Abstract
The human microbiome is a complex ecosystem of microorganisms that inhabit the human body and have a crucial role in human health. Microbiome composition is shaped by its interaction with many factors, including human genetics. Advances in genomic technologies are improving the ability to quantify the effect of human genetics on the microbiome through improved heritability studies and microbiome genome-wide association studies (GWAS). Complementary studies using transcriptomic analyses are providing a more comprehensive view of the bidirectional relationship between host gene expression and the microbiome. The resulting insights into the genetic mechanisms driving host–microbiome interactions will ultimately contribute to the development of personalized medicine and targeted therapies.
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Acknowledgements
The authors thank T. Vilgalys, R. Abdill and members of the Blekhman laboratory for their valuable feedback. R.B. acknowledges funding from National Institutes of Health (NIH) grants R35-GM128716 and R01-HD109830. K.J. acknowledges funding from NIH grants K99-HD113834 and R01-HD109830. S.P. acknowledges funding from the Duchossois Family Institute Fellowship (Chicago Fellows programme) at the University of Chicago.
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Glossary
- 16S rRNA gene amplicon sequencing
-
A targeted sequencing approach that amplifies and sequences regions of the 16S ribosomal RNA gene, which is present in the genomes of all bacteria. This method enables taxonomic profiling of microbial communities without sequencing entire genomes, allowing for a cost-effective way to characterize the taxonomic composition of microbiome samples.
- Alpha diversity
-
A measure of microbial community complexity within a single sample, quantifying the number of different species and their relative abundances. Alpha-diversity metrics can be used to assess how factors such as genetics, diet and disease affect the ecological structure of microbial communities.
- Beta diversity
-
A measure of the difference in microbial community composition between two or more samples. Beta-diversity metrics quantify how samples differ from each other in terms of which microorganisms are present and their relative abundances, allowing the quantification of microbiome variation across conditions, environments and host factors.
- Heritability
-
The proportion of phenotypic variation in a population that can be attributed to genetic differences; heritability is expressed as a value between 0 and 1, where 0 indicates that none of the observed variation is due to genetic factors and 1 indicates that all variation is genetic.
- Quantitative trait locus
-
A specific region of DNA that contributes to variation in a measurable characteristic or quantitative trait, such as height, blood pressure or disease susceptibility. In microbiome research, quantitative trait locus mapping identifies host genetic regions that influence microbial community features, revealing how host genetic variation shapes microbiome composition.
- Shotgun metagenomic sequencing
-
A comprehensive sequencing technique that sequences all DNA found in a microbiome sample, which enables the capture of genomic information from bacteria, archaea, viruses and fungi found in a microbial community. Unlike 16S rRNA amplicon sequencing, shotgun metagenomic sequencing provides information on not only the taxonomic composition but also the functional potential, gene composition and genetic variation within microbial communities.
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Ferretti, P., Johnson, K., Priya, S. et al. Genomics of host–microbiome interactions in humans. Nat Rev Genet (2025). https://doi.org/10.1038/s41576-025-00849-8
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DOI: https://doi.org/10.1038/s41576-025-00849-8
