A functional significance for codon third bases

Most amino acids are specified by more than one trinucleotide codon. Here w e show that amino acids of differing functional importance may be distingui shed by the pattern of synonymous codon usage. GC-rich genes tend to be of a greater transcriptional (p <0.01) and mitogenic (p <0.0001) significance than AT-rich genes, consistent with GC-->AT mutational drift in methylated genomic regions. Third-base GC retention also identifies critical amino aci ds within individual proteins, as indicated by nonrandom patterns of codon variation between gene homologs and also by differential sequelae of site-d irected mutagenesis, Sequence analysis of human receptor tyrosine kinase ge nes confirms that functionally important transmembrane hydrophobic amino ac ids are specified by codons containing GC third bases more often than are t ransmembrane neutral amino acids (chi(2) = 134.2). Amino acids encoded by G C third bases thus appear more tightly linked to cell function and survival than are those encoded by AT third bases. (C) 2000 Elsevier Science B.V. A ll rights reserved.