Evolutionary insights into host–pathogen interactions from mammalian sequence data

Key Points

• Infections are possibly the major selective pressure acting on humans, and host–pathogen interactions contribute to shaping the genetic diversity of both organisms.

• Comparisons among species provide a snapshot of selective events that have been unfolding over long timescales. These approaches use extant genetic diversity and phylogenetic relationships among species to identify positively selected sites.

• Positive selection often acts on a limited number of sites in a protein that is otherwise selectively constrained; one example is the localized signal of selection at Niemann–Pick C1 protein (NPC1), the receptor for the Ebola virus.

• As epitomized by the evolutionary history of tripartite motif-containing 5 ( TRIM5), past infection events may leave a signature that affects the ability of extant species to fight emerging pathogens.

• Protein regions at the host–pathogen interface are expected to be targeted by the strongest selective pressure (this is the case for dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme 2 (ACE2), which act as receptors for coronaviruses).

• Other mammals host a wide range of viruses that are highly pathogenic for humans. Sequencing the genomes of these pathogens will be instrumental in refining our understanding of the process of host–pathogen interaction.

• Pathogen-driven natural selection is not limited to the immune system: genes that encode incidental pathogen receptors and components of the contact system and coagulation cascade can also be targeted.

Supplementary information

The online version of this article (doi:10.1038/nrg3905) contains supplementary material, which is available to authorized users.

Abstract

Host–pathogen interactions influence genetic diversity, and comparative genomic analyses are beginning to dissect genetic determinants involved in this process. This Review describes examples of such host–pathogen interactions and outline evolutionary approaches that are useful for identifying genomic regions associated with susceptibility to infection in mammals.

Supplementary information

The online version of this article (doi:10.1038/nrg3905) contains supplementary material, which is available to authorized users.

Abstract

Infections are one of the major selective pressures acting on humans, and host-pathogen interactions contribute to shaping the genetic diversity of both organisms. Evolutionary genomic studies take advantage of experiments that natural selection has been performing over millennia. In particular, inter-species comparative genomic analyses can highlight the genetic determinants of infection susceptibility or severity. Recent examples show how evolution-guided approaches can provide new insights into host–pathogen interactions, ultimately clarifying the basis of host range and explaining the emergence of different diseases. We describe the latest developments in comparative immunology and evolutionary genetics, showing their relevance for understanding the molecular determinants of infection susceptibility in mammals.

Supplementary information

The online version of this article (doi:10.1038/nrg3905) contains supplementary material, which is available to authorized users.