Inherent instability of simple DNA repeats shapes an evolutionarily stable distribution of repeat lengths

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Simple tandem repeats (STRs) are prevalent in mammalian genomes.
• The evolutionary forces shaping STR length distribution are not fully understood.
• Longer STRs are associated with various genetic disorders.

Purpose of the Study:

• To analyze the distribution of STR lengths in the human and over 300 mammalian genomes.
• To investigate the mutation dynamics and evolutionary processes governing STR lengths.
• To determine the role of selection versus mutation in shaping STR distributions.

Main Methods:

• Assembly of STR length distribution using the Telomere-to-Telomere reference.
• Analysis of over 300 mammalian genomes.
• Quantitative modeling of mutation rates (expansion, contraction, interruption) and per-generation dynamics.
• Assessment of long-term behavior shaping STR length distribution.

Main Results:

• Remarkable consistency in STR length distribution shape across mammalian evolution.
• All analyzed genomes exhibit an excess of long STRs, potentially linked to repeat expansion disorders.
• Short repetitive sequences result from random substitution.
• Longer STRs (>10 nt) are maintained by a dynamic balance of expansion, contraction, and interruption mutations.
• These mutational processes sufficiently explain the abundance of long STRs without invoking natural selection.

Conclusions:

• STR length distribution is shaped by mutation dynamics, not natural selection.
• The balance of expansion, contraction, and interruption mutations explains the persistence of long STRs.
• Understanding these mutation mechanisms is crucial for insights into genome fidelity and repeat instability disorders.