Detection of nonneutral substitution rates on mammalian phylogenies.

By Katherine S. Pollard, Melissa J. Hubisz, Kate R. Rosenbloom, Adam C. Siepel. 2010

2,303 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Plant Science

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Citations in the corpus

CADD: predicting the deleteriousness of variants throughout the human genome (2018, positive): “PhyloP (16), PhastCons (17), GERP++ (18)), different tracks from the UCSC genome browser (19) as well as flat files of epigenetic information from the ENCODE and NIH RoadMap projects.”
A general framework for estimating the relative pathogenicity of human genetic variants (2014, background): “Whereas the latter are limited in scope to a small set of genetically or experimentally well-characterized mutations and subject to major ascertainment biases, deleteriousness can be measured systematically across the genome assembly (see refs 8, 9, 10 and below).”
Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks (2015, methodology): “AP-1 complex members JUN and JUND ChIP-seq in H1-hESCs support the binding event, and PhyloP conservation statistics support the precise relevance of the TGASTCA motif (Pollard et al. 2010).”
The UCSC Genome Browser database: extensions and updates 2011 (2011, background): “…( Pan troglodytes ) assembly (CGSC 2.1.3/panTro3) from the Chimpanzee Sequencing and Analysis Consortium (10) includes standard mapping and sequence tracks, RefSeq Genes, N-SCAN gene predictions (11), and a 12-species multiple alignment and conservation scoring by phastCons and phyloP (12,13).”
Ensembl comparative genomics resources (2016, background): “The UCSC Genome Browser also provides PhyloP conservation scores for these multiple alignments (59).”
Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors (2012, methodology): “Sequence conservation was computed using phyloP (Pollard et al. 2010).”