Population genetic tools for dissecting innate immunity in humans

Abstract

Innate immunity involves direct interactions between the host and microorganisms, both pathogenic and symbiotic, so natural selection is expected to strongly influence genes involved in these processes. Population genetics investigates the impact of past natural selection events on the genome of present-day human populations, and it complements immunological as well as clinical and epidemiological genetic studies. Recent data show that the impact of selection on the different families of innate immune receptors and their downstream signalling molecules varies considerably. This Review discusses these findings and highlights how they help to delineate the relative functional importance of innate immune pathways, which can range from being essential to being redundant.

Figure 1. Types of selection and their legacy on the human genome.

The evolutionary fate of different types of mutations is represented in a sample of eight chromosomes. Blue circles indicate neutral polymorphisms. a | Purifying selection removes deleterious alleles (indicated by black circles) from the population. The pace at which deleterious mutations are purged from the population depends on their effect on host survival, which can range from lethal (immediately removed from the population) to mildly deleterious (tolerated but kept at low population frequencies). These mutations tend to be associated with rare, severe disorders (for example, Mendelian susceptibility to infection at the individual level). b | Positive selection increases the frequency of an advantageous mutation (indicated by a red circle) in the population. Advantageous mutations can be fixed (completed selective sweep) or polymorphic (ongoing selective sweep; not shown) in the population. Positively selected mutations are often associated with common traits (for example, higher resistance to infection at the population level), which present complex modes of inheritance. c | Balancing selection maintains polymorphism in the population as a result of heterozygote advantage and frequency-dependent advantage (not shown). In the illustrated example, a mutation (indicated by a purple circle) confers a selective advantage at the heterozygote state, so individuals who are heterozygous at this particular position (for example, individuals who possess the anaemia-associated haemoglobin D (HbS) allele sickle-cell variant and are exposed to Plasmodium falciparum) have a greater fitness than homozygous individuals.

Figure 2. Evolutionary dynamics and biological relevance of innate immunity genes.

Genes that have undergone purifying selection are shown in red, and those that have evolved under weaker selective constraints are shown in blue. Genes for which no significant evidence of a selective constraint was observed are shown in grey. Colours reflect the intensity of the selective constraints on amino acid-altering variation, as obtained by the McDonald–Kreitman Poisson random field method McDonald-Kretiman Poisson random field method (omega and gamma) (Box 2). Genes presenting robust signatures of positive selection in all humans are outlined with a thick black line, whereas genes presenting robust signatures of positive selection that are restricted to specific human populations are outlined with a dashed black line. Endosomal Toll-like receptors (TLRs) show signs of stronger purifying selection than do cell-surface TLRs. Myeloid differentiation primary response protein 88 (MYD88) is the TLR adaptor molecule that has evolved under the strongest purifying selection, which indicates its central role as a pan-adaptor molecule. Furthermore, all adaptors have been targeted by positive selection, either in the entire human lineage (MYD88 and sterile alpha and TIR motif-containing protein (SARM)) or in specific human populations (TIR domain-containing adapter molecule 1 (TRIF), TIR domain-containing adapter molecule 2 (TRAM) and Toll/interleukin-1 receptor domain-containing adapter protein (MAL)), suggesting advantages in terms of immunity that are shared by all humans or that are due to geographically restricted microbial exposure, respectively. Purifying selection has driven the evolution of most NACHT, LRR and pyrin domain-containing proteins (NALPs), whereas other cytosolic microbial sensors, such as the NOD-like receptors (NLRs), Ice protease-activating factor (IPAF) and MHC class II transactivator (CIITA) and most NOD subfamily members, as well as the RIG-I-like receptors (RLRs), have evolved under weaker constraints. NLR family, apoptosis inhibitory protein (NAIP) is not represented in the figure as no population genetic data are available. DAMPs, damage-associated molecular pattern molecules; HA, haemagglutinin; IFNs, interferons; IRFs, IFN-regulatory factors; LAM, lipoarabinomannan; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MAPK, mitogen-activated protein kinase; MDA5, melanoma differentiation-associated protein 5; NF-κB, nuclear factor-κB; NLRC, NLR family CARD domain containing; NLRX1, NLR family member X1; NOD, nucleotide-binding oligomerization domain-containing; PG, peptidoglycan; PLM, phospholipomannan; RIG-I, retinoic acid-inducible gene I protein; tGPI, Trypanosoma cruzi-derived glycosylphosphatidylinositol.

Figure 3. Major differences in selective pressures characterize the evolution of the human interferon families.

a | Type I, type II and type III interferons (IFNs) display different levels of functional diversity. The circles represent the proportion of chromosomes for each IFN subtype carrying different types of functional variants in the general population. For each circle, the proportion of chromosomes carrying at least one non-synonymous polymorphism is shown in red, and the proportion carrying at least one nonsense polymorphism is shown in black. The blue segment corresponds to the proportion of chromosomes carrying neither non-synonymous nor nonsense polymorphisms. The IFN subtypes in boxes are those for which statistical significance of strong purifying selection was obtained^,. A schematic representation of the signalling pathways activated by the interaction of type I, type II and type III IFNs with their corresponding receptors is also presented. b | Type III IFNs are the only group of IFNs that have evolved under the action of positive selection, specifically in European and Asian populations. The scheme shows the distribution of the genetic variants under positive selection across the genomic region in which the three type III IFN genes are located. Note that one of the positively selected single-nucleotide polymorphisms (SNPs) in the interleukin-28B (IL28B) region (SNP −3180A>G, rs12979860) has been recently found to lay within the newly discovered IFNL4 gene, which is located upstream of IL28B. Highlighted mutations result in amino acid changes, whereas the rest are non-coding SNPs. Signatures of positive selection were detected in Asia for the variants in IL28A and IL28B, and in both Asia and Europe for that in IL29. Figure is modified from Ref. . GAS, IFNγ-activated site; IFNAR, IFNα/β receptor; IFNγR, IFNγ receptor; IFNλR1, IFNλ receptor 1 (also known as IL-28Rα); IL-10Rβ, IL-10 receptor-β; IRF9, IFN regulatory factor 9; ISRE, interferon-stimulated response element; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase.