Human genetic variations reveal Chromosomal Instability aiding Variants (CIVa) in kinetochore-microtubule associated proteins

Abstract

The vast majority of Chromosomal Instability (CIN) promoting mutations remain unknown. We assess the prevalence of Chromosomal Instability aiding Variants (CIVa) by collating Loss-of-Function (LoF) variants predicted in 135 chromosome segregation genes from over 150,000 humans, including consanguineous individuals. Surprisingly, we observe heterozygous and homozygous CIVa in Astrin and SKA3 genes that encode evolutionarily conserved microtubule-associated proteins essential for chromosome segregation. By combining high-resolution microscopy and controlled protein expression, we show the naturally occurring Astrin variant, p.Q1012*, as potentially harmful because it fails to localise normally, delays anaphase onset, induces chromosome misalignment and promotes chromosome missegregation. We show that N-terminal frameshift variants in Astrin and SKA3 are likely to generate shorter isoforms that do not compromise chromosome segregation revealing resilient mechanisms to cope with harmful variants. This study provides a framework to predict and stratify naturally occurring CIVa, an important step towards precision medicine for CIN syndromes.

Contribution of histone variants to aneuploidy: a cancer perspective

“…Overall, this work lays the ground for research into the role of histones and their variants in the disruption of chromosomal stability in cancer. For instance, comprehensive analyses of mutations in chromosome segregation genes have shed light on their contribution to genomic stability in health and disease states (Islam et al, 2022), highlighting the importance of investing functional effects of such alterations. Beside the fundamental and well-characterised contribution of the H3 variant CENP-A to the Frontiers in Genetics frontiersin.org specification and maintenance of the centromere, the data collected altogether may indicate that other histone variants could also contribute to the specify and/or maintain a correct centromeric/ kinetochore function.…”