Identifying branch-specific positive selection throughout the regulatory genome using an appropriate proxy neutral.

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BACKGROUND:Adaptive 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. RESULTS:We 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. CONCLUSION:Here, 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.





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Berrio, Alejandro, Ralph Haygood and Gregory A Wray (2020). Identifying branch-specific positive selection throughout the regulatory genome using an appropriate proxy neutral. BMC genomics, 21(1). p. 359. 10.1186/s12864-020-6752-4 Retrieved from

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Gregory Allan Wray

Professor of Biology

I study the evolution of genes and genomes with the broad aim of understanding the origins of biological diversity. My approach focuses on changes in the expression of genes using both empirical and computational approaches and spans scales of biological organization from single nucleotides through gene networks to entire genomes. At the finer end of this spectrum of scale, I am focusing on understanding the functional consequences and fitness components of specific genetic variants within regulatory sequences of several genes associated with ecologically relevant traits. At the other end of the scale, I am developing molecular and analytical methods to detect changes in gene function throughout entire genomes, including statistical frameworks for detecting natural selection on regulatory elements and empirical approaches to identify functional variation in transcriptional regulation. At intermediate scales, I am investigating functional variation within a dense gene network in the context of wild populations and natural perturbations. My research leverages the advantages of several different model systems, but primarily focuses on sea urchins and primates (including humans).

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