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Gene duplication and loss are major sources of genetic polymorphism in populations, and are important forces shaping the evolution of genome content and organization. We have reconstructed the origin and history of a 127 kbp segmental duplication,R2d, in the house mouse (Mus musculus). R2dcontains a single protein-coding gene,Cwc22. De novoassembly of both the ancestral (R2d1) and the derived (R2d2) copies reveals that they have been subject to non-allelic gene conversion events spanning tens of kilobases.R2d2is also a hotspot for structural variation: its diploid copy number ranges from zero in the mouse reference genome to more than 80 in wild mice sampled from around the globe. Hemizgyosity for high-copy-number alleles ofR2d2is associated inciswith meiotic drive, suppression of meiotic crossovers, and copy-number instability, with a mutation rate in excess of 1 per 100 transmissions in laboratory populations. We identify an additional 57 loci covering 0.8% of the mouse genome with patterns of sequence variation similar to those atR2d1andR2d2. Our results provide a striking example of allelic diversity generated by duplication and demonstrate the value ofde novoassembly in a phylogenetic context for understanding the mutational processes affecting duplicate genes.

Reports of P. vivax infections among Duffy-negative hosts have accumulated throughout sub-Saharan Africa. Despite this growing body of evidence, no nationally representative epidemiological surveys of P. vivax in sub-Saharan Africa have been performed. To overcome this gap in knowledge, we screened over 17,000 adults in the Democratic Republic of the Congo (DRC) for P. vivax using samples from the 2013-2014 Demographic Health Survey. Overall, we found a 2.97% (95% CI: 2.28%, 3.65%) prevalence of P. vivax infections across the DRC. Infections were associated with few risk-factors and demonstrated a relatively flat distribution of prevalence across space with focal regions of relatively higher prevalence in the north and northeast. Mitochondrial genomes suggested that DRC P. vivax were distinct from circulating non-human ape strains and an ancestral European P. vivax strain, and instead may be part of a separate contemporary clade. Our findings suggest P. vivax is diffusely spread across the DRC at a low prevalence, which may be associated with long-term carriage of low parasitemia, frequent relapses, or a general pool of infections with limited forward propagation., Plasmodium vivax generally accounts for a low proportion of malaria cases in Africa, but population-level data on the distribution of infections is limited. Here, the authors use data from the Democratic Republic of the Congo and show that the prevalence is low (~3%) and diffusely spread.

BackgroundReports of P. vivax infections among Duffy-negative hosts have begun to accumulate throughout sub-Saharan Africa. Despite this growing body of evidence, no nationally representative epidemiological surveys of P. vivax in sub-Saharan Africa nor population genetic analyses to determine the source of these infections have been performed.MethodsTo overcome this critical gap in knowledge, we screened nearly 18,000 adults in the Democratic Republic of the Congo (DRC) for P. vivax using samples from the 2013-2014 Demographic Health Survey. Infections were identified by quantitative PCR and confirmed with nested-PCR. P. vivax mitochondrial genomes were constructed after short-read sequencing. Risk factors, spatial distributions and population genetic analyses were explored.FindingsOverall, we found a 2.96% (95% CI: 2.28%, 3.65%) prevalence of P. vivax infections across the DRC. Nearly all infections were among Duffy-negative adults (486/489). Infections were not associated with typical malaria risk-factors and demonstrated small-scale heterogeneity in prevalence across space. Mitochondrial genomes suggested that DRC P. vivax is an older clade that shares its most recent common ancestor with South American isolates.InterpretationP. vivax is more prevalent across the DRC than previously believed despite widespread Duffy-negativity. Comparison to global and historical P. vivax sequences suggests that historic DRC P. vivax may have been transported to the New World on the wave of European expansion. Our findings suggest congolese P. vivax is an innocuous threat given its relatively flat distribution across space, lack of malaria risk factors, and potentially ancestral lineage.FundingNational Institutes of Health and the Wellcome Trust.

