Mammalian housekeeping genes evolve more slowly than tissue-specific genes.

Do housekeeping genes, which are turned on most of the time in almost every tissue, evolve more slowly than genes that are turned on only at specific developmental times or tissues? Recent large-scale gene expression studies enable us to have a better definition of housekeeping genes and to address the above question in detail. In this study, we examined 1581 human-mouse orthologous gene pairs for their patterns of sequence evolution, contrasting housekeeping genes with tissue-specific genes. Our results show that, in comparison to tissue-specific genes, housekeeping genes on average evolve more slowly and are under stronger selective constraints as reflected by significantly smaller values of Ka/Ks. Besides stronger purifying selection, we explored several other factors that can possibly slow down nonsynonymous rates in housekeeping genes. Although mutational bias might slightly slow the nonsynonymous rates in housekeeping genes, it is unlikely to be the major cause of the rate difference between the two types of genes. The codon usage pattern of housekeeping genes does not seem to differ from that of tissue-specific genes. Moreover, contrary to the old textbook concept, we found that approximately 74% of the housekeeping genes in our study belong to multigene families, not significantly different from that of the tissue-specific genes ( approximately 70%). Therefore, the stronger selective constraints on housekeeping genes are not due to a lower degree of genetic redundancy.

[1]  J. Warrington,et al.  Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. , 2000, Physiological genomics.

[2]  Kagawa Yasuo,et al.  Regulation of mitochondrial ATP synthesis in mammalian cells by transcriptional control. , 1990 .

[3]  M. Gouy,et al.  HOVERGEN: a database of homologous vertebrate genes. , 1994, Nucleic acids research.

[4]  A. Butte,et al.  Further defining housekeeping, or "maintenance," genes Focus on "A compendium of gene expression in normal human tissues". , 2001, Physiological genomics.

[5]  Y. Kagawa,et al.  Regulation of mitochondrial ATP synthesis in mammalian cells by transcriptional control. , 1990, The International journal of biochemistry.

[6]  L. Duret,et al.  Determinants of substitution rates in mammalian genes: expression pattern affects selection intensity but not mutation rate. , 2000, Molecular biology and evolution.

[7]  G. Stephanopoulos,et al.  A compendium of gene expression in normal human tissues. , 2001, Physiological genomics.

[8]  Martin J. Lercher,et al.  Clustering of housekeeping genes provides a unified model of gene order in the human genome , 2002, Nature Genetics.

[9]  F. Wright.  The 'effective number of codons' used in a gene. , 1990, Gene.

[10]  Austin L. Hughes,et al.  Self peptides bound by HLA class I molecules are derived from highly conserved regions of a set of evolutionarily conserved proteins , 2004, Immunogenetics.

[11]  F. Wilcoxon.  Individual Comparisons by Ranking Methods , 1945 .

[12]  Grace Jordison.  Molecular Biology of the Gene , 1965, The Yale Journal of Biology and Medicine.

[13]  K. Hastings.  Strong evolutionary conservation of broadly expressed protein isoforms in the troponin I gene family and other vertebrate gene families , 1996, Journal of Molecular Evolution.

[14]  O. Mor,et al.  The human Surfeit locus. , 1998, Genomics.

[15]  Ziheng Yang,et al.  PAML: a program package for phylogenetic analysis by maximum likelihood , 1997, Comput. Appl. Biosci..