Selection acting on indels and substitutions in protein coding sequences

• Patterns of selection acting on an expressed protein act to maintain or adapt its structure and function over time. The most widely used method for studying these selective forces is the ratio of synonymous to non-synonymous substitutions (dN/dS), which helps distinguish between neutral, purifying (negative), and adaptive (positive) selection. This ratio, however, examines only amino acid substitutions and ignores other evolutionary forces like small-scale insertions and deletions (indels) that may affect protein evolution. There are currently no statistically robust methods for studying the forces acting on protein sequence indels, with the few ad hoc solutions highly dependent on the gap patterns produced by alignment and filtering steps. This study broadens our understanding of how selection acts on indels in proteins by explicitly examining the relationship between selective constraint acting on substitutions and indels. We present a probabilistic model that jointly estimates dN/dS and the indel rate through statistical alignment, which removes biases in both parameter estimates caused by alignment error. We apply our method to thousands of genes from human-mouse and human-chicken pairwise analyses, revealing that the indel rate and selection (dN/dS) tends to be related, demonstrating that purifying selection acting in proteins tends to affect non-synonymous mutations and indels in a quantifiably similar way. We also investigate how the selective forces acting on substitutions and indels vary along genes. Our findings and methods offer the opportunity to begin studying the interaction between substitutions and indels, and the first widely applicable tools for understanding how they impact protein evolution.

Ämnesord

NATURVETENSKAP  -- Biologi -- Evolutionsbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Evolutionary Biology (hsv//eng)

Nyckelord

Natural Selection

Protein Evolution

Pair hidden Markov models

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