Background Tanzania’s Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination. Despite consistent implementation of effective tools since 2002, elimination has not been achieved. Importation of parasites from outside of the archipelago is thought to be an important cause of malaria’s persistence, but this paradigm has not been studied using modern genetic tools. Methods Whole-genome sequencing (WGS) was used to investigate the impact of importation, employing population genetic analyses of Plasmodium falciparum isolates from both the archipelago and mainland Tanzania. Ancestry, levels of genetic diversity and differentiation, patterns of relatedness, and patterns of selection between these two populations were assessed by leveraging recent advances in deconvolution of genomes from polyclonal malaria infections. Results Significant decreases in the effective population sizes were inferred in both populations that coincide with a period of decreasing malaria transmission in Tanzania. Identity by descent analysis showed that parasites in the two populations shared long segments of their genomes, on the order of 5 cM, suggesting shared ancestry within the last 10 generations. Even with limited sampling, two of isolates between the mainland and Zanzibar were identified that are related at the expected level of half-siblings, consistent with recent importation. Conclusions These findings suggest that importation plays an important role for malaria incidence on Zanzibar and demonstrate the value of genomic approaches for identifying corridors of parasite movement to the island.

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1–58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2−/− mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.

The goal of the Collaborative Cross (CC) project was to generate and distribute over 1000 independent mouse recombinant inbred strains derived from eight inbred founders. With inbreeding nearly complete, we estimated the extinction rate among CC lines at a remarkable 95%, which is substantially higher than in the derivation of other mouse recombinant inbred populations. Here, we report genome-wide allele frequencies in 347 extinct CC lines. Contrary to expectations, autosomes had equal allelic contributions from the eight founders, but chromosome X had significantly lower allelic contributions from the two inbred founders with underrepresented subspecific origins (PWK/PhJ and CAST/EiJ). By comparing extinct CC lines to living CC strains, we conclude that a complex genetic architecture is driving extinction, and selection pressures are different on the autosomes and chromosome X. Male infertility played a large role in extinction as 47% of extinct lines had males that were infertile. Males from extinct lines had high variability in reproductive organ size, low sperm counts, low sperm motility, and a high rate of vacuolization of seminiferous tubules. We performed QTL mapping and identified nine genomic regions associated with male fertility and reproductive phenotypes. Many of the allelic effects in the QTL were driven by the two founders with underrepresented subspecific origins, including a QTL on chromosome X for infertility that was driven by the PWK/PhJ haplotype. We also performed the first example of cross validation using complementary CC resources to verify the effect of sperm curvilinear velocity from the PWK/PhJ haplotype on chromosome 2 in an independent population across multiple generations. While selection typically constrains the examination of reproductive traits toward the more fertile alleles, the CC extinct lines provided a unique opportunity to study the genetic architecture of fertility in a widely genetically variable population. We hypothesize that incompatibilities between alleles with different subspecific origins is a key driver of infertility. These results help clarify the factors that drove strain extinction in the CC, reveal the genetic regions associated with poor fertility in the CC, and serve as a resource to further study mammalian infertility.

The Democratic Republic of the Congo (DRC) harbors 11% of global malaria cases, yet little is known about the spatial and genetic structure of the parasite population in that country. We sequence 2537 Plasmodium falciparum infections, including a nationally representative population sample from DRC and samples from surrounding countries, using molecular inversion probes - a high-throughput genotyping tool. We identify an east-west divide in haplotypes known to confer resistance to chloroquine and sulfadoxine-pyrimethamine. Furthermore, we identify highly related parasites over large geographic distances, indicative of gene flow and migration. Our results are consistent with a background of isolation by distance combined with the effects of selection for antimalarial drug resistance. This study provides a high-resolution view of parasite genetic structure across a large country in Africa and provides a baseline to study how implementation programs may impact parasite populations., The genome of the malaria parasite Plasmodium falciparum contains a record of past evolutionary forces. Here, using 2537 parasite sequences from the Democratic Republic of the Congo, the authors demonstrate how drug pressure and human movement have shaped the present-day parasite population.

