Abstract
Interpreting genetic changes observed in individual patients is a critical challenge. The array of immune deficiency syndromes is typically caused by genetic variation unique to individuals. Therefore, new approaches are needed to interpret functional variation and accelerate genomics interpretation. We constructed the first full-length structural model of human RAG recombinase across four functional states of the recombination process. We functionally tested 182 clinically observed RAG missense mutations. These experiments revealed dysfunction due to recombinase dysfunction and altered chromatin interactions. Structural modeling identified mechanical and energetic roles for each mutation. We built regression models for RAG1 (R2= 0.91) and RAG2 (R2= 0.97) to predict RAG activity changes. We applied our model to 711 additional RAG variants observed in population studies and identified a subset that may impair RAG function. Thus, we demonstrated a fundamental advance in the mechanistic interpretation of human genetic variations spanning from rare and undiagnosed diseases to population health.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.