ArticlePLoS genetics2014
8.2% of the Human genome is constrained: variation in rates of turnover across functional element classes in the human lineage.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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Who cites it
115 citing papers in PubMed, 269 citations in OpenAlex.
- Genomic indicators of gene function: a systematic assessment of the human genome.G3 (Bethesda, Md.) · 2026Article
- Dynamics of mutators of arbitrary dominance in humans.bioRxiv : the preprint server for biology · 2026Article
- Genetic architectures of brain-related traits are shaped by strong selective constraints.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals.PLoS biology · 2026Article
- From junk to deleterious: Natural subtelomeric repeat amplifications impact fitness and cellular phenotypes in yeast.bioRxiv : the preprint server for biology · 2026Article
- Pervasive cryptic selection in the human noncoding genome.bioRxiv : the preprint server for biology · 2026Article
- Genetic architectures of brain-related traits are shaped by strong selective constraints.bioRxiv : the preprint server for biology · 2026Article
- The distribution of fitness effects of new mutations in regulatory regions of thebioRxiv : the preprint server for biology · 2026Article
- The performance of genetic-constraint metrics varies significantly across the human noncoding genome.bioRxiv : the preprint server for biology · 2026Article
- Semiparametric efficient estimation of small genetic effects in large-scale population cohorts.Biostatistics (Oxford, England) · 2025Article
- Unveiling the regulatory potential of the non-coding genome: Insights from the human genome project to precision medicine.Genes & diseases · 2025Review
- Article
- Evolution of GC-biased gene conversion by natural selection.Genetics · 2025Article
- In silico prediction of variant effects: promises and limitations for precision plant breeding.TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik · 2025Review
- Substitution-Mutation Rate Ratio (c/µ) As Molecular Adaptation Test Beyond Ka/Ks: A SARS-COV-2 Case Study.Journal of molecular evolution · 2025Article
- The distribution of highly deleterious variants across human ancestry groups.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The landscape of fitness effects of putatively functional noncoding mutations in humans.bioRxiv : the preprint server for biology · 2025Article
- Comprehensive dissection of cis-regulatory elements in a 2.8 Mb topologically associated domain in six human cancers.Nature communications · 2025Article
- How relevant is the mouse model for understanding human sex determination?International journal of biological sciences · 2025Article
- Biases in ARG-Based Inference of Historical Population Size in Populations Experiencing Selection.Molecular biology and evolution · 2024Article
55 more citing papers are in PubMed but not listed here.
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4 authors at 2 institutions in 1 country.
Funding
Abstract
Ten years on from the finishing of the human reference genome sequence, it remains unclear what fraction of the human genome confers function, where this sequence resides, and how much is shared with other mammalian species. When addressing these questions, functional sequence has often been equated with pan-mammalian conserved sequence. However, functional elements that are short-lived, including those contributing to species-specific biology, will not leave a footprint of long-lasting negative selection. Here, we address these issues by identifying and characterising sequence that has been constrained with respect to insertions and deletions for pairs of eutherian genomes over a range of divergences. Within noncoding sequence, we find increasing amounts of mutually constrained sequence as species pairs become more closely related, indicating that noncoding constrained sequence turns over rapidly. We estimate that half of present-day noncoding constrained sequence has been gained or lost in approximately the last 130 million years (half-life in units of divergence time, d1/2 = 0.25-0.31). While enriched with ENCODE biochemical annotations, much of the short-lived constrained sequences we identify are not detected by models optimized for wider pan-mammalian conservation. Constrained DNase 1 hypersensitivity sites, promoters and untranslated regions have been more evolutionarily stable than long noncoding RNA loci which have turned over especially rapidly. By contrast, protein coding sequence has been highly stable, with an estimated half-life of over a billion years (d1/2 = 2.1-5.0). From extrapolations we estimate that 8.2% (7.1-9.2%) of the human genome is presently subject to negative selection and thus is likely to be functional, while only 2.2% has maintained constraint in both human and mouse since these species diverged. These results reveal that the evolutionary history of the human genome has been highly dynamic, particularly for its noncoding yet biologically functional fraction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.