Abstract
Chromosome stability is a key point in genome evolution, particularly that of the Y chromosome. The Y chromosome loss in blood and tumor cells is well established. Through processes that are common to other chromosomes too, the Y chromosome undergoes degradation and fragmentation in the blood stream before elimination. This process gives rise to circulating DNA (cirDNA) fragments, whose examination may provide potential insight into the role of DNA fragmentation in blood for the Y chromosome elimination. In this study, we employed shallow whole genome sequencing (sWGS) to comprehensively assess the total cirDNA and the individual chromosome fragment size profiles in the plasma of healthy male individuals. Here, we show that (i) the fragment size profiles of total circulating DNA (cirDNA) and DNA fragments originating from autosomes and the X chromosome in blood plasma are homogeneous, and have a remarkably low variability (mean CV = 7%) among healthy individuals, (ii) the Y chromosome has a distinct fragment size profile with the accumulation of the fragment < 145 bp and depletion of the dinucleosome-associated fragments (290–390 bp), and its fragment fraction in blood decreases with age. These results indicate a higher fragmentation of the Y chromosome compared to other chromosomes and this in turn might be due to its increased susceptibility to degradation. Our findings pave the way for an elucidation of the impact of chromosomal origin on DNA degradation and the Y chromosome biology.
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Data availability
Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001006830.
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Acknowledgements
The authors thank the excellent technical assistance of F. Frayssinoux (IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, F-34134298, France) and Cormac Mc Carthy (Mc Carthy Consultant, Montpellier) for English editing (financial compensation). We thank the healthy donors who participated in this study.
Funding
This work was partially supported by SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553.
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Conceptualization: AT, EP. Methodology: AT, EP. Investigation: EP, CS. Visualization: AT, EP, CS. Supervision: AT, EP. Writing—original draft: AT, EP. Writing—review and editing: AT, EP.
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Thierry, A.R., Sanchez, C., Colinge, J. et al. Circulating DNA reveals a specific and higher fragmentation of the Y chromosome. Hum. Genet. 142, 1603–1609 (2023). https://doi.org/10.1007/s00439-023-02600-x
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DOI: https://doi.org/10.1007/s00439-023-02600-x