Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes

Siepel, Adam; Bejerano, Gill; Pedersen, Jakob Skou; Hinrichs, Angie S.; Hou, Minmei; Rosenbloom, Kate R.; Clawson, Hiram; Strouboulis, John; Hillier, LaDeana W.; Richards, Stephen; Weinstock, George M.; Wilson, Richard K.; Gibbs, Richard A.; Kent, W. James; Miller, Webb; Haussler, David

doi:10.1101/gr.3715005

Cited by 3,667 publications

(3,942 citation statements)

References 96 publications

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“…The variants were evaluated for conservation level, including genomic evolutionary rate profiling, 16 PhastCons, 17 and PhyloP scores. Pathogenicity prediction programs that assess the functional significance of amino acid substitutions were used, including Polyphen 2, 18 Grantham score, 19 and Sorting intolerant from tolerant 20 score.…”

Section: Pathogenicity Of Variantsmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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Purpose: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Methods:Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current populationbased allele frequencies.Results: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Conclusion:Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

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Section: Pathogenicity Of Variantsmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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“…1A). For interpretability, it is useful to reparameterize µ and ν as ω = 1 µ , the expected length of conserved elements, and γ = ν µ+ν , the expected fraction of bases in conserved elements [6]. The third free parameter, φ, is the probability that an element is lineage-specific given that it is conserved.…”

Section: The Modelmentioning

confidence: 99%

“…DLESS's model is a generalization of the two-state phylo-HMM used by the phastCons program [6]. PhastCons has a state c for conserved sequences and a state n for nonconserved .…”

Section: The Modelmentioning

confidence: 99%

“…In the comparative genomics community, much attention has focused on two problems in particular: (1) identifying (especially noncoding) sequences that are unusually conserved across species, and thus are likely to be subject to negative selection (e.g., [3][4][5][6]); and (2) identifying protein-coding genes that show unusually high d N /d S ratios, and thus might be subject to positive selection (e.g., [7][8][9][10][11][12]). Methods focused on problem (1) generally have made the assumption (explicitly or implicitly) that selectional pressures are the same across all branches of a phylogeny-i.e., that each candidate sequence is under selection in all species or not under selection in any species.…”

Section: Introductionmentioning

confidence: 99%

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New Methods for Detecting Lineage-Specific Selection

Siepel

Pollard

Haussler

2006

Lecture Notes in Computer Science

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210

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Abstract. So far, most methods for identifying sequences under selection based on comparative sequence data have either assumed selectional pressures are the same across all branches of a phylogeny, or have focused on changes in specific lineages of interest. Here, we introduce a more general method that detects sequences that have either come under selection, or begun to drift, on any lineage. The method is based on a phylogenetic hidden Markov model (phylo-HMM), and does not require element boundaries to be determined a priori, making it particularly useful for identifying noncoding sequences. Insertions and deletions (indels) are incorporated into the phylo-HMM by a simple strategy that uses a separately reconstructed "indel history." To evaluate the statistical significance of predictions, we introduce a novel method for computing P -values based on prior and posterior distributions of the number of substitutions that have occurred in the evolution of predicted elements. We derive efficient dynamic-programming algorithms for obtaining these distributions, given a model of neutral evolution. Our methods have been implemented as computer programs called DLESS (Detection of LinEage-Specific Selection) and phyloP (phylogenetic P -values). We discuss results obtained with these programs on both real and simulated data sets.

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“…Only SNVs and InDels of up to 30 bp and found within 150 bp of the ends of the enriched targets were considered for subsequent analysis. Functional annotation of high-quality variants was performed using Annovar, 11 providing a comparison of the predicted variants to the National Center for Biotechnology Information (NCBI) SNP Database build 132 (dbSNP132), the March 2010 pilot release of the 1000 Genomes project (1000G; www.1000genomes.org), conservation around variants based on phastCons, 12 segmental duplication filter, gene annotation (exon/intron/UTR), amino-acid substitutions and splice variants based on UCSC Genome Browser 13 tracks, as well as multiple estimates of the impact of amino-acid substitution on the structure and function of proteins (tools: Sift, 14 Polyphen2, 15 PhyloP, 16 and MutationTaster 17 ). The reference sequences used for the four genes targeted in this study were NM_000277 (PAH), NM_000320 (QDPR), NM_000161 (GCH1), and NM_000317 (PTS).…”

Section: Bioinformatics Analysis Of Dna Variantsmentioning

confidence: 99%

Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing

et al. 2013

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Genetic diagnostics of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficient hyperphenylalaninemia (BH4DH) rely on methods that scan for known mutations or on laborious molecular tools that use Sanger sequencing. We have implemented a novel and much more efficient strategy based on high-throughput multiplex-targeted resequencing of four genes (PAH, GCH1, PTS, and QDPR) that, when affected by loss-of-function mutations, cause PKU and BH4DH. We have validated this approach in a cohort of 95 samples with the previously known PAH, GCH1, PTS, and QDPR mutations and one control sample. Pooled barcoded DNA libraries were enriched using a custom NimbleGen SeqCap EZ Choice array and sequenced using a HiSeq2000 sequencer. The combination of several robust bioinformatics tools allowed us to detect all known pathogenic mutations (point mutations, short insertions/deletions, and large genomic rearrangements) in the 95 samples, without detecting spurious calls in these genes in the control sample. We then used the same capture assay in a discovery cohort of 11 uncharacterized HPA patients using a MiSeq sequencer. In addition, we report the precise characterization of the breakpoints of four genomic rearrangements in PAH, including a novel deletion of 899 bp in intron 3. Our study is a proof-of-principle that high-throughputtargeted resequencing is ready to substitute classical molecular methods to perform differential genetic diagnosis of hyperphenylalaninemias, allowing the establishment of specifically tailored treatments a few days after birth.

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Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes

Cited by 3,667 publications

References 96 publications

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

New Methods for Detecting Lineage-Specific Selection

Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing

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