Detecting coevolution through allelic association between physically unlinked loci

Am J Hum Genet. 2010 May 14;86(5):674-85. doi: 10.1016/j.ajhg.2010.03.001. Epub 2010 Apr 8.


Coevolving interacting genes undergo complementary mutations to maintain their interaction. Distinct combinations of alleles in coevolving genes interact differently, conferring varying degrees of fitness. If this fitness differential is adequately large, the resulting selection for allele matching could maintain allelic association, even between physically unlinked loci. Allelic association is often observed in a population with the use of gametic linkage disequilibrium. However, because the coevolving genes are not necessarily in physical linkage, this is not an appropriate measure of coevolution-induced allelic association. Instead, we propose using both composite linkage disequilibrium (CLD) and a measure of association between genotypes, which we call genotype association (GA). Using a simple selective model, we simulated loci and calculated power for tests of CLD and GA, showing that the tests can detect the allelic association expected under realistic selective pressure. We apply CLD and GA tests to the polymorphic, physically unlinked, and putatively coevolving human gamete-recognition genes ZP3 and ZP3R. We observe unusual allelic association, not attributable to population structure, between ZP3 and ZP3R. This study shows that selection for allele matching can drive allelic association between unlinked loci in a contemporary human population, and that selection can be detected with the use of CLD and GA tests. The observation of this selection is surprising, but reasonable in the highly selected system of fertilization. If confirmed, this sort of selection provides an exception to the paradigm of chromosomal independent assortment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Egg Proteins / genetics*
  • Genotype
  • Humans
  • Linkage Disequilibrium*
  • Membrane Glycoproteins / genetics*
  • Polymorphism, Genetic
  • Receptors, Cell Surface / genetics*
  • Zona Pellucida Glycoproteins


  • Egg Proteins
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • ZP3 protein, human
  • Zona Pellucida Glycoproteins
  • egg surface sperm receptor