Transcription factors help distinguish humans

Most gene expression is under stabilizing selection in primates, but humans show directional evolution of regulatory genes

By | March 9, 2006

Transcription factor expression levels are evolving faster in humans than in other primates, reports a study in this week's Nature. Since transcription factors affect the actions of many downstream genes, rapid evolution of transcription factor expression may in part underlie the dramatic phenotypic differences between humans and chimpanzees, according to the authors. "It helps to explain the paradox of very few changes in the protein-coding complement of the genome" between humans and chimpanzees, said senior author Kevin White of Yale University. "That has to be responsible for major changes in morphology and in lifestyle." Led by first author Yoav Gilad, now at the University of Chicago, the authors created a multi-species DNA microarray of 1,056 corresponding genes expressed in the liver of four primate species: humans, chimpanzees, orangutans, and rhesus macaques. The authors picked out genes that were expressed at a different level in humans than in the other three primates, indicating that the genes' expression went through directional selection in the 5 million years since humans diverged from chimpanzees. A disproportionate number of the 14 genes with higher expression in humans coded for transcription factors. Among the five genes with lower expression in humans, none were transcription factors. In addition, there was no excess of transcription factors among genes upregulated in chimpanzees. "They don't evolve at any different rate than other classes of proteins," White said. "That's what's kind of cool about this result -- it seems very specific to the human lineage." Other studies have shown that the coding sequences of transcription factors also evolve more quickly in humans than in other primates, said Carlos Bustamante of Cornell University. Fast evolution of human transcription factors -- at both the sequence level and the expression level -- suggests that differences between humans and chimpanzees may be "driven by fundamental changes in the timing and expression of genes," said Bustamante, who was not involved in the study. Outside of the handful of genes under positive selection, Gilad and his colleagues found that about 60% of the genes they analyzed were expressed at essentially the same levels in all four species, suggesting that their expression has been under stabilizing selection in each primate lineage, White said. This result conflicts with studies that have suggested that most gene expression differences between primates evolved neutrally. But, according to Maryellen Ruvolo of Harvard University, "Ruling out neutral evolution of gene expression as the predominant mode of evolution and confirming that stabilizing selection is widespread brings primate gene expression studies in line with what's been observed in other species." Among the genes under stabilizing selection, the authors found a slight enrichment for genes involved in human cancers, including several that are altered in liver carcinoma. If a gene's expression level is critical enough to have been stabilized over millions of years of evolution, then changes in that gene or its expression may lead to disease, White said. "It will be interesting to look further into our list and do functional studies [of conserved genes] in disease models." This is the first study of gene expression in primates to use a multi-species microarray with probes designed specifically for each species, White said. Previous studies have used human-specific probes to estimate gene expression in other primates, which can cause biases in the measurement of expression in these species. "It's a careful paper," Bustamante told The Scientist. "They worked hard to control a lot of the factors that may have been problems in previous studies." "It's a good solid piece of work," agreed Daniel Geschwind of the University of California, Los Angeles. However, he added that it would have been more powerful if the authors had studied the expression of more genes, as well as expression in organs other than the liver. "It's hard to make really strong conclusions from one organ system and a small number of genes," Geschwind said. "But this study is moving in the right direction." Melissa Lee Phillips Links within this article Y. Gilad et al., "Expression profiling in primates reveals a rapid evolution of human transcription factors," Nature, March 9, 2006. L. Pray, "Evolutionists present their 1.3% solution," The Scientist, August 19, 2002. I. Ganguli, "Chimp papers by the barrel," The Scientist, September 1, 2005. Kevin White Yoav Gilad C. D. Bustamante et al., "Natural selection on protein-coding genes in the human genome," Nature, October 20, 2005. PM_ID: 16237444 Carlos Bustamante P. Khaitovich et al., "A neutral model of transcriptome evolution," PLoS Biology, May 2004. PM_ID: 15138501 Maryellen Ruvolo S. A. Rifkin et al., "Evolution of gene expression in the Drosophila melanogaster subgroup," Nature Genetics, February 2003. PM_ID: 12548287 Daniel Geschwind

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