Methods to detect selection on noncoding DNA

Abstract

Vast tracts of noncoding DNA contain elements that regulate gene expression in higher eukaryotes. Describing these regulatory elements and understanding how they evolve represent major challenges for biologists. Advances in the ability to survey genome-scale DNA sequence data are providing unprecedented opportunities to use evolutionary models and computational tools to identify functionally important elements and the mode of selection acting on them in multiple species. This chapter reviews some of the current methods that have been developed and applied on noncoding DNA, what they have shown us, and how they are limited. Results of several recent studies reveal that a significantly larger fraction of noncoding DNA in eukaryotic organisms is likely to be functional than previously believed, implying that the functional annotation of most noncoding DNA in these organisms is largely incomplete. In Drosophila, recent studies have further suggested that a large fraction of noncoding DNA divergence observed between species may be the product of recurrent adaptive substitution. Similar studies in humans have revealed a more complex pattern, with signatures of recurrent positive selection being largely concentrated in conserved noncoding DNA elements. Understanding these patterns and the extent to which they generalize to other organisms awaits the analysis of forthcoming genome-scale polymorphism and divergence data from more species.

Fig. 1

The effect of directional selection on the distribution of polymorphism frequencies (DPFs). Plotted are expected proportion of polymorphisms on the y-axis and frequency in a sample of 20 chromosomes based on equations in Bustamante et al. (90). Selected variants are assumed to have additive effects on fitness. In brown is a mixture model that posits 50% of newly arising mutations being neutral, 40% being negatively selected, and 10% positively selected. The similarity of this mixture model to neutral expectations implies that it may be difficult to detect positive or negative selection in regions of the genome with pluralistic selective pressures based on the shape of the DPF alone.

Fig. 2

Selective constraint and positive selection on noncoding DNA inferred using polymorphism and divergence. Shown is the inferred distribution of fitness effects of newly arising mutations and the fraction of divergence in excess of expectations (α) for a sample of intronic sites in D. melanogaster (from Table 6 of 77). The method uses the DPF for synonymous sites to estimate parameters of a population size change model. The method then uses this demographic model, with the DPF and divergence at synonymous and intronic sites, to estimate selection on the latter class of sites. The implication is that 30% of newly arising mutations in these introns are subject to deterministic negative selection and that 20% of the nucleotide divergence observed between species is in excess of expectations under the neutral model. The error bars indicate standard errors on the estimates.