title: Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.
abstract: Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Julian R
authors.initials: JR
authors.lastname: Homburger
authors.affiliation: MyoKardia, Inc., South San Francisco, CA 94080;
authors.forename: Eric M
authors.initials: EM
authors.lastname: Green
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305;
authors.forename: Colleen
authors.initials: C
authors.lastname: Caleshu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India;
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Sunitha
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ruppel
authors.affiliation: Collaborative Bioinformatics Lab, Geisinger Clinic, Danville, PA 17822;
authors.forename: Raghu Prasad Rao
authors.initials: RP
authors.lastname: Metpally
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.affiliation: Department of Cardiology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands;
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
authors.affiliation: Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy 50134;
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; Department of Biomedical Data Sciences, Stanford University, Stanford, CA 94305;
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Regeneron Genetics Center, Tarrytown, NY 10591;
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; jspudich@stanford.edu euan@stanford.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Spudich
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305; jspudich@stanford.edu euan@stanford.edu.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
mesh_terms: D024722:Cardiac Myosins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics; D030541:Databases, Genetic; D016757:Death, Sudden, Cardiac; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics; D014644:Genetic Variation; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008958:Models, Molecular; D018995:Myosin Heavy Chains / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: genetic burden; hypertrophic cardiomyopathy; myosin; rare disease genetics