unique species of Canidae.

Dogs display a remarkable amount of phenotypic diversity in coat color, texture, and cranial and skeletal proportions, yet as a species they are distinct from wild canids (Wayne 1986a,b). Similarly, considerable variation in behavior and physiology are evident among breeds and between dogs and wild species (Hart 1995, Hare et al. 2002, Spady and Ostrander 2008). Considering the great diversity of dogs, Darwin and others postulated that domestic dogs were founded from more than one canid species (Darwin 1859, Lorenz 1954, Coppinger and Schneider 1995). However, molecular data showed conclusively that dogs originated from the gray wolf (Canis lupus) (Morey 1994, Vilà et al. 1997, Savolainen et al. 2002, Pang et al. 2009). Nonetheless, because of the morphologic divergence between dogs and gray wolves, identifying a specific ancestral gray wolf population is difficult.

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Abstract Relatively little is known about the mating behavior, and factors that influence the mating behavior, of socially monogamous mammals. We used a combination of behavioral and genetic data to examine the mating tactics of a socially monogamous population of bat-eared foxes (Otocyon megalotis). In contrast to some other canid species, we found no evidence that either sex increased range size or traveling distance during the mating season, demonstrating that neither sex roams widely in pursuit of extrapair copulations. Mated partners maintained close proximity during, and sometimes outside, the mating season, suggesting that females looking to engage with extrapair mates might find it difficult to do so. Consistent with these findings, microsatellite analyses revealed lower levels of extrapair paternity (EPP) than have been reported in other canid species, with only 9.8% of cubs produced outside of the pair-bond. We suggest that the relatively low level of EPP in the bat-eared fox may be influenced partly by diet and foraging behavior, which makes it easy for males to maintain close proximity to partners and costly for either sex to roam in search of extrapair mates.

This article is a response to Klütsch and Crapon de Caprona See correspondence article http://www.biomedcentral.com/1741-7007/8/119 and our original research article http://www.biomedcentral.com/1741-7007/8/16 .

Background: A selective sweep containing the insulin-like growth factor 1 (IGF1) gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP) found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog. Results: We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves. Conclusions: The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East. See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10