Abstract
BackgroundAdaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype.ResultsWe used ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We applied the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. Then, we evaluated the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity and specificity. We found that the length of the query alignment can vary between 150 bp and 1 kb without affecting the estimation of selection, while for the reference alignment, we found that a length of 3 kb is adequate for proper testing. We also simulated sequence alignments under different classes of evolution and validated our ability to distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we re-confirmed that a quarter of all non-coding Human Accelerated Elements are evolving by positive selection.ConclusionHere, we introduce a method we called adaptiPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome.
Highlights
Adaptive changes in cis-regulatory elements are an essential component of evolution by natural selection
We tallied the number of Non-Functional Region (NFR) located within 10, 40 and 100 kb of a set of 1000 random DNA Hypersensitive Site (DHS) sites, non-coding Human Accelerated Elements, and a control subset of “global” NFRs from throughout the genome
58.5% of DHSs and 43.3% of non-coding Human Accelerated Elements (ncHAE) had no local NFRs within 100 kb
Summary
Adaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. The other seeks an elevated rate of substitution along the human lineage in a query region hypothesized to contain regulatory elements relative to a nearby reference (proxy neutral) region thought to contain few functional elements [20, 21] Both approaches test for branch-specific accelerated substitution, but differ in the reference point against which they assess acceleration: the first tests for accelerated substitution within otherwise conserved regions against a putatively neutral region that is usually obtained from local Ancient Repeats (ARs) or fourfold degenerate sites (4D) [15, 17,18,19], while the second employs a putatively non-functional local intron of the genome as a neutral reference against which to identify branch-specific accelerated substitution [20, 21]. To detect significance in the departures from neutrality, both approaches typically use maximum likelihood estimation and likelihood ratio tests (LRTs) that compare a null model allowing neutrality against an alternative model that allows for positive selection
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