A5011609163- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Evolution and Genetic Dynamics
- DNA Repair Mechanisms
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Connexins and lens biology
Neurological Research Institute
2022-2025
Texas Children's Hospital
2022-2025
Baylor College of Medicine
2022-2024
Abstract The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant variation—regions often implicated disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries test several key intolerance metrics, including Residual Variance Intolerance Score...
Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it caused by mutation broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; importance this other vulnerable remains unknown. Here, we mutated 154Q knockin allele Atxn1154Q/2Q mice to prevent ATXN1-CIC globally. This normalized genome-wide...
Summary Rapidly expanding genomic databases have enabled the identification of regions in human genome intolerant to variation and thus likely relevant disease. However, despite their unprecedented scale, these datasets remain constrained by limited ancestral diversity. Here, we systematically evaluate how genetic diversity impacts gene- sub-genic intolerance metrics analyzing whole-exome sequencing data from 460,551 UK Biobank participants 125,748 gnomAD across diverse backgrounds. Through...