Mechanisms of Mendelian dominance

Clin Genet. 2018 Mar;93(3):419-428. doi: 10.1111/cge.13107. Epub 2017 Oct 26.


Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non-linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Dominance can also be due to the presence of a heterozygous null allele, as is the case of haploinsufficiency. Dominance can also be influenced by epistatic (interloci) interactions. For instance, a pre-existing genetic variant can make possible the expression of a pathogenic variant in a seemingly "dominant" fashion. Such interactions, which can make an individual more or less sensitive to a particular pathogenic variant, will also be discussed here.

Keywords: cooperativity; dominant negative mutations; gain-of-function; haploinsufficiency; loss-of-function; macromolecular complexes; transcriptional synergy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Epistasis, Genetic
  • Gene Dosage
  • Genes, Dominant*
  • Genetic Association Studies*
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / metabolism
  • Genomics / methods
  • Genotype*
  • Haploinsufficiency
  • Humans
  • Inheritance Patterns*
  • Mutation
  • Phenotype*