Faithful segregation of mammalian X and Y chromosomes in male meiosis depends on pairing and recombination in a short interval of residual sequence homology known as the pseudoautosomal region (PAR)... Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here, we estimate the genetic map in a previously documented expansion of the PAR in the M. musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the M. musculus musculus subspecies and show that it involves a complex rearrangement, but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus, and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance of unusual levels of polymorphism in the population of unknown functional significance.

Inflammatory bowel disease (IBD) is an immune-mediated condition driven by improper responses to intestinal microflora in the context of environmental and genetic background. GWAS in humans have identified many loci associated with IBD, but animal models are valuable for dissecting the underlying molecular mechanisms, characterizing environmental and genetic contributions and developing treatments. Mouse models rely on interventions such as chemical treatment or introduction of an infectious agent to induce disease. Here, we describe a new model for IBD in which the disease develops spontaneously in 20-week-old mice in the absence of known murine pathogens. The model is part of the Collaborative Cross and came to our attention due to a high incidence of rectal prolapse in an incompletely inbred line. Necropsies revealed a profound proliferative colitis with variable degrees of ulceration and vasculitis, splenomegaly and enlarged mesenteric lymph nodes with no discernible anomalies of other organ systems. Phenotypic characterization of the CC011/Unc mice with homozygosity ranging from 94.1 to 99.8 % suggested that the trait was fixed and acted recessively in crosses to the colitis-resistant C57BL/6J inbred strain. Using a QTL approach, we identified four loci, Ccc1, Ccc2,Ccc3 and Ccc4 on chromosomes 12, 14, 1 and 8 that collectively explain 27.7 % of the phenotypic variation. Surprisingly, we also found that minute levels of residual heterozygosity in CC011/Unc have significant impact on the phenotype. This work demonstrates the utility of the CC as a source of models of human disease that arises through new combinations of alleles at susceptibility loci. Electronic supplementary material The online version of this article (doi:10.1007/s00335-013-9499-2) contains supplementary material, which is available to authorized users.

