A novel test for selection on cis-regulatory elements reveals positive and negative selection acting on mammalian transcriptional enhancers

Measuring natural selection on genomic elements involved in the cis-regulation of gene expression--such as transcriptional enhancers and promoters--is critical for understanding the evolution of genomes, yet it remains a major challenge. Many studies have attempted to detect positive or negative sel...

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Bibliographic Details
Published in:Molecular biology and evolution 2013-11, Vol.30 (11), p.2509-2518
Main Authors: Smith, Justin D, McManus, Kimberly F, Fraser, Hunter B
Format: Article
Language:English
Subjects:
Animals
Computational Biology - methods
Enhancer Elements, Genetic
Evolution, Molecular
Gene expression
Gene Expression Regulation, Developmental
Genomes
Humans
Mammals
Mammals - genetics
Methods
Models, Genetic
Mutagenesis
Mutation
Phylogenetics
Phylogeny
Promoter Regions, Genetic
Proteins
Regulatory Elements, Transcriptional
Regulatory Sequences, Nucleic Acid
Selection, Genetic
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Summary:Measuring natural selection on genomic elements involved in the cis-regulation of gene expression--such as transcriptional enhancers and promoters--is critical for understanding the evolution of genomes, yet it remains a major challenge. Many studies have attempted to detect positive or negative selection in these noncoding elements by searching for those with the fastest or slowest rates of evolution, but this can be problematic. Here, we introduce a new approach to this issue, and demonstrate its utility on three mammalian transcriptional enhancers. Using results from saturation mutagenesis studies of these enhancers, we classified all possible point mutations as upregulating, downregulating, or silent, and determined which of these mutations have occurred on each branch of a phylogeny. Applying a framework analogous to Ka/Ks in protein-coding genes, we measured the strength of selection on upregulating and downregulating mutations, in specific branches as well as entire phylogenies. We discovered distinct modes of selection acting on different enhancers: although all three have experienced negative selection against downregulating mutations, the selection pressures on upregulating mutations vary. In one case, we detected positive selection for upregulation, whereas the other two had no detectable selection on upregulating mutations. Our methodology is applicable to the growing number of saturation mutagenesis data sets, and provides a detailed picture of the mode and strength of natural selection acting on cis-regulatory elements.
ISSN:0737-4038
1537-1719
DOI:10.1093/molbev/mst134