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bioRxiv · 10.1101/2024.09.05.611508

Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding

Burghardt, T. P.
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Abstract

BackgroundHuman ventriculum myosin ({beta}mys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates {beta}mys activity and impacts overall cardiac function. Nonsynonymous single nucleotide variants (SNVs) change protein sequence in {beta}mys or MYBPC3 causing inheritable heart diseases by affecting the {beta}mys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by continuously processing new information content from diverse data modalities in partnership with the human agent. MethodsA general neural-network contraction model characterizes SNV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SNVs genetic characteristics and in this sense decodes {beta}mys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When a SNV modified domain locates to an inter-protein contact in {beta}mys/MYBPC3 it affects complex coordination. Domains involved, one in {beta}mys and the other in MYBPC3, form coordinated domains (co-domains). Co-domains are bilateral implying potential for their SNV modification probabilities to respond jointly to a common perturbation to reveal their location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains that are mapped by a methodology called 2-dimensional correlation genetics (2D-CG). ResultsInterpreting the general neural-network contraction model output involves 2D-CG co-domain mapping that provides natural language expressed structural insights. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein interaction data into a nascent digital twin. This process is the template for combining new information content from diverse data modalities into a digital model that can evolve. The nascent digital twin interprets SNV implications to discover disease mechanism, can evaluate potential remedies for efficacy, and does so without animal models. HighlightsNeural-symbolic hybrid model decodes muscle genetics into contraction mechanisms And evolves in virtuous cycle Optimize-Interpret-Revise-Repeat aided by human partner Nascent digital twin unravels inheritable disease mechanism without animal models And estimates cardiac phenotype coupling strength to myosin thick-filament structures

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Burghardt, T. P.. 2024-09-10. Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding. https://doi.org/10.1101/2024.09.05.611508

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