Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice

Smith, Clare M.; Proulx, Megan K.; Lai, Rocky; Kiritsy, Michael C.; Bell, Timothy A; Hock, Pablo; Villena, Fernando P Pardo Manuel De; Ferris, Martin T.; Baker, Richard E.; Behar, Samuel M.; Sassetti, Christopher M.

doi:10.1128/mbio.02791-19

Cited by 49 publications

(48 citation statements)

References 57 publications

(65 reference statements)

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“…CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made alpha L gene (Itgal, also known as Cd11a) resulting in a defect in T cell recruitment (39,41). Finally, the remaining 18 CC strains we screened survived the full study period.…”

Section: Discussionmentioning

confidence: 99%

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Scoggin

Lynch

Gupta

et al. 2022

Preprint

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Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection.

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Section: Discussionmentioning

confidence: 99%

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Scoggin

Lynch

Gupta

et al. 2022

Preprint

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“…We have also illustrated examples of how this array can be used for new genetic discovery, including sex chromosome abnormalities, genomic duplications and also in the expansion of genetic mapping approaches. This array and these associated data highlight the utility of genetic quality control for more robust and reproducible science in the mouse and is already being widely used by the research community (Smith et al 2019, Gu et al 2020, Yu et al 2020. Figure 1.…”

Section: Minimuga As a Tool For Discoverymentioning

confidence: 99%

Content and Performance of the MiniMUGA Genotyping Array: A New Tool To Improve Rigor and Reproducibility in Mouse Research

et al. 2020

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The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well annotated genome, wealth of genetic resources and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost effective, informative and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole genome sequencing. Here we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array, MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: 1) chromosomal sex determination, 2) discrimination between substrains from multiple commercial vendors, 3) diagnostic SNPs for popular laboratory strains, 4) detection of constructs used in genetically engineered mice, and 5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA we genotyped 6,899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived and recombinant inbred lines. Here we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC and an important new tool to the increase rigor and reproducibility of mouse research.

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“…New mutations originate and became fixed in the CC strains (Shorter et al, 2019;Srivastava et al, 2017) (Figure 1a). As a proof of concept, we first confirmed the loss of expression of proteins with known deletions, such as the 80 kbp deletion in CC026 that includes C3 and a 15 bp deletion for CC042 in Itgal (Figure 7a-b) that increases susceptibility to tuberculosis (Smith et al, 2019) and salmonella (Zhang et al, 2019). Next, we estimated CC strain-specific effects for each protein in the CC and identified CC strains with extreme abundance of a given protein, referred to as strain-protein outliers (Methods).…”

Section: Strain-private Variants Affect Protein Abundancementioning

confidence: 77%

Regulation of protein abundance in genetically diverse mouse populations

Keele

Zhang

Pham

et al. 2020

Preprint

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Proteins constitute much of the structure and functional machinery of cells, forming signaling networks, metabolic pathways, and large multi-component complexes. Protein abundance is regulated at multiple levels spanning transcription, translation, recycling, and degradation to maintain proper balance and optimal function. To better understand how protein abundances are maintained across varying genetic backgrounds, we analyzed liver proteomes of three genetically diverse mouse populations. We observe strong concordance of genetic and sex effects across populations. Differences between the populations arise from the contributions of additive, dominance, and epistatic components of heritable variation. We find that the influence of genetic variation on proteins that form complexes relates to their co-abundance. We identify effects on protein abundance from mutations that arose and became fixed during breeding and can lead to unique regulatory responses and disease states. Genetically diverse mouse populations provide powerful tools for understanding proteome regulation and its relationship to whole-organism phenotypes.

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Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice

Cited by 49 publications

References 57 publications

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Content and Performance of the MiniMUGA Genotyping Array: A New Tool To Improve Rigor and Reproducibility in Mouse Research

Regulation of protein abundance in genetically diverse mouse populations

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