Evolution of the TIR domain-containing adaptors in humans: swinging between constraint and adaptation

Mol Biol Evol. 2011 Nov;28(11):3087-97. doi: 10.1093/molbev/msr137. Epub 2011 Jun 9.


Natural selection is expected to act strongly on immune system genes as hosts adapt to novel, diverse, and coevolving pathogens. Population genetic studies of host defense genes with parallel functions in model organisms have revealed distinct evolutionary histories among the different components-receptors, adaptors, and effectors-of the innate immune system. In humans, however, detailed evolutionary studies have been mainly confined to the receptors and in particular to Toll-like receptors (TLRs). By virtue of a toll/interleukin-1 receptor (TIR) domain, TLRs activate distinct signaling pathways, which are mediated by the five TIR-containing adaptors: myeloid differentiation factor-88 (MyD88), myeloid differentiation factor-88 adaptor-like protein (MAL), toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon (IFN)β (TRIF), toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNβ-related adaptor molecule (TRAM), and sterile α- and armadillo motif-containing protein (SARM). Here, we have examined the extent to which natural selection has affected immune adaptors in humans, using as a paradigm the TIR-containing adaptors. To do so, we characterized their levels of naturally occurring genetic variation in various human populations. We found that MyD88 and TRIF have mainly evolved under purifying selection, suggesting that their role in the early stages of signal transduction is essential and nonredundant for host survival. In addition, the adaptors have been targeted by multiple episodes of positive selection, differing in timing and spatial location. MyD88 and SARM display signatures of a selective sweep that has occurred in all humans, whereas for the other three adaptors, we detected signatures of adaptive evolution that are restricted to specific populations. Our study provides evidence that the contemporary diversity of the five TIR-containing adaptors results from the intermingling of different selective events, swinging between constraint and adaptation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Biological / genetics
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Vesicular Transport / genetics*
  • Analysis of Variance
  • Animals
  • Armadillo Domain Proteins / genetics*
  • Base Sequence
  • Bayes Theorem
  • Cluster Analysis
  • Computer Simulation
  • Cytoskeletal Proteins / genetics*
  • Genetic Variation*
  • Haplotypes / genetics
  • Humans
  • Immunity, Innate / genetics*
  • Membrane Glycoproteins / genetics*
  • Models, Genetic
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88 / genetics*
  • Pan troglodytes / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Interleukin-1 / genetics*
  • Receptors, Interleukin-1 / metabolism
  • Selection, Genetic*
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1
  • SARM1 protein, human
  • TICAM1 protein, human
  • TICAM2 protein, human
  • TIRAP protein, human
  • Toll-Like Receptors