Little is known about the genetic basis of convergent traits that originate repeatedly over broad taxonomic scales. The myogenic electric organ has evolved six times in fishes to produce electric fields used in communication, navigation, predation, or defense. We have examined the genomic basis of the convergent anatomical and physiological origins of these organs by assembling the genome of the electric eel (Electrophorus electricus) and sequencing electric organ and skeletal muscle transcriptomes from three lineages that have independently evolved electric organs. Our results indicate that, despite millions of years of evolution and large differences in the morphology of electric organ cells, independent lineages have leveraged similar transcription factors and developmental and cellular pathways in the evolution of electric organs.

Bifidobacteria are important members of the human gut flora, especially in infants. Comparative genomic analysis of two Bifidobacterium animalis subsp. lactis strains revealed evolution by internal deletion of consecutive spacer-repeat units within a novel clustered regularly interspaced short palindromic repeat locus, which represented the largest differential content between the two genomes. Additionally, 47 single nucleotide polymorphisms were identified, consisting primarily of nonsynonymous mutations, indicating positive selection and/or recent divergence. A particular nonsynonymous mutation in a putative glucose transporter was linked to a negative phenotypic effect on the ability of the variant to catabolize glucose, consistent with a modification in the predicted protein transmembrane topology. Comparative genome sequence analysis of three Bifidobacterium species provided a core genome set of 1,117 orthologs complemented by a pan-genome of 2,445 genes. The genome sequences of the intestinal bacterium B. animalis subsp. lactis provide insights into rapid genome evolution and the genetic basis for adaptation to the human gut environment, notably with regard to catabolism of dietary carbohydrates, resistance to bile and acid, and interaction with the intestinal epithelium. The high degree of genome conservation observed between the two strains in terms of size, organization, and sequence is indicative of a genomically monomorphic subspecies and explains the inability to differentiate the strains by standard techniques such as pulsed-field gel electrophoresis.

SUMMARY Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp . and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2 . Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.

26 The microbial communities that inhabit the distal gut of humans and other mammals exhibit large 27 inter-individual variation. While host genetics is a known factor that influences gut microbiota 28 composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) 29 are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as 30 environmental cues and nutrients to microbes, but they can also have antibacterial effects. We 31 hypothesized that host genetic variation in BA metabolism and homeostasis influence gut 32 microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population 33 of genetically distinct mice derived from eight founder strains. We characterized the fecal 34 microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a 35 high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we 36 identified several genomic regions associated with variations in both bacterial and BA profiles.37 Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped 38 to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and 39 subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression 40 associated with the different strains influences levels of both traits and revealed novel interactions 41 between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to 42 generate testable hypotheses and provide insight into host-microbe interactions. 44Author summary 45 Inter-individual variation in the composition of the intestinal microbiota can in part be attributed 46 to host genetics. However, the specific genes and genetic variants underlying differences in the 47 microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition 3 48 of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of 49 the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is 50 also associated with changes in the abundance of plasma bile acidsmetabolites generated by the 51 host that influence both microbiota composition and host physiology. Follow up validation 52 experiments provide mechanistic insights linking host genetic differences, with changes in ileum 53 gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work 54 demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel 55 insight into how host genetics shape gut microbiota composition. 56 57 Introduction 58The intestinal microbiota has profound effects on host physiology and health (1-3). The 59 composition of the gut microbiota is governed by a combination of environmental factors, 60 including diet, drugs, maternal seeding, cohabitation, and host genetics (4-7). Together, these 61 factors cause substantial inter-i...