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  1. Evaluation Summary:

    The paper uses hybrid mouse lines to estimate the heritability of the microbiome and map variants in the mouse genome that are associated with the composition of the microbiome. The findings are of broad interest to microbiome researchers and improve on knowledge in the field, as they focus on mucosa-associated (rather than fecal) microbiome profiles and report a novel correlation between heritability and cospeciation rates. The results are intriguing, but technical and biological confounders are incompletely addressed in the manuscript's present form, potentially leading to surprisingly high estimates of microbiome trait heritability relative to previous work.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  2. Reviewer #1 (Public Review):

    Gut microbiome variation is relevant to host health. In turn, the environment provided by the host influences gut microbiome community composition. Recent studies suggest that this environment is at least in part shaped by host genetics, making microbial abundances in the gut a heritable class of traits. Here, Doms et al use a powerful crossing design in hybrid mice (Mus musculus musculus x Mus musculus domesticus, derived from a well-studied hybrid zone in Europe) to estimate heritability, map genetic associations with microbial taxon abundance, and link within-species heritability estimates to macroevolutionary patterns of phylosymbiosis (i.e., diversification in gut microbes that mirrors diversification in their hosts).

    Strengths of the manuscript include the clever use of a crossing design with mostly inbred hybrid lines as founders, which confers impressive power, and integration of the mouse data with external estimates of co-speciation rates to test for predictors of phylosymbiosis. The latter result, in particular, suggests a potentially generalizable principle for why some microbes are closely associated with host phylogenies, while others are not. The authors also analyze 16S rRNA data from both DNA (the typical approach in 16S studies) and RNA, which generates largely concordant but complementary results. Together, these analyses generate a substantial number of candidate genotype-microbiome phenotype associations, several of which replicate previous findings but many of which are new.

    In their current form, however, it is not clear how robust some of these analyses are. Neither the heritability analyses or mapping analyses control for technical or biological covariates/confounders. It is extremely rare that genomic data sets are free of technical or batch effects; housing conditions, experimental timing, or other factors could also influence heritability and/or mapping estimates. Additionally, because the study population includes both recent kin and historically admixed individuals, controlling for relatedness in the mapping analysis may not be sufficient to control for genetic structure. These possibilities should be probed further, and even if they don't affect the results, the supporting analyses should be shown.

    Finally, the most interesting results surround the mapping and genetic architecture results, especially the possibility that genetic architecture predicts phylosymbiosis. However, the results section feels asymmetrically focused on the descriptive results of many different enrichment analyses. While these kinds of analyses can provide context, the paper would benefit from sharpening, and potentially shortening, this section, especially where the motivation for a given analysis is unclear.

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  3. Reviewer #2 (Public Review):

    This study maps the genetic determinants of gut microbiota composition through laboratory crossing experiments using two subspecies of mice: Mus musculus domesticus and Mus musculus musculus.

    A major strength of the study is the generation of a large experimental population of mice reared under controlled conditions, providing unprecedented resolution for identifying associations between host genotype and the microbiota. In contrast to previous mouse microbiota QTL mapping studies, this work uses relatively outbred and genetically diverse mouse lines, thereby capturing a higher levels of genetic variation and providing greater power to detect genotype-microbiota associations.

    Another strength of the work is its focus on mucosal associated microbiota, as these communities are expected to be most affected by direct interactions with host cells and their products. Previous work in this area has focused only on either fecal or cecal microbiota.

    The molecular and statistical methods employed were appropriate to address the questions posed, and the results supported the study's conclusions.

    Cumulatively, this study provides a list of mammalian genomic loci that appear to influence the composition of the gut microbiota, including several loci associated with human diseases. Identification of these candidates set the stage for future functional genetics studies that employ gene editing approaches to directly test host genotype-microbiota interactions.

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  4. Reviewer #3 (Public Review):

    This is an interesting study by Doms et al., reporting on using inbred mouse lines to genetically map loci in the mouse genome that are associated with the composition of the microbiome.

    The study has several strengths:: it focuses on the mucosa-associated microbiome, which more directly interacts with host cells, while previous studies used fecal microbiome data. In addition, the correlation between heritability estimates and cospeciation rate estimates is a novel result. The finding that ​​16S rRNA transcript profiling allows for detecting more heritable taxa is also a relevant result that will be interesting for the field.

    Although the study is important, there is one major point of concern, relating to the heritability estimates reported in the paper. The heritability results may be a bit surprising considering the current knowledge and literature: the heritability values are very high, with several values around 90% or higher. This is unexpected, and I am not sure how this is reconciled with the expectation that most variation in the microbiome is environmental rather than genetic. Although some potential reasons are given in the Discussion (mice raised in a controlled environment, using cecal content, etc), these values are substantially higher than can be expected.

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