Leveraging base-pair mammalian constraint to understand genetic variation and human disease-Reference-Cited by-同舟云学术

Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Published:2023-04-28 Issue:6643 Volume:380 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Sullivan Patrick F.¹²^ORCID,Meadows Jennifer R. S.³^ORCID,Gazal Steven⁴⁵^ORCID,Phan BaDoi N.⁶^ORCID,Li Xue⁷⁸^ORCID,Genereux Diane P.⁷^ORCID,Dong Michael X.³^ORCID,Bianchi Matteo³^ORCID,Andrews Gregory⁷^ORCID,Sakthikumar Sharadha³⁸^ORCID,Nordin Jessika³^ORCID,Roy Ananya⁹,Christmas Matthew J.³^ORCID,Marinescu Voichita D.³^ORCID,Wang Chao³^ORCID,Wallerman Ola³^ORCID,Xue James⁸¹⁰^ORCID,Yao Shuyang²^ORCID,Sun Quan¹^ORCID,Szatkiewicz Jin¹^ORCID,Wen Jia¹,Huckins Laura M.¹¹^ORCID,Lawler Alyssa¹²¹³^ORCID,Keough Kathleen C.¹⁴¹⁵^ORCID,Zheng Zhili¹⁶^ORCID,Zeng Jian¹⁶^ORCID,Wray Naomi R.¹⁶^ORCID,Li Yun¹^ORCID,Johnson Jessica¹¹^ORCID,Chen Jiawen¹⁷^ORCID,Paten Benedict¹⁸^ORCID,Reilly Steven K.¹⁹^ORCID,Hughes Graham M.²⁰^ORCID,Weng Zhiping⁷^ORCID,Pollard Katherine S.¹⁴¹⁵²¹^ORCID,Pfenning Andreas R.⁶¹²^ORCID,Forsberg-Nilsson Karin⁹²²^ORCID,Karlsson Elinor K.⁷⁸²³^ORCID,Lindblad-Toh Kerstin³⁸^ORCID,Andrews Gregory,Armstrong Joel C.,Bianchi Matteo,Birren Bruce W.,Bredemeyer Kevin R.,Breit Ana M.,Christmas Matthew J.,Clawson Hiram,Damas Joana,Di Palma Federica,Diekhans Mark,Dong Michael X.,Eizirik Eduardo,Fan Kaili,Fanter Cornelia,Foley Nicole M.,Forsberg-Nilsson Karin,Garcia Carlos J.,Gatesy John,Gazal Steven,Genereux Diane P.,Goodman Linda,Grimshaw Jenna,Halsey Michaela K.,Harris Andrew J.,Hickey Glenn,Hiller Michael,Hindle Allyson G.,Hubley Robert M.,Hughes Graham M.,Johnson Jeremy,Juan David,Kaplow Irene M.,Karlsson Elinor K.,Keough Kathleen C.,Kirilenko Bogdan,Koepfli Klaus-Peter,Korstian Jennifer M.,Kowalczyk Amanda,Kozyrev Sergey V.,Lawler Alyssa J.,Lawless Colleen,Lehmann Thomas,Levesque Danielle L.,Lewin Harris A.,Li Xue,Lind Abigail,Lindblad-Toh Kerstin,Mackay-Smith Ava,Marinescu Voichita D.,Marques-Bonet Tomas,Mason Victor C.,Meadows Jennifer R. S.,Meyer Wynn K.,Moore Jill E.,Moreira Lucas R.,Moreno-Santillan Diana D.,Morrill Kathleen M.,Muntané Gerard,Murphy William J.,Navarro Arcadi,Nweeia Martin,Ortmann Sylvia,Osmanski Austin,Paten Benedict,Paulat Nicole S.,Pfenning Andreas R.,Phan BaDoi N.,Pollard Katherine S.,Pratt Henry E.,Ray David A.,Reilly Steven K.,Rosen Jeb R.,Ruf Irina,Ryan Louise,Ryder Oliver A.,Sabeti Pardis C.,Schäffer Daniel E.,Serres Aitor,Shapiro Beth,Smit Arian F. A.,Springer Mark,Srinivasan Chaitanya,Steiner Cynthia,Storer Jessica M.,Sullivan Kevin A. M.,Sullivan Patrick F.,Sundström Elisabeth,Supple Megan A.,Swofford Ross,Talbot Joy-El,Teeling Emma,Turner-Maier Jason,Valenzuela Alejandro,Wagner Franziska,Wallerman Ola,Wang Chao,Wang Juehan,Weng Zhiping,Wilder Aryn P.,Wirthlin Morgan E.,Xue James R.,Zhang Xiaomeng,

Affiliation:

1. Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.

2. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden.

3. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.

4. Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

5. Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

6. Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

7. Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

8. Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.

9. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.

10. Center for System Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

11. Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

12. Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

13. Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

14. Gladstone Institutes, San Francisco, CA 94158, USA.

15. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.

16. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.

17. Department of Biostatistics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.

18. UC Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.

19. Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.

20. School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland.

21. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

22. Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK.

23. Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.

Abstract

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.abn2937

Reference159 articles.

1. Expanded encyclopaedias of DNA elements in the human and mouse genomes

2. The GTEx Consortium atlas of genetic regulatory effects across human tissues

3. The mutational constraint spectrum quantified from variation in 141,456 humans

4. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

5. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data

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