Nekhai, S. | bioRxiv Science

bioRxiv2023

Validation of human telomere length trans-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as novel human telomere length regulation genes

Telomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enrichment analyses of chromatin state and cell-type heritability we identified blood and immune cells as the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6, a component of an E3 ubiquitin ligase complex, and POP5, a component of the Ribonuclease P/MRP complex, and demonstrating that both lengthened telomeres as predicted by our statistical analyses. CRISPR/Cas9 deletion of the predicted causal regions of these association peaks in K562 immortalized blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5, respectively. Together our results demonstrate the utility of telomere length GWAS in the identification of novel telomere length regulation mechanisms and highlight the importance of the proteasome-ubiquitin pathway in telomere length regulation.

genetics↗

bioRxiv2020

Velcro-like mannose and slime-like sialic acid interactions guide self- adhesion and aggregation of virus N-glycan shields

The surfaces of cells and pathogens are covered with short polymers of sugars known as glycans. Complex N-glycans have a core of three mannose sugars, with distal repeats of N-acetylglucosamine and galactose sugars terminating with sialic acid (SA). Long-range slime-like and short-range Velcro-like self-adhesions were observed between SA and mannose residues, respectively, in ill-defined monolayers. We investigated if and how these adhesions translate when SA and mannose residues are presented in complex N-glycan shields on two pseudo-typed viruses brought together in force spectroscopy (FS). Slime-like adhesions were observed between the shields at higher ramp rates, whereas Velcro-like adhesions were observed at lower rates. The complex glycan shield appears penetrable at the lower ramp rates allowing the adhesion from the mannose core to be accessed; whereas the whole virus appears compressed at higher rates permitting only surface SA adhesions to be sampled. The slime-like and velcro-like adhesions were lost when SA and mannose, respectively, were cleaved with glycosidases. While virus self-adhesion in FS was modulated by glycan penetrability, virus self-aggregation in solution was only determined by the surface sugar. Mannose-terminal viruses self-aggregated in solution, while SA-terminal ones required Ca2+ ions to self-aggregate. Viruses with galactose or N-acetylglucosamine surfaces did not self-aggregate, irrespective of whether or not a mannose core was present below the N-acetylglucosamine surface. Well-defined rules appear to govern the self-adhesion and -aggregation of N-glycosylated surfaces, regardless of whether the sugars are presented in ill-defined monolayer, or N-glycan, or even polymer architecture.

biophysics↗