Mitsainas, George/0000-0003-4976-8275; Lindholm, Anna K/0000-0001-8460-9769; Mathias, Maria da Luz/0000-0003-3876-958X; Foerster, Daniel/0000-0002-6934-0404; Hauffe, Heidi Christine C/0000-0003-3098-8964; Threadgill, David W/0000-0003-3538-1635; Gabriel, Sofia I/0000-0003-3702-4631; Chesler, Elissa/0000-0002-5642-5062; Didion, John/0000-0002-8111-6261; solano, emanuela/0000-0001-8482-9243; Weinstock, George/0000-0002-2997-4592; McMullan, Rachel/0000-0003-0297-4549; Holt, James/0000-0001-6411-9236; Rehermann, Barbara/0000-0001-6832-9951 WOS: 000376170300001 PubMed: 26882987 A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding inmultiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32GM067553, F30MH103925, P50GM076468, K01MH094406, DK-076050, DK-056350, AG038070]; National Science FoundationNational Science Foundation (NSF) [IOS-1121273]; Vaadia-BARD Postdoctoral Fellowship AwardUS-Israel Binational Science Foundation [FI-478-13]; U.S. Army Medical Research and Materiel CommandU.S. Army Medical Research & Materiel Command (USAMRMC) [W81XWH-11-1-0762]; Jackson Laboratory new investigator funds; National Center for Scientific Research, France [ISEM 2016-002]; University of Rome "La Sapienza"; Claraz-Stiftung; Natural Environment Research Council (UK)NERC Natural Environment Research Council; EU Human Capital and Mobility Programme [CHRX-CT93-0192]; Foundation for Science and Technology, PortugalPortuguese Foundation for Science and Technology [PTDC/BIA-EVF/116884/2010, UID/AMB/50017/2013]; Spanish "Ministerio de Ciencia y Tecnologia"Spanish Government [CGL2007-62111]; "Ministerio de Economia y Competitividad"Spanish Government [CGL2010-15243]; School of Medicine at University of North Carolina We wish to thank all the scientists and research personnel who collected and processed the samples used in this study. In particular we acknowledge Luanne Peters and Alex Hong-Tsen Yu for providing critical samples; Ryan Buus and T. Justin Gooch for isolating DNA for high-density genotyping of wild-caught mice; and Vicki Cappa, A. Cerveira, Guila Ganem, Ron and Annabelle Lesher, K. Said, Toni Schelts, Dan Small, and J. Tapisso for aiding in mouse trapping. We thank Muriel Davisson at the Jackson Laboratory for maintaining, for several decades, tissue samples from breeding colonies used to generate wild-derived inbred strains. We also thank Francis Collins, Jim Evans, Matthew Hahn, and Corbin Jones for comments on an earlier version of this manuscript. This work was supported by the National Institutes of Health T32GM067553 to J.P.D. and A.P.M., F30MH103925 to A.P.M., P50GM076468 to E.J.C., G.A.C., and F.P.M.V., K01MH094406 to J.J.C., DK-076050 and DK-056350 to D.P., AG038070 to G.A.C, and the intramural research program to B.R. and S.P.R.; National Science Foundation IOS-1121273 to T.G.; Vaadia-BARD Postdoctoral Fellowship Award FI-478-13 to L.Y.; U.S. Army Medical Research and Materiel Command W81XWH-11-1-0762 to C.J.B.; The Jackson Laboratory new investigator funds to E.J.C.; The National Center for Scientific Research, France to J.B.D. (this is contribution no ISEM 2016-002); the University of Rome "La Sapienza" to R.C. and E.S.; Claraz-Stiftung to S.G. and A.L.; Natural Environment Research Council (UK) to M.D.G., H.C.H., and J.B.S.; EU Human Capital and Mobility Programme (CHRX-CT93-0192) to H.C.H. and J.B.S.; Foundation for Science and Technology, Portugal PTDC/BIA-EVF/116884/2010 and UID/AMB/50017/2013 to S.I.G., M.L.M., and J.B.S.; Spanish "Ministerio de Ciencia y Tecnologia" CGL2007-62111 and "Ministerio de Economia y Competitividad" CGL2010-15243 to J.V.;and the Oliver Smithies Investigator funds provided by the School of Medicine at University of North Carolina to F.P.M.V. All data are made available at http://csbio.unc.edu/r2d2/. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to F.P.M.V. (fernando@med.unc.edu).

