A high-resolution map of human evolutionary constraint using 29 mammals

By Kerstin Lindblad-Toh, Manuel Garber, Or Zuk, Michael F. Lin, B. Parker, Stefan Washietl, Pouya Kheradpour, Jason Ernst, Gregory E. Jordan, E. Mauceli and 76 more. Nature, 2011

867 citations recorded by the source corpus.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Subfields: Aging, Genetics

View Paper: https://www.semanticscholar.org/paper/74447f943216707da1a0e047d5e80e10597600bf

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In Genetics

Citations in the corpus

Molecular phylogenetics: principles and practice (2012, neutral): “In this context, it is used: to classify metagenomic sequences 7 ; to identify genes, regulatory elements and non-coding RNAs in newly sequenced genomes 8–10 ; to interpret modern and ancient individual genomes 11–13 ; and to reconstruct ancestral genomes 14,15 .”
GENCODE: The reference human genome annotation for The ENCODE Project (2012, neutral): “A similar figure was suggest by Lindblad-Toh et al. (2011), who recently reported the sequencing and comparative analysis of 29 eutherian mammals.”
The UCSC Genome Browser database: 2015 update (2014, neutral): “The browsers for eight species were updated with new assemblies this year, including five from the Broad Institute’s 29 mammal comparative genomics project (30) (alpaca, hedgehog, pika, shrew and tenrec) and an updated cow assembly (bosTau8, UMD 3.”
The UCSC Genome Browser database: 2014 update (2013, neutral): “Nucleic Acids Research, 2014, Vol. 42, Database issue D765 sequenced and assembled for the Mammalian Genome Project (11).”
Next-Generation Sequencing — An Overview of the History, Tools, and “Omic” Applications (2016, neutral): “[141] Lindblad-Toh K, Garber M, Zuk O: A high-resolution map of human evolutionary constraint using 29 mammals.”
Partitioning heritability by functional annotation using genome-wide association summary statistics (2015, neutral): “The 24 main annotations include: coding, UTR, promoter, and intron [14, 17]; histone marks H3K4me1, H3K4me3, H3K9ac [3–5] and two versions of H3K27ac [18, 19]; open chromatin reflected by DNase I hypersensitivity Site (DHS) regions [5, 14]; combined chromHMM/Segway predictions [20], which make use o”
HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease (2015, neutral): “Mammalian evolutionarily constrained elements are defined as originally reported, using both SiPhy elements (18) and GERP elements (19).”
PlantRegMap: charting functional regulatory maps in plants (2019, neutral): “Conservation landscapes in humans and fruit flies have been widely used to illustrate their genome sequences (20,21); thus, our conservation landscapes of 63 plants provide the research community with a unique chance to decode plant genomes.”
miRmap: Comprehensive prediction of microRNA target repression strength (2012, neutral): “considered as islands of natural selection in a sea of mostly neutrally evolving sequence; 5% of the human 30-UTR bases are constrained (37).”