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

Kerstin Lindblad-Toh; Manuel Garber; Or Zuk; Michael F. Lin; Brian J. Parker; Stefan Washietl; Pouya Kheradpour; Jason Ernst; Gregory Jordan; Evan Mauceli; Lucas D. Ward; Craig B. Lowe; Alisha K. Holloway; Michele Clamp; Sante Gnerre; Jessica Alföldi; Kathryn Beal; Jean Chang; Hiram Clawson; James Cuff; Federica Di Palma; Stephen Fitzgerald; Paul Flicek; Mitchell Guttman; Melissa J. Hubisz; David B. Jaffe; Irwin Jungreis; W. James Kent; Dennis Kostka; Marcia Lara; Andre L. Martins; Tim Massingham; Ida Moltke; Brian J. Raney; Matthew D. Rasmussen; Jim Robinson; Alexander Stark; Albert J. Vilella; Jiayu Wen; Xiaohui Xie; Michael C. Zody; Kim C. Worley; Christie L. Kovar; Donna M. Muzny; Richard A. Gibbs; Wesley C. Warren; Elaine R. Mardis; George M. Weinstock; Richard K. Wilson; Ewan Birney; Elliott H. Margulies; Javier Herrero; Eric D. Green; David Haussler; Adam Siepel; Nick Goldman; Katherine S. Pollard; Jakob S. Pedersen; Eric S. Lander; Manolis Kellis; Jen Baldwin; Toby Bloom; Chee Whye Chin; Dave Heiman; Robert Nicol; Chad Nusbaum; Sarah Young; Jane Wilkinson; Andrew Cree; Huyen H. Dihn; Gerald Fowler; Shalili Jhangiani; Vandita Joshi; Sandra Lee; Lora R. Lewis; Lynne V. Nazareth; Geoffrey Okwuonu; Jireh Santibanez; Kim Delehaunty; David Dooling; Catrina Fronik; Lucinda Fulton; Bob Fulton; Tina Graves; Patrick Minx; Erica Sodergren

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, Stefan Washietl, Pouya Kheradpour, Jason Ernst, Gregory Jordan, Evan Mauceli, Lucas D. Ward, Craig B. Lowe, Alisha K. Holloway, Michele Clamp, Sante Gnerre, Jessica Alföldi, Kathryn Beal, Jean Chang, Hiram Clawson, James CuffFederica Di Palma, Stephen Fitzgerald, Paul Flicek, Mitchell Guttman, Melissa J. Hubisz, David B. Jaffe, Irwin Jungreis, W. James Kent, Dennis Kostka, Marcia Lara, Andre L. Martins, Tim Massingham, Ida Moltke, Brian J. Raney, Matthew D. Rasmussen, Jim Robinson, Alexander Stark, Albert J. Vilella, Jiayu Wen, Xiaohui Xie, Michael C. Zody, Kim C. Worley, Christie L. Kovar, Donna M. Muzny, Richard A. Gibbs, Wesley C. Warren, Elaine R. Mardis, George M. Weinstock, Richard K. Wilson, Ewan Birney, Elliott H. Margulies, Javier Herrero, Eric D. Green, David Haussler, Adam Siepel, Nick Goldman, Katherine S. Pollard, Jakob S. Pedersen, Eric S. Lander, Manolis Kellis, Jen Baldwin, Toby Bloom, Chee Whye Chin, Dave Heiman, Robert Nicol, Chad Nusbaum, Sarah Young, Jane Wilkinson, Andrew Cree, Huyen H. Dihn, Gerald Fowler, Shalili Jhangiani, Vandita Joshi, Sandra Lee, Lora R. Lewis, Lynne V. Nazareth, Geoffrey Okwuonu, Jireh Santibanez, Kim Delehaunty, David Dooling, Catrina Fronik, Lucinda Fulton, Bob Fulton, Tina Graves, Patrick Minx, Erica Sodergren

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

833 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
Pages (from-to)	476-482
Number of pages	7
Journal	Nature
Volume	478
Issue number	7370
DOIs	https://doi.org/10.1038/nature10530
Publication status	Published - 27 Oct 2011
Externally published	Yes

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Lindblad-Toh, K., Garber, M., Zuk, O., Lin, M. F., Parker, B. J., Washietl, S., Kheradpour, P., Ernst, J., Jordan, G., Mauceli, E., Ward, L. D., Lowe, C. B., Holloway, A. K., Clamp, M., Gnerre, S., Alföldi, J., Beal, K., Chang, J., Clawson, H., ... Sodergren, E. (2011). A high-resolution map of human evolutionary constraint using 29 mammals. Nature, 478(7370), 476-482. https://doi.org/10.1038/nature10530

