Publications of Selections on Non-coding Sequences

"The second hypothesis proposes that natural selection operates differently on mutations in cis-regulatory sequences^{6, 7, 8, 11}. This hypothesis is based on two properties of the organization and function of cis-regulatory regions. First, allele-specific measures of transcript abundance indicate that each allele in a diploid organism is transcribed largely independently^{11, 12, 13, 14}, suggesting that mutations in cis-regulatory regions are often co-dominant."

Natural selection operates far more efficiently on co-dominant mutations because they can have fitness consequences as heterozygotes: a new variant is visible to selection immediately rather than requiring drift to raise allele frequencies to the point at which homozygotes begin to appear in the population¹¹.

Review: the evolutionary significance of cis-regulatory mutations

Purifying Selection in Deeply Conserved Human Enhancers Is More Consistent than in Coding Sequences

Genome-wide inference of natural selection on human transcription factor binding sites

The high degree of protein sequence similarity between phenotypically diverged species has led some to propose that regulatory evolution may be of considerably more importance than protein evolution^{4, 5}.

Most of our direct knowledge regarding the evolution of regulatory elements comes from a handful of direct functional studies^{5, 6}. A second, indirect approach is based on comparative genomics⁷. The rationale for this second approach is that if newly arising mutations are typically detrimental to gene function, functionally important parts of the genome are expected to evolve more slowly than those lacking function^{8, 9, 10, 11}.

There are some limitations to the comparative genomics approach. First, a given genomic region might be conserved owing simply to a lower mutation rate¹². Second, known regulatory elements do not seem to be particularly well conserved as a class, at least in Drosophila¹⁰. This finding suggests that taking an approach based on sequence conservation alone may lead to a biased view of regulatory evolution. Functionality of DNA sequences implies that they can be subject to both negative and positive selection. If a significant fraction of divergence between species observed in non-coding DNA is positively selected rather than selectively neutral or constrained, this could lead to underestimates of the functional importance of non-coding DNA and cause researchers to overlook the contribution of arguably the most interesting class of mutations in genome evolution—those reflecting adaptive differences between populations and species.

Adaptive evolution of non-coding DNA in Drosophila