Genome (in)stability at tandem repeats

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Repeat sequences comprise over half of the human genome, contributing to physiological and pathological variations.
• Tandem repeats (TRs), a class of repetitive DNA, exhibit mutation rates 10-10,000 times higher than other genomic regions.
• TR instability is linked to diseases like cancer, diabetes, neurodegenerative, and neuromuscular disorders.

Purpose of the Study:

• To review current knowledge on surveillance and repair mechanisms in human tandem repeat (TR) regions.
• To elucidate how disruptions in protective processes at TRs lead to pathological mutations.
• To discuss the role of TRs in human evolution and potential strategies to mitigate their detrimental effects.

Main Methods:

• Literature review of studies on tandem repeat (TR) mutation mechanisms.
• Analysis of genomic surveillance and DNA repair pathways associated with TRs.
• Review of evidence linking TR instability to human diseases and evolution.

Main Results:

• Tandem repeats (TRs) are prone to instability due to their repetitive nature and high homology, leading to aberrant recombination and genomic rearrangements.
• Mutagenic mechanisms contributing to TR instability are not fully understood but involve DNA repair pathway alterations.
• Altered repair processes at TRs generate specific mutational signatures associated with various human diseases.

Conclusions:

• Dysregulation of DNA repair and surveillance at tandem repeats (TRs) is a key driver of genomic instability and human diseases.
• Understanding TR dynamics is crucial for developing therapeutic strategies and appreciating their evolutionary significance.
• TRs, despite their instability, are conserved and play a role in human evolution.