Molecular population genetics of the gene encoding the human fertilization protein zonadhesin reveals rapid adaptive evolution

Am J Hum Genet. 2006 Nov;79(5):820-30. doi: 10.1086/508473. Epub 2006 Sep 15.


A hallmark of positive selection (adaptive evolution) in protein-coding regions is a d(N)/d(S) ratio >1, where d(N) is the number of nonsynonymous substitutions/nonsynonymous sites and d(S) is the number of synonymous substitutions/synonymous sites. Zonadhesin is a male reproductive protein localized on the sperm head, comprising many domains known to be involved in cell-cell interaction or cell adhesion. Previous studies have shown that VWD domains (homologous to the D domains of the von Willebrand factor) are involved directly in binding to the female zona pellucida (ZP) in a species-specific manner. In this study, we sequenced 47 coding exons in 12 primate species and, by using maximum-likelihood methods to determine sites under positive selection, we show that VWD2, membrane/A5 antigen mu receptor, and mucin-like domains in zonadhesin are rapidly evolving and, thus, may be involved in binding to the ZP in a species-specific manner in primates. In addition, polymorphism data from 48 human individuals revealed significant polymorphism-to-divergence heterogeneity and a significant departure from equilibrium-neutral expectations in the frequency spectrum, suggesting balancing selection and positive selection occurring in zonadhesin (ZAN) within human populations. Finally, we observe adaptive evolution in haplotypes segregating for a frameshift mutation that was previously thought to indicate that ZAN was a potential pseudogene.

Publication types

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

MeSH terms

  • Animals
  • Evolution, Molecular*
  • Exons
  • Female
  • Genetics, Population
  • Humans
  • Introns
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Molecular Sequence Data
  • Phylogeny
  • Polymorphism, Genetic
  • Primates / genetics
  • Protein Structure, Tertiary
  • Selection, Genetic
  • Species Specificity
  • Spermatozoa / chemistry
  • Spermatozoa / physiology


  • Membrane Proteins
  • zonadhesin

Associated data

  • GENBANK/AY046055
  • GENBANK/DQ383284
  • GENBANK/DQ383285
  • GENBANK/DQ383286
  • GENBANK/DQ383287
  • GENBANK/DQ383288
  • GENBANK/DQ383289
  • GENBANK/DQ383290
  • GENBANK/DQ383291
  • GENBANK/DQ383292
  • GENBANK/DQ383293
  • GENBANK/DQ383294
  • OMIM/602372