Genetic adaptation of the antibacterial human innate immunity network

Abstract

BackgroundPathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection.ResultsHere, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection.ConclusionsWe found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

Survey of Global Genetic Diversity Within theDrosophilaImmune System

“…While we have not shown that this variation drives changes in pathogen recognition, previous lines of evidence suggest that the variation in recognition receptors does carry phenotypic effects. First, this observation is in line with theoretical predictions that recognition molecules serve as the main locus of host-pathogen coevolution (Nuismer and Dybdahl 2016) and with observations in mice that upstream initiation genes are more likely to undergo positive selection (Casals et al 2011;Webb et al 2015). Second, past quantitative genetic studies in Drosophila have suggested that natural variation in immune resistance is largely driven by polymorphisms in recognition and, to a lesser extent, signaling genes (Lazzaro et al 2006;Sackton et al 2010).…”

Natural Selection in the Great Apes

“…We also find evidence for pervasive positive selection on immune-related processes, as seen in H. sapiens and other Hominidae before (Mikkelsen et al 2005; Cagliani et al 2010; Casals et al 2011). MK, HKA and FWH candidate targets of positive selection all are significantly enriched in genes related to immune response (supplementary tables S16–55, S75–86 and S99, Supplementary Material online).…”

Innate Immune Function by Toll-like Receptors: Distinct Responses in Newborns and the Elderly

“…Genetic defects of pattern recognition probably manifest themselves throughout life as limited, focused immunodeficiencies (Casanova and Abel, 2007; Netea et al, 2011b). On the basis of the paradigm of evolutionary purifying selection (Casals et al, 2011), one would predict that genetic programs of innate immune ontogeny more likely direct developmental patterns in early rather than late life. Indeed, the influence of genetic programs in early life can readily be identified in the strong influence of family history of atopy on lower IL-12p70 responses in infants suffering from allergy and asthma (Gabrielsson et al, 2001; Nilsson et al, 2004; van den Biggelaar et al, 2009).…”