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

Kerstin Lindblad-Toh; Manuel Garber; Or Zuk; Michael F Lin; Brian J Parker; Gregory Jordan; Evan Mauceli; Lucas D Ward; Craig B Lowe; Alisha K Holloway; Michele Clamp; Sante Gnerre; Ida Moltke; Jiayu Wen; Jakob Skou Pedersen

doi:10.1038/nature10530

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

Kerstin Lindblad-Toh, Manuel Garber, Or Zuk, Michael F Lin, Brian J Parker, Gregory Jordan, Evan Mauceli, Lucas D Ward, Craig B Lowe, Alisha K Holloway, Michele Clamp, Sante Gnerre, Ida Moltke, Jiayu Wen, Jakob Skou Pedersen

Computational and RNA Biology

665 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nature
Volume	478
Issue number	7370
Pages (from-to)	476-82
Number of pages	7
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature10530
Publication status	Published - 27 Oct 2011

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title = "A high-resolution map of human evolutionary constraint using 29 mammals",

abstract = "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.",

author = "Kerstin Lindblad-Toh and Manuel Garber and Or Zuk and Lin, {Michael F} and Parker, {Brian J} and Gregory Jordan and Evan Mauceli and Ward, {Lucas D} and Lowe, {Craig B} and Holloway, {Alisha K} and Michele Clamp and Sante Gnerre and Ida Moltke and Jiayu Wen and Pedersen, {Jakob Skou}",

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T1 - A high-resolution map of human evolutionary constraint using 29 mammals

AU - Lindblad-Toh, Kerstin

AU - Garber, Manuel

AU - Zuk, Or

AU - Lin, Michael F

AU - Parker, Brian J

AU - Jordan, Gregory

AU - Mauceli, Evan

AU - Ward, Lucas D

AU - Lowe, Craig B

AU - Holloway, Alisha K

AU - Clamp, Michele

AU - Gnerre, Sante

AU - Moltke, Ida

AU - Wen, Jiayu

AU - Pedersen, Jakob Skou

PY - 2011/10/27

Y1 - 2011/10/27

N2 - 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.

AB - 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.

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VL - 478

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JO - Nature

JF - Nature

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

Abstract

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