Abstract
Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal variations and footprints of transposable elements. High-throughput sequencing has led to increasing detection of mosaicism in healthy individuals which is related to ageing, neuro-degenerative disorders, diabetes mellitus, cardiovascular diseases and cancer. These age-related disorders are also known to be associated with significant increase in DNA damage and inflammation. Herein, we discuss a newly described phenomenon wherein the genome is under constant assault by illegitimate integration of cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body every day. We propose that such repeated genomic integration of cfCh followed by dsDNA breaks and repair by non-homologous-end-joining as well as physical damage to chromosomes occurring throughout life may lead to somatic/chromosomal mosaicism which would increase with age. We also discuss the recent finding that genomic integration of cfCh and the accompanying DNA damage is associated with marked activation of inflammatory cytokines. Thus, the triple pathologies of somatic mosaicism, DNA/chromosomal damage and inflammation brought about by a common mechanism of genomic integration of cfCh may help to provide an unifying model for the understanding of aetiologies of the inter-related conditions of ageing, degenerative disorders and cancer.
Highlights
Human genetic research has been concerned with variations that are transmitted through the germ line
Increasingly focusing on post-zygotic non-heritable genetic mutations that accumulate in the human soma throughout life leading to somatic mosaicism that ceases to exist following the death of an individual [1,2,3,4,5]
These findings indicated that Cell-Free Chromatin (cfCh), rather than a result of chromatinization of intracellular cell-free DNA (cfDNA) particles with newly synthesized histones of the cfDNA, have the ability to efficiently integrate into host cell genomes
Summary
Human genetic research has been concerned with variations that are transmitted through the germ line. A recent study of SNVs analysis by single-cell sequencing of 36 neurons of three normal individuals detected thousands of mutations [38]. These mutations appearing in non-dividing neuronal cells apparently reflect DNA damage during active transcription [38]. A recent report has suggested a novel mechanism for generation of somatic mosaicism in the brain of healthy individuals and those with sporadic Alzheimer’s disease (SAD), which involves the reverse transcription and genomic re-integration of the Alzheimer’s disease-related (APP) gene [40]. Aberrant clonal expansion (ACEs) containing various mosaic genetic changes has been observed in normal individuals which increase with age [41,42] and appear to be related to haematological malignancies and cardiovascular disease [43].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
