Expression profiling in primates reveals a rapid evolution of human transcription factors

Although it has been hypothesized for thirty years that many human adaptations are likely to be due to changes in gene regulation, almost nothing is known about the modes of natural selection acting on regulation in primates. Here we identify a set of genes for which expression is evolving under natural selection. We use a new multi-species complementary DNA array to compare steady-state messenger RNA levels in liver tissues within and between humans, chimpanzees, orangutans and rhesus macaques. Using estimates from a linear mixed model, we identify a set of genes for which expression levels have remained constant across the entire phylogeny (∼70 million years), and are therefore likely to be under stabilizing selection. Among the top candidates are five genes with expression levels that have previously been shown to be altered in liver carcinoma. We also find a number of genes with similar expression levels among non-human primates but significantly elevated or reduced expression in the human lineage, features that point to the action of directional selection. Among the gene set with a human-specific increase in expression, there is an excess of transcription factors; the same is not true for genes with increased expression in chimpanzee.

[1]  J. Gregg,et al.  Allele-specific Holliday junction formation: a new mechanism of allelic discrimination for SNP scoring. , 2003, Genome research.

[2]  D. Bates,et al.  Mixed-Effects Models in S and S-PLUS , 2001 .

[3]  S. Pääbo,et al.  Parallel Patterns of Evolution in the Genomes and Transcriptomes of Humans and Chimpanzees , 2005, Science.

[4]  J. Davis.  Bioinformatics and Computational Biology Solutions Using R and Bioconductor , 2007 .

[5]  G. Gibson,et al.  Mixed-model reanalysis of primate data suggests tissue and species biases in oligonucleotide-based gene expression profiles. , 2003, Genetics.

[6]  Mark Gerstein,et al.  Multi-species microarrays reveal the effect of sequence divergence on gene expression profiles. , 2005, Genome research.

[7]  D. Hartl,et al.  RATES OF DIVERGENCE IN GENE EXPRESSION PROFILES OF PRIMATES, MICE, AND FLIES: STABILIZING SELECTION AND VARIABILITY AMONG FUNCTIONAL CATEGORIES , 2005, Evolution; international journal of organic evolution.

[8]  Rafael A. Irizarry,et al.  Bioinformatics and Computational Biology Solutions using R and Bioconductor , 2005 .

[9]  S. Pääbo,et al.  A Neutral Model of Transcriptome Evolution , 2004, PLoS biology.

[10]  Lauren M McIntyre,et al.  Common pattern of evolution of gene expression level and protein sequence in Drosophila. , 2004, Molecular biology and evolution.

[11]  Gordon K. Smyth,et al.  limma: Linear Models for Microarray Data , 2005 .

[12]  M. Lynch,et al.  The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans , 2005, Nature Genetics.

[13]  S. Pääbo,et al.  Intra- and Interspecific Variation in Primate Gene Expression Patterns , 2002, Science.

[14]  M. Feitelson,et al.  Inhibitory effect of tumor suppressor p33(ING1b) and its synergy with p53 gene in hepatocellular carcinoma. , 2005, World journal of gastroenterology.

[15]  J. Hacia,et al.  Comparative analysis of gene-expression patterns in human and African great ape cultured fibroblasts. , 2003, Genome research.

[16]  H. D. Patterson,et al.  Recovery of inter-block information when block sizes are unequal , 1971 .

[17]  Philipp Khaitovich,et al.  Toward a Neutral Evolutionary Model of Gene Expression , 2005, Genetics.

[18]  Kevin P. White,et al.  A mutation accumulation assay reveals a broad capacity for rapid evolution of gene expression , 2005, Nature.

[19]  E. Eichler,et al.  Regional patterns of gene expression in human and chimpanzee brains. , 2004, Genome research.

[20]  K. Ogawa,et al.  Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma. , 2004, Anticancer research.

[21]  Scott A. Rifkin,et al.  Evolution of gene expression in the Drosophila melanogaster subgroup , 2003, Nature Genetics.

[22]  M. King,et al.  Evolution at two levels in humans and chimpanzees. , 1975, Science.

[23]  Matthew A. Zapala,et al.  Elevated gene expression levels distinguish human from non-human primate brains , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Colin D. Meiklejohn,et al.  Sex-Dependent Gene Expression and Evolution of the Drosophila Transcriptome , 2003, Science.

[25]  G. Glazko,et al.  Estimation of divergence times for major lineages of primate species. , 2003, Molecular biology and evolution.

[26]  Ryan D. Hernandez,et al.  Natural selection on protein-coding genes in the human genome , 2005, Nature.

[27]  J. Ludes-Meyers,et al.  Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma , 2004, British Journal of Cancer.

[28]  M. Magnasco,et al.  Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. , 2003, Genome research.

[29]  Tetsuhiro Chiba,et al.  Identification and investigation of methylated genes in hepatoma. , 2005, European journal of cancer.

[30]  M. Kreitman,et al.  Functional Evolution of a cis-Regulatory Module , 2005, PLoS biology.

[31]  Jon D. McAuliffe,et al.  Phylogenetic Shadowing of Primate Sequences to Find Functional Regions of the Human Genome , 2003, Science.

[32]  D. Hartl,et al.  RATES OF DIVERGENCE IN GENE EXPRESSION PROFILES OF PRIMATES, MICE, AND FLIES: STABILIZING SELECTION AND VARIABILITY AMONG FUNCTIONAL CATEGORIES , 2005, Evolution; international journal of organic evolution.

[33]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .