Cited by 1,757Genomics and Phylogenetic StudiesGenomics and Chromatin DynamicsChromosomal and Genetic Variations

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Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++

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Davydov, Eugene V., Goode, David L., Sirota, Marina, Cooper, Gregory M., Sidow, Arend, Batzoglou, Serafim·2010·PLoS Computational Biology

DOI 10.1371/journal.pcbi.1001025PMC PMC2996323

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Abstract

Computational efforts to identify functional elements within genomes leverage comparative sequence information by looking for regions that exhibit evidence of selective constraint. One way of detecting constrained elements is to follow a bottom-up approach by computing constraint scores for individual positions of a multiple alignment and then defining constrained elements as segments of contiguous, highly scoring nucleotide positions. Here we present GERP++, a new tool that uses maximum likelihood evolutionary rate estimation for position-specific scoring and, in contrast to previous bottom-up methods, a novel dynamic programming approach to subsequently define constrained elements. GERP++ evaluates a richer set of candidate element breakpoints and ranks them based on statistical significance, eliminating the need for biased heuristic extension techniques. Using GERP++ we identify over 1.3 million constrained elements spanning over 7% of the human genome. We predict a higher fraction than earlier estimates largely due to the annotation of longer constrained elements, which improves one to one correspondence between predicted elements with known functional sequences. GERP++ is an efficient and effective tool to provide both nucleotide- and element-level constraint scores within deep multiple sequence alignments.

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Authors: Davydov, E. V., Goode, D. L., Sirota, M., Cooper, G. M., Sidow, A., & Batzoglou, S.
Affiliations: Stanford University (US)
Stanford Medicine (US)
Howard Hughes Medical Institute (US)
Corresponding author: Sidow, Arend
ORCID: Goode, David L.
Sirota, Marina
Cooper, Gregory M.
Sidow, Arend
Batzoglou, Serafim
Venue: PLoS Computational Biology
Publisher: Public Library of Science (PLoS)
Published: 2010-12-02
Volume: 6
Issue: 12
Pages: e1001025
ISSN: 1553-734X (ISSN-L)
1553-7358
DOI: 10.1371/journal.pcbi.1001025
PMC: PMC2996323
OpenAlex: W2038473742
Cited by: 1,757
References: 28
Citations by year: 2026: 105 · 2025: 116 · 2024: 128 · 2023: 134 · 2022: 142 · 2021: 174 · 2020: 156 · 2019: 164 · 2018: 134 · 2017: 107 · 2016: 118 · 2015: 100 · 2014: 69 · 2013: 71 · 2012: 25
FWCI: 14.08
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Computational Biology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders: National Science Foundation (0347952)
National Institutes of Health (LM007033)
National Human Genome Research Institute
U.S. National Library of Medicine (K22LM008261, LM007033, T15LM007033)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
Keywords: GERP, selective constraint, functional elements, human genome, sequence comparison, multiple sequence alignment, dynamic programming
MeSH terms: Algorithms, Animals, Humans, Mammals, Models, Genetic, Phylogeny, Software, User-Computer Interface, Genome, Human, Sequence Alignment, Sequence Analysis, DNA, Genomics

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Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++

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