Of genes and microbes: solving the intricacies in host genomes

Abstract

Microbiome research is a quickly developing field in biomedical research, and we have witnessed its potential in understanding the physiology, metabolism and immunology, its critical role in understanding the health and disease of the host, and its vast capacity in disease prediction, intervention and treatment. However, many of the fundamental questions still need to be addressed, including the shaping forces of microbial diversity between individuals and across time. Microbiome research falls into the classical nature vs. nurture scenario, such that host genetics shape part of the microbiome, while environmental influences change the original course of microbiome development. In this review, we focus on the nature, i.e., the genetic part of the equation, and summarize the recent efforts in understanding which parts of the genome, especially the human and mouse genome, play important roles in determining the composition and functions of microbial communities, primarily in the gut but also on the skin. We aim to present an overview of different approaches in studying the intricate relationships between host genetic variations and microbes, its underlying philosophy and methodology, and we aim to highlight a few key discoveries along this exploration, as well as current pitfalls. More evidence and results will surely appear in upcoming studies, and the accumulating knowledge will lead to a deeper understanding of what we could finally term a "hologenome", that is, the organized, closely interacting genome of the host and the microbiome.

Keywords: gene-microbiome association; gut microbiota; host genetics; quantitative genetics.

Figure 1

A simplified illustration of the host gene-microbiome interactions at the interface of various types of epithelia. The mucosal layer of the GI tract, airway, skin surface and reproductive tract surface are the primary interfaces of host-microbe interactions. Those microbes that we consider as beneficial usually produce nutrients, essential functional molecules and maintain the normal functions of the immune systems; thus the primary aim of host genes is to ensure their immune tolerance and facilitate their growth by secreting mucus, etc. as substrates. While harmful bacteria usually produce toxins, pro-inflammatory molecules and lead to infections, the host genes must clear them from the normal community and defend against inflammation and infections

Figure 2

Schematic overview of quantitative trait loci (QTL, panel A) and genome-wide-association studies (GWAS, panel B). Both work on genetic variations, but result from different processes, either by intentional crosses (QTL) or extant (GWAS), and the linkage blocks are of a different size due to the number of recombinations. Association tests were carried out for SNPs and interpolated for a region in QTL analysis, while in GWAS it is done for each SNP and a “peak” in the Manhattan plot indicates a haplotype that might be significantly associated with the trait. In both cases, usually the P-values were transformed into −log(P) to indicate the significance level, and the genome-wide significance for QTL is usually determined by permutation tests. For GWAS, it is commonly accepted to be set at 1E−08 to 5E−08

Figure 3

Overview of microbiome QTL in mouse and GWAS in humans to date. Left half shows the six QTLs in mice, coloured by different studies and the confidence intervals are marked on the mouse chromosome. Please note that Belheouane and Srinivas studies are skin microbiome QTLs. The right half shows the genes implicated in human GWAS, including UK Twins, FoCus/PopGen (both original publication and later with modified methods), LifeLines-DEEP and GEM studies. Links in the middle show potential overlapping genes that showed up in human GWASs and fall into a confidence interval in mouse QTLs, which might be supportive of each other in terms of the association with microbiome variations