@article{caccabd987724f51b47f97e92ab70091,

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 Stefan Washietl and Pouya Kheradpour and Jason Ernst 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 Jessica Alf{\"o}ldi and Kathryn Beal and Jean Chang and Hiram Clawson and James Cuff and {Di Palma}, Federica and Stephen Fitzgerald and Paul Flicek and Mitchell Guttman and Hubisz, {Melissa J.} and Jaffe, {David B.} and Irwin Jungreis and Kent, {W. James} and Dennis Kostka and Marcia Lara and Martins, {Andre L.} and Tim Massingham and Ida Moltke and Raney, {Brian J.} and Rasmussen, {Matthew D.} and Jim Robinson and Alexander Stark and Vilella, {Albert J.} and Jiayu Wen and Xiaohui Xie and Zody, {Michael C.} and Worley, {Kim C.} and Kovar, {Christie L.} and Muzny, {Donna M.} and Gibbs, {Richard A.} and Warren, {Wesley C.} and Mardis, {Elaine R.} and Weinstock, {George M.} and Wilson, {Richard K.} and Ewan Birney and Margulies, {Elliott H.} and Javier Herrero and Green, {Eric D.} and David Haussler and Adam Siepel and Nick Goldman and Pollard, {Katherine S.} and Pedersen, {Jakob S.} and Lander, {Eric S.} and Manolis Kellis and Jen Baldwin and Toby Bloom and Chin, {Chee Whye} and Dave Heiman and Robert Nicol and Chad Nusbaum and Sarah Young and Jane Wilkinson and Andrew Cree and Dihn, {Huyen H.} and Gerald Fowler and Shalili Jhangiani and Vandita Joshi and Sandra Lee and Lewis, {Lora R.} and Nazareth, {Lynne V.} and Geoffrey Okwuonu and Jireh Santibanez and Kim Delehaunty and David Dooling and Catrina Fronik and Lucinda Fulton and Bob Fulton and Tina Graves and Patrick Minx and Erica Sodergren",

year = "2011",

month = oct,

day = "27",

doi = "10.1038/nature10530",

language = "English",

volume = "478",

pages = "476--482",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7370",

}

Lindblad-Toh, K, Garber, M, Zuk, O, Lin, MF, Parker, BJ, Washietl, S, Kheradpour, P, Ernst, J, Jordan, G, Mauceli, E, Ward, LD, Lowe, CB, Holloway, AK, Clamp, M, Gnerre, S, Alföldi, J, Beal, K, Chang, J, Clawson, H, Cuff, J, Di Palma, F, Fitzgerald, S, Flicek, P, Guttman, M, Hubisz, MJ, Jaffe, DB, Jungreis, I, Kent, WJ, Kostka, D, Lara, M, Martins, AL, Massingham, T, Moltke, I, Raney, BJ, Rasmussen, MD, Robinson, J, Stark, A, Vilella, AJ, Wen, J, Xie, X, Zody, MC, Worley, KC, Kovar, CL, Muzny, DM, Gibbs, RA, Warren, WC, Mardis, ER, Weinstock, GM, Wilson, RK, Birney, E, Margulies, EH, Herrero, J, Green, ED, Haussler, D, Siepel, A, Goldman, N, Pollard, KS, Pedersen, JS, Lander, ES, Kellis, M, Baldwin, J, Bloom, T, Chin, CW, Heiman, D, Nicol, R, Nusbaum, C, Young, S, Wilkinson, J, Cree, A, Dihn, HH, Fowler, G, Jhangiani, S, Joshi, V, Lee, S, Lewis, LR, Nazareth, LV, Okwuonu, G, Santibanez, J, Delehaunty, K, Dooling, D, Fronik, C, Fulton, L, Fulton, B, Graves, T, Minx, P & Sodergren, E 2011, 'A high-resolution map of human evolutionary constraint using 29 mammals', Nature, vol. 478, no. 7370, pp. 476-482. https://doi.org/10.1038/nature10530

TY - JOUR

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 - Washietl, Stefan

AU - Kheradpour, Pouya

AU - Ernst, Jason

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 - Alföldi, Jessica

AU - Beal, Kathryn

AU - Chang, Jean

AU - Clawson, Hiram

AU - Cuff, James

AU - Di Palma, Federica

AU - Fitzgerald, Stephen

AU - Flicek, Paul

AU - Guttman, Mitchell

AU - Hubisz, Melissa J.

AU - Jaffe, David B.

AU - Jungreis, Irwin

AU - Kent, W. James

AU - Kostka, Dennis

AU - Lara, Marcia

AU - Martins, Andre L.

AU - Massingham, Tim

AU - Moltke, Ida

AU - Raney, Brian J.

AU - Rasmussen, Matthew D.

AU - Robinson, Jim

AU - Stark, Alexander

AU - Vilella, Albert J.

AU - Wen, Jiayu

AU - Xie, Xiaohui

AU - Zody, Michael C.

AU - Worley, Kim C.

AU - Kovar, Christie L.

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Warren, Wesley C.

AU - Mardis, Elaine R.

AU - Weinstock, George M.

AU - Wilson, Richard K.

AU - Birney, Ewan

AU - Margulies, Elliott H.

AU - Herrero, Javier

AU - Green, Eric D.

AU - Haussler, David

AU - Siepel, Adam

AU - Goldman, Nick

AU - Pollard, Katherine S.

AU - Pedersen, Jakob S.

AU - Lander, Eric S.

AU - Kellis, Manolis

AU - Baldwin, Jen

AU - Bloom, Toby

AU - Chin, Chee Whye

AU - Heiman, Dave

AU - Nicol, Robert

AU - Nusbaum, Chad

AU - Young, Sarah

AU - Wilkinson, Jane

AU - Cree, Andrew

AU - Dihn, Huyen H.

AU - Fowler, Gerald

AU - Jhangiani, Shalili

AU - Joshi, Vandita

AU - Lee, Sandra

AU - Lewis, Lora R.

AU - Nazareth, Lynne V.

AU - Okwuonu, Geoffrey

AU - Santibanez, Jireh

AU - Delehaunty, Kim

AU - Dooling, David

AU - Fronik, Catrina

AU - Fulton, Lucinda

AU - Fulton, Bob

AU - Graves, Tina

AU - Minx, Patrick

AU - Sodergren, Erica

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.

UR - http://www.scopus.com/inward/record.url?scp=80054973803&partnerID=8YFLogxK

U2 - 10.1038/nature10530

DO - 10.1038/nature10530

M3 - Article

SN - 0028-0836

VL - 478

SP - 476

EP - 482

JO - Nature

JF - Nature

IS - 7370

ER -

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

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