Pathogen selection drives nonoverlapping associations between HLA loci

Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19645-50. doi: 10.1073/pnas.1304218110. Epub 2013 Nov 13.

Abstract

Pathogen-mediated selection is commonly invoked as an explanation for the exceptional polymorphism of the HLA gene cluster, but its role in generating and maintaining linkage disequilibrium between HLA loci is unclear. Here we show that pathogen-mediated selection can promote nonrandom associations between HLA loci. These associations may be distinguished from linkage disequilibrium generated by other population genetic processes by virtue of being nonoverlapping as well as nonrandom. Within our framework, immune selection forces the pathogen population to exist as a set of antigenically discrete strains; this then drives nonoverlapping associations between the HLA loci through which recognition of these antigens is mediated. We demonstrate that this signature of pathogen-driven selection can be observed in existing data, and propose that analyses of HLA population structure can be combined with laboratory studies to help us uncover the functional relationships between HLA alleles. In a wider coevolutionary context, our framework also shows that the inclusion of memory immunity can lead to robust cyclical dynamics across a range of host-pathogen systems.

Keywords: human evolution; infectious disease; major histocompatibility complex; mathematical model; population genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics
  • Animals
  • Biological Evolution*
  • Ethnic Groups / genetics
  • Genetics, Population / methods*
  • HLA Antigens / genetics*
  • Histocompatibility Antigens / genetics*
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Linkage Disequilibrium
  • Models, Biological*
  • Selection, Genetic*

Substances

  • HLA Antigens
  • Histocompatibility Antigens