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

Autor: Sullivan PF; Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden., Meadows JRS; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Gazal S; Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Phan BN; Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA., Li X; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA., Genereux DP; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Dong MX; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Bianchi M; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Andrews G; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Sakthikumar S; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA., Nordin J; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Roy A; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden., Christmas MJ; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Marinescu VD; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Wang C; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Wallerman O; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden., Xue J; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.; Center for System Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA., Yao S; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden., Sun Q; Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA., Szatkiewicz J; Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA., Wen J; Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA., Huckins LM; Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Lawler A; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA.; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA., Keough KC; Gladstone Institutes, San Francisco, CA 94158, USA.; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA., Zheng Z; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia., Zeng J; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia., Wray NR; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia., Li Y; Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA., Johnson J; Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Chen J; Department of Biostatistics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA., Paten B; UC Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA., Reilly SK; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Hughes GM; School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland., Weng Z; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Pollard KS; Gladstone Institutes, San Francisco, CA 94158, USA.; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA., Pfenning AR; Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA., Forsberg-Nilsson K; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.; Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Karlsson EK; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.; Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA., Lindblad-Toh K; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Apr 28; Vol. 380 (6643), pp. eabn2937. Date of Electronic Publication: 2023 Apr 28.
DOI: 10.1126/science.abn2937
Abstrakt: 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.
Databáze: MEDLINE
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