Abstract
BackgroundMouse E11.5 embryonic heart enhancers were found to exhibit exceptionally weak sequence conservation during vertebrate evolution compared to enhancers of other developing organs. However, it is unknown whether this phenomenon is due to elevated mutation rates, or is a consequence of natural selection.ResultsIn this study, based on the aligned orthologous genomic sequences of mouse and other closely related mammals, the substitution rates of fourfold degenerate sites or intron sequences in neighboring genes were used as neutral references to normalize substitution rates of mouse enhancers. Subsequent comparisons indicated that heart enhancers' evolutionary rates were increased by natural selection. Correspondingly, the results of Fisher's exact tests to examine the differential enrichment of substitutions between enhancers and neutral sequences suggest that both relaxed purifying selection and positive selection caused the rapid evolution of heart enhancers. Analyses on recombination rates and substitution patterns indicated that GC-biased gene conversion does not contribute to evolutionary rate variations among enhancers. In general, pleiotropic enhancers and enhancers in proximity to weakly expressed genes, tend to evolve slowly. Although heart enhancers are less pleiotropic and are adjacent to highly expressed genes, these biases do not account for the rapid evolution observed.ConclusionsIn combination, the results of the present study suggest that factors associated with functions or characteristics of the tissue may exert direct and profound effects on the intensity and direction of the natural selection applied to regulatory DNAs, such as enhancers.
Highlights
Mouse E11.5 embryonic heart enhancers were found to exhibit exceptionally weak sequence conservation during vertebrate evolution compared to enhancers of other developing organs
Natural selection leads to rapid evolution of embryonic heart enhancers In a previous study, an analysis of conservation depth using DNA alignments from a wide range of vertebrates identified the rapid evolution of embryonic heart enhancers [9]
If the differences in D determined for enhancers of forebrain, midbrain, limb and heart tissues is only due to variations in local mutation rates, these differences should disappear when D is normalized to neutral substitution rates
Summary
Mouse E11.5 embryonic heart enhancers were found to exhibit exceptionally weak sequence conservation during vertebrate evolution compared to enhancers of other developing organs. It is unknown whether this phenomenon is due to elevated mutation rates, or is a consequence of natural selection. Enhancers have been shown to regulate many of the processes that affect organismal development [6,7] To locate these important regulatory non-coding DNAs in the mouse (Mus musculus) genome, several thousand mouse enhancers that function in the embryonic heart, forebrain, midbrain, or limbs were recently identified using a p300 ChIP-Seq approach [8,9,10]. The underlying cause for the rapid sequence evolution observed in embryonic heart enhancers remains unknown, this unexpected phenomenon has challenged the use of sequence conservation as a criterion for predicting functionally important non-coding DNAs [12,13]
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