The origin of mirror repeats in the human genome

Mirror DNA repeats were found in genomic DNA several decades ago, but their role and the mechanisms leading to their abundance have remained a mystery. The only firmly established functional property was that the subset of long homopurine-homopyrimidine mirror repeats (H-motifs) can form a triple-helical DNA secondary structure (H-DNA). Here, we analyzed the sequence content of mirror repeats in the telomere-to-telomere human genome sequence. Our findings suggest that long mirror repeats in genomic DNA originate exclusively from the expansion of simple tandem repeats (STRs). Strikingly, long H-motifs are highly overrepresented compared to all other mirror repeats and STRs. We hypothesize that long H-motif STRs could be particularly expansion-prone owing to H-DNA-mediated genome instability, pointing to the length at which this structure becomes a significant hindrance.