Dispensability of mammalian DNA.

In the lab, the cis-regulatory network seems to exhibit great functional redundancy. Many experiments testing enhancer activity of neighboring cis-regulatory elements show largely overlapping expression domains. Of recent interest, mice in which cis-regulatory ultraconserved elements were knocked out showed no obvious phenotype, further suggesting functional redundancy. Here, we present a global evolutionary analysis of mammalian conserved nonexonic elements (CNEs), and find strong evidence to the contrary. Given a set of CNEs conserved between several mammals, we characterize functional dispensability as the propensity for the ancestral element to be lost in mammalian species internal to the spanned species tree. We show that ultraconserved-like elements are over 300-fold less likely than neutral DNA to have been lost during rodent evolution. In fact, many thousands of noncoding loci under purifying selection display near uniform indispensability during mammalian evolution, largely irrespective of nucleotide conservation level. These findings suggest that many genomic noncoding elements possess functions that contribute noticeably to organism fitness in naturally evolving populations.