The role of the microbiota in human genetic adaptation

Getting to the guts of local evolution The microbiota of mammals is a product of coevolution. However, humans exhibit a range of adaptive peculiarities that can be quite geographically specific. The human microbiota also displays a variety of community compositions and a range of overlapping and redundant metabolic characteristics that can alter host physiology. For example, lactase persistence is a genetic characteristic of European populations, but in populations lacking the lactase gene, milk sugar digestion is endowed by the microbiota instead. Suzuki and Ley review the evidence for the role that the microbiota plays in local adaptation to new and changing human circumstances. Science, this issue p. eaaz6827 BACKGROUND When human populations expanded across the globe, they adapted genetically to local environments in response to novel selection pressures. Drivers of selection include exposure to new diets, climates, or pathogens. Humans harbor microbiotas that also respond to changes in local conditions and changes in their hosts. As a result, microbiotas may alter the adaptive landscape of the host through modification of the environment. Examples include changes to a food’s nutritional value, the host’s tolerance to cold or low amounts of oxygen, or susceptibility to invading pathogens. By buffering or altering drivers of selection, the microbiota may change host phenotypes without coevolution between host and microbiota. Functions of the microbiota that are beneficial to the host may arise randomly or be acquired from the environment. These beneficial functions can be selected without the host exerting genetic control over them. Hosts may evolve the means to maintain beneficial microbes or to pass them to offspring, which will affect the heritability and transmission modes of these microbes. Examples in humans include the digestion of lactose via lactase activity (encoded by the LCT gene region) in adults and the digestion of starch by salivary amylase (encoded by the AMY1 gene)—both are adaptations resulting from shifts in diet. The allelic variation of these genes also predicts compositional and functional variation of the gut microbiota. Such feedback between host alleles and microbiota function has the potential to influence variation in the same adaptive trait in the host. How the microbiota modifies host genetic adaptation remains to be fully explored. ADVANCES In this paper, we review examples of human adaptations to new environments that indicate an interplay between host genes and the microbiota, and we examine in detail the LCT–Bifidobacterium and the AMY1–Ruminococcus interactions. In these examples, the adaptive host allele and adaptive microbial functions are linked. We propose host mechanisms that can replace or recruit beneficial microbiota functions during local adaptation. Finally, we search for additional examples where microbiotas are implicated in human genetic adaptations, in which the genetic basis of adaptation is well described. These range from dietary adaptations, where host and microbial enzymes can metabolize the same dietary components (e.g., fatty acid and alcohol metabolism), through climate-related adaptations, where host and microbes can induce the same physiological pathway (e.g., cold-induced thermogenesis, skin pigmentation, and blood pressure regulation), to adaptations where hosts and microbes defend against the same local pathogens (e.g., resistance to malaria, cholera, and others). These examples suggest that microbiota has the potential to affect host evolution by modifying the adaptive landscape without requiring coevolution. OUTLOOK Well-studied examples of local adaptation across diverse host species can be revisited to elucidate previously unappreciated roles for the microbiota in host-adaptive evolution. In the context of human adaptation, knowledge of microbial functions and host gene–microbe associations is heavily biased toward observations made in Western populations, as these have been the most intensively studied to date. Testing many of the interactions proposed in this Review between host genes under selection and the microbiota will require a wider geographic scope of populations in their local contexts. Because genes under strong selection in humans are often involved in metabolic and other disorders and can vary between populations, future investigations of host gene–microbe interactions that relate to human adaptation may contribute to a deeper understanding of microbiota-related diseases in specific populations. Investigating host gene–microbe interactions in a wider variety of human populations will also help researchers go beyond collections of anecdotes to form the basis of a theory that takes microbial contributions to host adaptation into account in a formal framework. A better understanding of reciprocal interactions between the host genome and microbiota in the context of adaptive evolution will add another dimension to our understanding of human evolution as we moved with our microbes through time and space. Local adaptation by humans and their microbiotas. When human populations adapt genetically to new environments, their microbiotas may also participate in the process. Microbes can evolve faster than their host, which allows them to respond quickly to environmental change. They also filter the host’s environment, thereby altering selective pressures on the host. Illustrated here are examples of interactions between adaptive host alleles and adaptive microbiota functions where the microbiota likely modified the adaptive landscape in response to changes in diet (e.g., changes in levels of starch and milk consumption), exposure to local pathogens (e.g., malaria parasites and Plasmodium spp.), and changes in local climate (e.g., cold stress and hypoxia). In this paper, we discuss the resulting relationships between host-adaptive alleles and microbiota functions. GRAPHIC: DAPHNE WELTER As human populations spread across the world, they adapted genetically to local conditions. So too did the resident microorganism communities that everyone carries with them. However, the collective influence of the diverse and dynamic community of resident microbes on host evolution is poorly understood. The taxonomic composition of the microbiota varies among individuals and displays a range of sometimes redundant functions that modify the physicochemical environment of the host and may alter selection pressures. Here we review known human traits and genes for which the microbiota may have contributed or responded to changes in host diet, climate, or pathogen exposure. Integrating host–microbiota interactions in human adaptation could offer new approaches to improve our understanding of human health and evolution.