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Updated: Sep 1, 2025
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
11.1K
Correlations between alignment gaps and nucleotide substitution or amino acid replacement.
Tae-Kun Seo1, Benjamin D Redelings2,3,4, Jeffrey L Thorne5,6
1Division of Life Sciences, Korea Polar Research Institute, Yeonsu-gu, Incheon 21990, Republic of Korea.
Summary
This study introduces a test for alignment gaps in evolutionary inference, finding that gap locations often depend on evolutionary processes. Relying on single optimal alignments may lead to biased evolutionary inferences.
Area of Science:
- Bioinformatics
- Computational Biology
- Evolutionary Biology
Background:
- Alignment gaps are conventionally treated as missing data in evolutionary inference.
- The independence of gap locations from evolutionary processes is a common assumption.
Purpose of the Study:
- To develop and validate a nonparametric test for the null hypothesis that alignment gap locations are independent of nucleotide substitution or amino acid replacement.
- To assess the reliability of current alignment methods in evolutionary inference.
Main Methods:
- A nonparametric test was developed to assess the independence of gap locations and evolutionary processes.
- The test was applied to 1,390 protein alignments informed by tertiary structure.
- Simulations were conducted to evaluate test performance with true and inferred alignments.
Main Results:
- The null hypothesis was rejected for approximately 65% of protein alignments, indicating a dependence between amino acid replacement and gap location.
- Simulations showed the test performs well on true alignments.
- Widely used alignment software frequently rejected the null hypothesis even when it was true, suggesting issues with inferred alignments.
Conclusions:
- Optimal alignments inferred by software may not accurately represent true evolutionary alignments.
- Relying on individual optimal alignments can lead to biased evolutionary inferences.
- The assumption of independence between gap location and evolutionary processes may be invalid in many cases.
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