Insertion-Deletion Events Are Depleted in Protein Regions with Predicted Secondary Structure.

Area of Science:

• Evolutionary biology
• Population genetics
• Genomics
• Protein structure

Background:

• Understanding how natural selection acts on new mutations is crucial in evolutionary biology.
• Insertion-deletion (indel) events are a key source of genetic variation.
• The relationship between indels and protein secondary structures is not well understood.

Purpose of the Study:

• To test the hypothesis that indels in protein-coding regions occur randomly with respect to protein secondary structures.
• To investigate the impact of selection on indel distribution across different secondary structure types.
• To compare selection efficiency on indels between species with different effective population sizes.

Main Methods:

• Identified indels in 11,444 sequence alignments from mouse, rat, human, chimp, and dog genomes.
• Predicted protein secondary structures (alpha helices, beta strands, bends, turns) using AlphaFold2 deep-learning models.
• Quantified indel overlap with predicted secondary structures and analyzed indel frequencies in human genomes.

Main Results:

• Indels were underrepresented in protein secondary structures (54% less than expected), particularly in stable beta strands.
• Indels were enriched in regions lacking predicted secondary structures (155% more than expected).
• Selection against indels in secondary structures was stronger in rodents than primates, correlating with effective population size.
• Nonsynonymous substitutions were also less frequent in secondary structures, but less so than indels.
• Human genome analysis revealed significantly lower frequencies for indels within secondary structures compared to those outside.

Conclusions:

• Indels overlapping protein secondary structures are selected against, likely due to disruption of protein tertiary structure and function.
• The findings support the role of natural selection in shaping indel evolution based on functional constraints.
• Differences in selection efficiency between rodents and primates align with population genetic predictions.