Remarkable selective constraints on exonic dinucleotide repeats.

Area of Science:

• Genetics
• Evolutionary Biology
• Molecular Biology

Background:

• Long dinucleotide repeats in exons pose a significant mutation risk, often causing frameshifts.
• The evolutionary pressures on these exonic repeat regions are not fully understood.

Purpose of the Study:

• To investigate the selective constraints acting on exonic dinucleotide repeat lengths.
• To determine the role of purifying selection in maintaining these sequences.

Main Methods:

• Genotyping of 18 specific exonic dinucleotides in 200 human individuals across diverse populations.
• Analysis of sequence divergence data across primate phylogeny.
• Coalescent simulations to model mutation rates and selective pressures.

Main Results:

• A near-absence of polymorphism was observed in the genotyped exonic dinucleotides.
• Repeat lengths showed remarkable conservation across primate evolution, defying high mutational pressure.
• Coalescent simulations indicated that mutation rates alone cannot explain the observed patterns.

Conclusions:

• Exonic dinucleotides are under strong selective constraint, exhibiting both short-term intolerance to change and long-term prevention of length increases.
• Purifying selection is the primary mechanism eliminating deleterious mutations at these loci.
• The longest exonic dinucleotide repeat in humans (FGFRL1) presents a unique case for studying mutation dynamics and selection.