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Evolution of promoter affinity for transcription factors in the human lineage.

Molineris I, Grassi E, Ala U, Di Cunto F, Provero P

Dept. of Genetics, Biology and Biochemistry and Molecular Biotechnology Center, University of Turin, Italy.

Changes in gene regulation are believed to play an important role in the evolution of animals. It has been suggested that changes in cis-regulatory regions are responsible for many or most of the anatomical and behavioral differences between humans and apes. However the study of the evolution of cis-regulatory regions is made problematic by the degeneracy of transcription factor binding sites and the shuffling of their positions. In this work we use the predicted total affinity of a promoter for a large collection of transcription factors as the basis to study the evolution of cis-regulatory regions in mammals. We introduce the human specificity of a promoter, measuring the divergence between the affinity profile of a human promoter and its orthologous promoters in other mammals. The promoters of genes involved in functional categories such as neural processes and signal transduction, among others, have higher human specificity compared to the rest of the genome. Clustering of the human-specific affinities of neural genes reveals patterns of promoter evolution associated to functional categories such as synaptic transmission and brain development, and to diseases such as bipolar disorder and autism.

Published 21 February 2011 in Mol Biol Evol.
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