Article

Detection of non-neutral substitution rates on Mammalian phylogenies

Gladstone Institutes, University of California, San Francisco, San Francisco, California 94158, USA.
Genome Research (Impact Factor: 14.63). 10/2009; 20(1):110-21. DOI: 10.1101/gr.097857.109
Source: PubMed

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.

    • "This hallmark has been successfully applied to alternative splicing to identify putative regulatory elements in alternative exons and flanking intronic sequences (Sugnet et al. 2006; Wang et al. 2008). We compared the PhyloP conservation scores (placental mammals using a 46-way alignment) for different classes of alternative events associated with isoform-specific polyribosome association (Siepel et al. 2005; Pollard et al. 2010). As expected, cassette exons appear to be less conserved than adjacent constitutive exons, suggesting recent evolution (Gelfman et al. 2012). "
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    • "We used phyloP combined with the phastCons program in PHAST (Pollard et al. 2010; Hubisz et al. 2011) to scan whole-genome alignments in vertebrates for sequences that are present in therian and non-therian vertebrates but changed significantly in the therian mammal ancestor and remained highly conserved during therian diversification. We identified 177,346 vertebrate genomic regions that are conserved among therians (therian conserved regions; TCRs), of which 4797 have a strong signature for accelerated evolution in the therian ancestor (false discovery rate <1%, table S1, Supplementary Material online). "
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    • "Both the proband and the unaffected mother harboured the heterozygous sequence change NCBI36/hg18:chr18:2,631,610 T > C. This nucleotide is conserved in primates (human, chimpanzee , gorilla, orang-utan, gibbon, rhesus monkey, crab-eating macaque, baboon, green monkey and squirrel monkey); the evolutionary conservation score, phyloP[20], calculated across 44 vertebrates, was 0.557, indicating a conserved nucleotide. The second novel sequence change, NCBI36/hg18: 2,631,886 G > A, was found in the proband from family 2. Molecular testing based on EcoRI/BlnI analysis[10]identified two intact D4Z4 repeats in the proband and >11 in the mother. "
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