The amino-acid mutational spectrum of human genetic disease

Genome Biol. 2003;4(11):R72. doi: 10.1186/gb-2003-4-11-r72. Epub 2003 Oct 30.


Background: Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.

Results: We find that the disease spectrum correlates well with the amino-acid mutation frequencies based on the genetic code. Normalized by the mutation frequencies, the spectrum can be rationalized in terms of chemical similarities between amino acids. The disease spectrum is almost identical for membrane and non-membrane proteins. Mutations at arginine and glycine residues are together responsible for about 30% of genetic diseases, whereas random mutations at tryptophan and cysteine have the highest probability of causing disease.

Conclusions: The overall disease spectrum mainly reflects the mutability of the genetic code. We corroborate earlier results that the probability of a nonsynonymous mutation causing a genetic disease increases monotonically with an increase in the degree of evolutionary conservation of the mutation site and a decrease in the solvent-accessibility of the site; opposite trends are observed for non-disease polymorphisms. We estimate that the rate of nonsynonymous mutations with a negative impact on human health is less than one per diploid genome per generation.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Amino Acids / genetics*
  • Gene Frequency
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology
  • Genetic Variation
  • Humans
  • Mutation*
  • Polymorphism, Single Nucleotide


  • Amino Acids