Peter D. Keightley * and Daniel J. Gaffney

Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom

*To whom correspondence should be addressed.
E-mail:       p.keightley@ed.ac.uk

Abstract:

Selection against deleterious mutations imposes a mutation load on populations because individuals die or fail to reproduce. In vertebrates, estimates of genomic rates of deleterious mutations in protein-coding genes imply the existence of a substantial mutation load, but many functionally important regions of the genome are thought to reside in noncoding DNA, and the contribution of noncoding DNA to the mutation load has been unresolved. Here, we infer the frequency of deleterious mutations in noncoding DNA of rodents by comparing rates of substitution at noncoding nucleotides with rates of substitution at the fastest evolving intronic sites of adjacent genes sampled from the whole genome sequences of mouse and rat. We show that the major elements of selectively constrained noncoding DNA are within 2,500 bp upstream and downstream of coding sequences and in first introns. Our estimate of the genomic deleterious point mutation rate for noncoding DNA (0.22 per diploid per generation) is similar to that for coding DNA. Mammalian populations therefore experience a substantial genetic load associated with selection against deleterious mutations in noncoding DNA. Deleterious mutations in noncoding DNA have predominantly quantitative effects and could be an important source of the burden of
complex genetic disease variation in human populations.

Additional References:

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euchromatin: "the most active portion of the genome within the cell nucleus".