Search for chromosomal instability aiding variants reveal naturally occurring kinetochore gene variants that perturb chromosome segregation

• Published in: iScience Vol. 27; no. 3; p. 109007
• Main Authors: Islam, Asifa, Manjarrez-González, Janeth Catalina, Song, Xinhong, Gore, Trupti, Draviam, Viji M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2024; Elsevier
• Subjects: Cell biology; Chromosome organization; Genotyping; Molecular genetics; Phenotyping; Techniques in genetics; Cell biology; Techniques in genetics; Molecular genetics; Genotyping; Chromosome organization; Phenotyping
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109007

Chromosomal instability (CIN) is a hallmark of cancers, and CIN-promoting mutations are not fully understood. Here, we report 141 chromosomal instability aiding variant (CIVa) candidates by assessing the prevalence of loss-of-function (LoF) variants in 135 chromosome segregation genes from over 150,000 humans. Unexpectedly, we observe both heterozygous and homozygous CIVa in Astrin and SKA3, two evolutionarily conserved kinetochore and microtubule-associated proteins essential for chromosome segregation. To stratify harmful versus harmless variants, we combine live-cell microscopy and controlled protein expression. We find the naturally occurring Astrin p.Q1012∗ variant is harmful as it fails to localize normally and induces chromosome misalignment and missegregation, in a dominant negative manner. In contrast, the Astrin p.L7Qfs∗21 variant generates a shorter isoform that localizes and functions normally, and the SKA3 p.Q70Kfs∗7 variant allows wild-type SKA complex localisation and function, revealing distinct resilience mechanisms that render these variants harmless. Thus, we present a scalable framework to predict and stratify naturally occurring CIVa, and provide insight into resilience mechanisms that compensate for naturally occurring CIVa. [Display omitted] •We report 141 Chromosomal Instability aiding Variant (CIVa) candidates in humans•Astrin p.Q1012∗ is harmful; it dominant-negatively aids chromosome missegregation•Astrin p.L7Qfs∗21 is harmless, expressing a short isoform that localizes normally•SKA3 p.Q70Kfs∗7 allows endogenous SKA complex’s normal mitotic function Techniques in genetics; Molecular genetics; Phenotyping; Genotyping; Chromosome organization; Cell biology