The human noncoding genome defined by genetic diversity
Open accessPublished version of a preprint
Abstract
Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.
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NPncRNAs as a class were under greater selective constraint than all Gencode-annotated ncRNAs.
“As a class, NPncRNAs were under greater selective constraint compared to all Gencode annotated ncRNAs (Fig 1F), consistent with the observed increased purifying selection in brain-expressed genes (27).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [27]
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References 43 · Cited by 161
- Authors
- di Iulio, J., Bartha, I., Wong, E. H. M., Yu, H.-C., Lavrenko, V., Yang, D., Jung, I., Hicks, M. A., Shah, N., Kirkness, E. F., Fabani, M. M., Biggs, W. H., Ren, B., Venter, J. C., & Telenti, A.
- Affiliations
- Human Longevity (United States) (US)
- Korea Advanced Institute of Science and Technology (KR)
- Ludwig Cancer Research (US)
- J. Craig Venter Institute (US)
- Scripps Research Institute (US)
- Corresponding author
- Telenti, Amalio
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-02-26
- Volume
- 50
- Issue
- 3
- Pages
- 333-337
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2794373321
- Cited by
- 161
- References
- 43
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 19 · 2023: 14 · 2022: 29 · 2021: 30 · 2020: 19 · 2019: 20 · 2018: 13 · 2017: 4
- FWCI
- 12.85
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- 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
- Keywords
- non-coding genome, sequence constraints, genetic diversity, regulatory elements, heptamer, pathogenic variants, variant prioritization, essential genes, 3D genome organization, Hi-C
- MeSH terms
- Chromosome Mapping, Female, Humans, Male, Regulatory Sequences, Nucleic Acid, Genetic Variation, Genome, Human, Conserved Sequence, Evolution, Molecular, Computational Biology, RNA, Untranslated
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