The Red Queen's long race: human adaptation to pathogen pressure

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Pathogens, and the infectious diseases they cause, have been paramount among the threats encountered by humans in their expansions throughout the globe. Numerous studies have identified immunity and host defence genes as being among the functions most strongly targeted by selection, most likely pathogen-driven. The dissection of the form and intensity of such selective pressures have increased our knowledge of the biological relevance of the underlying immunological mechanisms in host defence. Although the identities of the specific infectious agents imposing these selective pressures remain, in most cases, elusive, the impact of several pathogens, notably malaria and cholera, has been described. However, past selection against infectious diseases may have some fitness costs upon environmental changes, potentially leading to maladaptation and immunopathology.

Introduction

“Now, here, you see, it takes all the running you can do, to keep in the same place.”

The words of the Red Queen to Alice in Lewis Carroll's Through the Looking Glass [1] reflect the need for species to continually evolve in the face of competition and changing environments, most notably pathogen presence. This competition leads to an evolutionary arms race, driving constant adaptation and counter-adaptation of competing species, as predicted by the Red Queen hypothesis [2].

Throughout their history, humans have co-existed and co-evolved with a wide range of microorganisms, both pathogenic and harmless, shaping genetic variation in both populations today. In humans, the study of biological adaptation has entered a golden era with the availability of genome-wide (GW) datasets, such as those provided by the HapMap project and the 1000 Genomes project [3, 4]. This has enabled the evaluation of the extent of selection acting on the genome and the occurrence of genetic adaptation to environmental pressures, with an unprecedented level of resolution. Likewise, improvements in statistical methods to detect the different forms that selection can take [5••] (Figure 1) have helped to separate the confounding effects of demography and selection and to elucidate the evolutionary trajectories involved in human adaptation. In this review, we explore the human side of the long race predicted by the Red Queen hypothesis. We highlight both the benefits and trade-offs of past selection against infectious diseases, and discuss the challenge of pinpointing the microbial agents exerting a selective pressure.

Section snippets

Pathogen pressure and human genome diversity

The pressure imposed by pathogens has been massive throughout human evolution. Before the advent of vaccines and antibiotics at the beginning of the 20th century  ‘yesterday’ from an evolutionary standpoint  diseases killed half of all children by the age of 15 and resulted in an average life expectancy of around 20 years [6] (Figure 2). It is thus not surprising that genes and functions related to immunity and host defence are among those exhibiting the strongest signatures of selection [7, 8, 9

Learning immunology through population genetics

An increased understanding of the degree of essentiality, redundancy or adaptability of immunity genes can be obtained from the dissection of the form and intensity of selection that these genes have been subject to over time. The additional insight brought by the integration of such selection studies into a clinical and epidemiological framework has established the value of population genetics in delineating the biological relevance of immunity genes in natura, and in predicting their

Adaptation and maladaptation in human transitions

Human history has been characterised by a series of shifts  geographic, temporal and cultural  that have exposed populations to changes in pathogen load. Analysing the degree of selective pressure exerted by pathogens during specific periods of human evolution can inform our understanding of the nature of such pathogenic challenges and the components of the immune system that have been crucial for pathogen resistance. However, adaptation to a given pathogenic challenge at a given time may no

Can we identify the agent(s) underlying pathogen-driven selection?

Though correlation studies strongly support pathogen-driven selection, identifying the specific pathogen(s) exerting pressure on host genes remains arduous. Our power to detect these specific effects, and the most appropriate strategy by which to do so, depends on numerous host-related and pathogen-related factors including the length of exposure, virulence and genetic diversity of the pathogen [9]. As such, the soundest evidence so far comes from pathogens that have had strong, enduring

The quest for adaptive immune phenotypes

The ultimate goal of selection studies is to uncover the organismal phenotypes that have conferred a selective advantage. In immunity, clues can be obtained from association studies; positively selected SNPs that are associated with infectious disease risk, for example, could help to delineate the underlying immunological mechanisms (Figure 3). However, progress in the area of GW association studies (GWAs) of infectious diseases has been much slower than for other complex diseases [59, 60].

Conclusion

Over the past few years, much has been learnt about the intensity of pathogen pressures on the human genome, and about genes and mechanisms that have contributed to human adaptation to variable pathogen loads. However, our understanding of the long arms race between the human host and our ever-present pathogenic neighbours remains far from complete. The detection of adaptive events related to infectious pressure, as well as other environmental variables, is most likely underestimated, as most

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The laboratory of LQ-M has received funding from the Institut Pasteur, the Centre Nationale de la Recherche Scientifique (CNRS), the French government's Investissement d’Avenir program, Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (grant no. ANR-10-LABX-62-IBEID), and the European Research Council under the European Union's Seventh Framework Programme (FP/2007–2013)/ERC grant agreement no. 281297. KJS is a scholar of the Pasteur-Paris University (PPU)

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