Detection of nonneutral substitution rates on mammalian phylogenies
- 1 Gladstone Institutes, University of California, San Francisco, San Francisco, California 94158, USA;
- 2 Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York 14850, USA;
- 3 Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA
Abstract
Methods for detecting nucleotide substitution rates that are faster or slower than expected under neutral drift are widely used to identify candidate functional elements in genomic sequences. However, most existing methods consider either reductions (conservation) or increases (acceleration) in rate but not both, or assume that selection acts uniformly across the branches of a phylogeny. Here we examine the more general problem of detecting departures from the neutral rate of substitution in either direction, possibly in a clade-specific manner. We consider four statistical, phylogenetic tests for addressing this problem: a likelihood ratio test, a score test, a test based on exact distributions of numbers of substitutions, and the genomic evolutionary rate profiling (GERP) test. All four tests have been implemented in a freely available program called phyloP. Based on extensive simulation experiments, these tests are remarkably similar in statistical power. With 36 mammalian species, they all appear to be capable of fairly good sensitivity with low false-positive rates in detecting strong selection at individual nucleotides, moderate selection in 3-bp elements, and weaker or clade-specific selection in longer elements. By applying phyloP to mammalian multiple alignments from the ENCODE project, we shed light on patterns of conservation/acceleration in known and predicted functional elements, approximate fractions of sites subject to constraint, and differences in clade-specific selection in the primate and glires clades. We also describe new “Conservation” tracks in the UCSC Genome Browser that display both phyloP and phastCons scores for genome-wide alignments of 44 vertebrate species.
Footnotes
↵4 Corresponding author.
E-mailkpollard{at}gladstone.ucsf.edu; fax (415) 355-0141.
[Supplemental material is available online athttp://www.genome.org.]
Article published online before print. Article and publication date are athttp://www.genome.org/cgi/doi/10.1101/gr.097857.109.
- ReceivedJune 26, 2009.
- AcceptedOctober 5, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
