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Despite the crucial roles of lipids in metabolism, we are still at the early stages of comprehensively annotating lipid species and their genetic basis. Mass spectrometry(MS)-based discovery lipidomics offers the potential to globally survey lipids and their relative abundances in various biological samples. To discover the genetics of lipid features obtained through high resolution LC-MS/MS, we analyzed liver and plasma from 384 Diversity Outbred (DO) mice, and quantified 3,283 molecular features. These features were mapped to 5,622 lipid quantitative trait loci (QTL) and compiled into a public web-resource termed LipidGenie. This data is cross-referenced to the human genome and offers a bridge between genetic associations in humans and mice. Harnessing this resource, we used genome-lipid association data as an additional aid to identify a number of lipids, for example gangliosides through their association with B4galnt1 , and found evidence for a group of sex-specific phosphatidylcholines through their shared locus. Finally, LipidGenie’s ability to query either mass or gene-centric terms, suggests acyl chain-specific functions for proteins of the ABHD family.

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe–host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila–host interactions and support the role of host genetics as a determinant of responses to gut microbes.

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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