The 28th International Mammalian Genome Conference (IMGC) was held October 26–29th, 2014 in scenic Bar Harbor, Maine. In addition to being the home of The Jackson Laboratory, Mount Desert Island is a popular summer vacation destination. More than 200 attendees of the conference enjoyed the last few days of the tourist season as the autumn leaves fell and the local residents prepared for winter. Darla Miller and Dasha Li Kappe organized the meeting, with the help of local organizers Ron Korstanje, Karen Svenson, Erin McDevitt, and Nancy Place. Scientists presented cutting-edge research in the fields of mammalian genetics and genomics that highlighted the importance of mammalian models for human genetics and disease research. The plenary presentations demonstrated the broad applicability of mammalian models to study a range of topics from gene evolution to rare human diseases. Meanwhile, the Verne Chapman lecture provided a historical account of mouse genetics research and encouraged a new, automated approach to forward genetics. Bioinformatics and Systems Genetics Workshops gave participants hands-on opportunities to become familiar with genetic and genomic tools. A student satellite symposium afforded budding scientists the chance to share their work and two poster sessions encouraged interaction among researchers. The meeting program and abstracts are available online at www.imgs.org/Archive/abstracts/2014Abstracts/IMGS2014Program.pdfwww.imgs.org. Online resources presented at the meeting are listed in Table 1. Table 1 Databases, resources, and tools Bioinformatics workshops Several workshops provided conference attendees with opportunities for hands-on guided tours of publicly available informatics resources relevant to IMGS members. The pre-conference Bioinformatics Workshop offered three mini-sessions: (1) a guide to genome annotations produced by the GENCODE consortium, and differences between annotation sets provided by popular databases (Laurens Wilming, Wellcome Trust Sanger Institute); (2) an overview of the International Knockout Mouse Consortium's pipeline and progress (Mark Thomas, Wellcome Trust Sanger Institute); and (3) a tour of the International Mouse Phenotyping Consortium's database of mutant mouse phenotypes (www.mousephenotype.org). An online link to these workshop powerpoint presentations can be found under the “History” tab on the IMGS home page (www.imgs.org). The System Genetics Workshops, led by Dan Gatti (The Jackson Laboratory), Marty Ferris (University of North Carolina at Chapel Hill), Gary Churchill (The Jackson Laboratory) along with Andrew Morgan and Fernando Pardo-Manuel de Villena (University of North Carolina at Chapel Hill) featured talks on the design and status of two important multiparental genetic reference populations, the Collaborative Cross (CC) and the Diversity Outbred (DO) mice. Didactic sessions were supplemented with small-group discussions on rational experimental designs using these populations and available online tools for analyses (www.csbio.unc.edu/CCstatus/index.py) were described by Leonard McMillan, Chen-Ping Fu, and Chia-yu Kao (University of North Carolina at Chapel Hill). This year's Mouse Genome Informatics(MGI) Workshops (www.informatics.jax.org) were led by Joanne Berghout and David Shaw (The Jackson Laboratory). The hands-on workshops included seminar-style demonstrations followed by the opportunity to navigate MGI using self-guided exercises. Participants were instructed on how to locate biological information by performing a variety of searches, and were also introduced to new tools such as the Human-Mouse: Disease Connection portal (www.informatics.jax.org/humanDisease.shtml), the Recombinase (Cre) Activity portal (www.informatics.jax.org/recombinase.shtml), and the MouseMine computational access platform (www.mousemine.org/mousemine/begin.do). In celebration of the 25th birthday of the MGI database, Janan Eppig (The Jackson Laboratory; O-30) tracked the history of the MGI from a pre-web version distributed on floppy disks to the MGI website (www.informatics.jax.org) that we know today. Janan emphasized the continued commitment of MGI to provide integrated genetic, genomic, and biological data for mouse and to provide increased access to translational data views to support discovery and hypothesis building for studies of human disease. Janan also recognized the contributions of many individuals who worked to develop MGI over the years and described future plans as MGI evolves to meet the growing needs of the scientific community.

Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 – 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system., Author Summary One of the strongest expectations in genetics is that chromosomes segregate randomly during meiosis. However, genetic loci that exhibit transmission ratio distortion (TRD) are sometimes observed in offspring of F1 hybrids. Meiotic drive is a type of non-Mendelian inheritance in which a “selfish” genetic element exploits asymmetric female meiotic cell division to promote its preferential inclusion in ova. We previously reported TRD on Chr 2 in the CC, a mouse recombinant inbred panel with contributions from three Mus musculus subspecies. Here we show that maternal TRD consistent with a novel meiotic drive system is caused by a copy number gain. This mutation is similar in size and structure to other known meiotic drive responders, such as the knobs of maize. A deletion of most of the copies is sufficient to restore Mendelian segregation, proving that the copy number variant is causative of the observed TRD. In the CC, and also the related DO population, the transmission frequency of the favored allele varies dependent on genetic background, demonstrating that this system is under genetic control. In conclusion, we describe a novel wild-derived meiotic drive locus on mouse Chr 2 that exploits female meiosis asymmetry to violate the Laws of Mendelian inheritance.

Summary Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. Video Abstract