Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features

Marie Dumont, Riccardo Gamba, Pierre Gestraud, Sjoerd Klaasen, Joseph T Worrall, Sippe G De Vries, Vincent Boudreau, Catalina Salinas-Luypaert, Paul S Maddox, Susanne Ma Lens, Geert Jpl Kops, Sarah E McClelland, Karen H Miga, Daniele Fachinetti

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

67 Citaten (Scopus)


Intrinsic genomic features of individual chromosomes can contribute to chromosome-specific aneuploidy. Centromeres are key elements for the maintenance of chromosome segregation fidelity via a specialized chromatin marked by CENP-A wrapped by repetitive DNA. These long stretches of repetitive DNA vary in length among human chromosomes. Using CENP-A genetic inactivation in human cells, we directly interrogate if differences in the centromere length reflect the heterogeneity of centromeric DNA-dependent features and whether this, in turn, affects the genesis of chromosome-specific aneuploidy. Using three distinct approaches, we show that mis-segregation rates vary among different chromosomes under conditions that compromise centromere function. Whole-genome sequencing and centromere mapping combined with cytogenetic analysis, small molecule inhibitors, and genetic manipulation revealed that inter-chromosomal heterogeneity of centromeric features, but not centromere length, influences chromosome segregation fidelity. We conclude that faithful chromosome segregation for most of human chromosomes is biased in favor of centromeres with high abundance of DNA-dependent centromeric components. These inter-chromosomal differences in centromere features can translate into non-random aneuploidy, a hallmark of cancer and genetic diseases.

Originele taal-2Engels
Pagina's (van-tot)e102924
TijdschriftEMBO Journal
StatusE-pub ahead of print - 21 nov. 2019


Duik in de onderzoeksthema's van 'Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features'. Samen vormen ze een unieke vingerafdruk.

Citeer dit