| Title: | Leveraging base-pair mammalian constraint to understand genetic variation and human disease |
| Journal: | Science |
| Published: | 28 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37104612/ |
| DOI: | https://doi.org/10.1126/science.abn2937 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028973 |
| Citations: | 43 (42 in last 2 years) as of 8 Aug 2024 |
Publication 11389
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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.</p>
10 Keywords
- Animals
- Biological Evolution
- Disease
- Genetic Variation
- Genome, Human
- Genome-Wide Association Study
- Genomics
- Humans
- Molecular Sequence Annotation
- Polymorphism, Single Nucleotide
142 Authors
- Patrick F. Sullivan
- Jennifer R. S. Meadows
- Steven Gazal
- BaDoi N. Phan
- Xue Li
- Diane P. Genereux
- Michael X. Dong
- Matteo Bianchi
- Gregory Andrews
- Sharadha Sakthikumar
- Jessika Nordin
- Ananya Roy
- Matthew J. Christmas
- Voichita D. Marinescu
- Chao Wang
- Ola Wallerman
- James Xue
- Shuyang Yao
- Quan Sun
- Jin Szatkiewicz
- Jia Wen
- Laura M. Huckins
- Alyssa Lawler
- Kathleen C. Keough
- Zhili Zheng
- Jian Zeng
- Naomi R. Wray
- Yun Li
- Jessica Johnson
- Jiawen Chen
- Benedict Paten
- Steven K. Reilly
- Graham M. Hughes
- Zhiping Weng
- Katherine S. Pollard
- Andreas R. Pfenning
- Karin Forsberg-Nilsson
- Elinor K. Karlsson
- Kerstin Lindblad-Toh
- Gregory Andrews
- Joel C. Armstrong
- Matteo Bianchi
- Bruce W. Birren
- Kevin R. Bredemeyer
- Ana M. Breit
- Matthew J. Christmas
- Hiram Clawson
- Joana Damas
- Federica Di Palma
- Mark Diekhans
- Michael X. Dong
- Eduardo Eizirik
- Kaili Fan
- Cornelia Fanter
- Nicole M. Foley
- Karin Forsberg-Nilsson
- Carlos J. Garcia
- John Gatesy
- Steven Gazal
- Diane P. Genereux
- Linda Goodman
- Jenna Grimshaw
- Michaela K. Halsey
- Andrew J. Harris
- Glenn Hickey
- Michael Hiller
- Allyson G. Hindle
- Robert M. Hubley
- Graham M. Hughes
- Jeremy Johnson
- David Juan
- Irene M. Kaplow
- Elinor K. Karlsson
- Kathleen C. Keough
- Bogdan Kirilenko
- Klaus-Peter Koepfli
- Jennifer M. Korstian
- Amanda Kowalczyk
- Sergey V. Kozyrev
- Alyssa J. Lawler
- Colleen Lawless
- Thomas Lehmann
- Danielle L. Levesque
- Harris A. Lewin
- Xue Li
- Abigail Lind
- Kerstin Lindblad-Toh
- Ava Mackay-Smith
- Voichita D. Marinescu
- Tomas Marques-Bonet
- Victor C. Mason
- Jennifer R. S. Meadows
- Wynn K. Meyer
- Jill E. Moore
- Lucas R. Moreira
- Diana D. Moreno-Santillan
- Kathleen M. Morrill
- Gerard Muntané
- William J. Murphy
- Arcadi Navarro
- Martin Nweeia
- Sylvia Ortmann
- Austin Osmanski
- Benedict Paten
- Nicole S. Paulat
- Andreas R. Pfenning
- BaDoi N. Phan
- Katherine S. Pollard
- Henry E. Pratt
- David A. Ray
- Steven K. Reilly
- Jeb R. Rosen
- Irina Ruf
- Louise Ryan
- Oliver A. Ryder
- Pardis C. Sabeti
- Daniel E. Schäffer
- Aitor Serres
- Beth Shapiro
- Arian F. A. Smit
- Mark Springer
- Chaitanya Srinivasan
- Cynthia Steiner
- Jessica M. Storer
- Kevin A. M. Sullivan
- Patrick F. Sullivan
- Elisabeth Sundström
- Megan A. Supple
- Ross Swofford
- Joy-El Talbot
- Emma Teeling
- Jason Turner-Maier
- Alejandro Valenzuela
- Franziska Wagner
- Ola Wallerman
- Chao Wang
- Juehan Wang
- Zhiping Weng
- Aryn P. Wilder
- Morgan E. Wirthlin
- James R. Xue
- Xiaomeng Zhang
1 Application
| Application ID | Title |
|---|---|
| 12505 | Dissecting the genetic basis of relationships between early-life and later-life events |
Enabling scientific discoveries that improve human health