DOI: 10.1101/gr.3577405. Distribution and intensity of constraint in mammalian genomic sequence

Distribution and intensity of constraint in mammalian genomic sequence

10.1101/gr.3577405

Crossref journal-article

Cold Spring Harbor Laboratory

Genome Research (246)

Abstract

Comparisons of orthologous genomic DNA sequences can be used to characterize regions that have been subject to purifying selection and are enriched for functional elements. We here present the results of such an analysis on an alignment of sequences from 29 mammalian species. The alignment captures ∼3.9 neutral substitutions per site and spans ∼1.9 Mbp of the human genome. We identify constrained elements from 3 bp to over 1 kbp in length, covering ∼5.5% of the human locus. Our estimate for the total amount of nonexonic constraint experienced by this locus is roughly twice that for exonic constraint. Constrained elements tend to cluster, and we identify large constrained regions that correspond well with known functional elements. While constraint density inversely correlates with mobile element density, we also show the presence of unambiguously constrained elements overlapping mammalian ancestral repeats. In addition, we describe a number of elements in this region that have undergone intense purifying selection throughout mammalian evolution, and we show that these important elements are more numerous than previously thought. These results were obtained with Genomic Evolutionary Rate Profiling (GERP), a statistically rigorous and biologically transparent framework for constrained element identification. GERP identifies regions at high resolution that exhibit nucleotide substitution deficits, and measures these deficits as “rejected substitutions.” Rejected substitutions reflect the intensity of past purifying selection and are used to rank and characterize constrained elements. We anticipate that GERP and the types of analyses it facilitates will provide further insights and improved annotation for the human genome as mammalian genome sequence data become richer.

Bibliography

Cooper, G. M., Stone, E. A., Asimenos, G., Green, E. D., Batzoglou, S., & Sidow, A. (2005). Distribution and intensity of constraint in mammalian genomic sequence. Genome Research, 15(7), 901â913.

Authors 6

Gregory M. Cooper (first)
Eric A. Stone (additional)
George Asimenos (additional)
Eric D. Green (additional)
Serafim Batzoglou (additional)
Arend Sidow (additional)

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Dates

Type	When
Created	20 years, 2 months ago (June 17, 2005, 8:34 p.m.)
Deposited	3 years, 9 months ago (Nov. 18, 2021, 2:36 p.m.)
Indexed	3 days, 7 hours ago (Aug. 29, 2025, 5:50 a.m.)
Issued	20 years, 2 months ago (June 17, 2005)
Published	20 years, 2 months ago (June 17, 2005)
Published Online	20 years, 2 months ago (June 17, 2005)
Published Print	20 years, 2 months ago (July 1, 2005)

Funders 0

None

BibTeX

@article{Cooper_2005, title={Distribution and intensity of constraint in mammalian genomic sequence}, volume={15}, ISSN={1088-9051}, url={http://dx.doi.org/10.1101/gr.3577405}, DOI={10.1101/gr.3577405}, number={7}, journal={Genome Research}, publisher={Cold Spring Harbor Laboratory}, author={Cooper, Gregory M. and Stone, Eric A. and Asimenos, George and Green, Eric D. and Batzoglou, Serafim and Sidow, Arend}, year={2005}, month=jun, pages={901–913} }

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    "1088-9051"
  ],
  "subject": [],
  "container-title-short": "Genome Res.",
  "published": {
    "date-parts": [
      [
        2005,
        6,
        17
      ]
    ]
  }
}