Mutability of Druggable Kinases and Pro-inflammatory Cytokines by Their Proximity to Telomeres and A+T Content

Abstract

Mutations of protein kinases are common and can cause cancer and other diseases. However, our understanding of the mutability in genes encoding kinases remains rudimentary. Given previously proposed factors associated with high mutation rates, we analyzed how many genes encoding druggable kinases match with (i) proximity to telomeres or (ii) high A+T content. We extracted genomic information using National Institute of Health Genome Data Viewer. Among 129 druggable human kinase genes studied, 106 genes satisfied either factors (i) or (ii), resulting in an 82% match. A similar 85% match rate was found in 73 genes encoding pro-inflammatory cytokines of multisystem inflammatory syndrome in children. As we further compared these two factors in 20 de novo mutations of mice exposed to space-like ionizing radiation, however, 10 of 20 murine genetic loci met (i) or (ii), leading to only a 50% match. When compared with the top selling approved drugs, the data suggest that matching rate analysis on factor-druggable genome is feasible to systematically prioritize the relative mutability of the novel druggable candidates. These two factors not only predict how mutations of the disease phenotype are attributed to genetic and/or environmental factors but also sort out druggable proteins by their relative mutability.

Reduced GLP-1R availability in the caudate nucleus with Alzheimer’s disease

“…Our prior studies on two factors of proximity to telomeres and high A + T content associated with genetics and epigenetics of human diseases (Lucas et al, 2021;McKnight et al, 2021;Raines et al, 2022;White et al, 2022;Hart et al, 2023;McKnight et al, 2023) suggest that G protein coupled receptors harbor a positive correlation with the fulllength nucleotide size (Raines et al, 2022). The result presented herein regarding two factors associated with high mutation rates in mice, rats, chimpanzees, and humans indicates that GLP-1R is an exception during evolution across mice (1,480 bp, 44%) and chimpanzees (16,610 bp, 57%), i.e., A + T contents of GLP-1R in four species are less than 59%, the average of human chromosomes.…”