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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Spectral analysis of sequence variability in basic-helix-loop-helix (bHLH) protein domains
1Graduate Program In Biomathematics And Bioinformatics, North Carolina State University, Raleigh, NC 27695-7614, USA.
Evolutionary Bioinformatics Online
|May 21, 2009
Summary
Transcription factor sequence variability, including the basic helix-loop-helix (bHLH) family, exhibits periodicity linked to alpha-helix structures. This study analyzes amino acid variation patterns to understand their structural underpinnings.
Area of Science:
- Structural biology
- Bioinformatics
- Molecular evolution
Background:
- The basic helix-loop-helix (bHLH) protein family is crucial in gene regulation.
- Understanding amino acid sequence variability is key to deciphering protein structure and function.
- Periodicity in protein sequences can reflect underlying structural constraints.
Purpose of the Study:
- To investigate the structural implications of periodicity patterns in amino acid sequence variability within the bHLH domain.
- To correlate sequence variation patterns with the known alpha-helix periodicity.
- To identify the causal components of bHLH sequence variability using physicochemical attributes.
Main Methods:
- Boltzmann-Shannon entropy profiling to quantify site-by-site amino acid variation.
- Spectral analysis of approximately 200 bHLH sequences to detect periodicity.
- Multivariate analysis of nearly 500 amino acid physicochemical attributes.
- Multiple regression analysis to link entropy values with attribute indices.
Main Results:
- Spectral analysis confirmed periodic patterns in bHLH sequence variation.
- These patterns strongly correlate with the 3.6 amino acids per turn periodicity of alpha-helices.
- Multivariate analyses identified key physicochemical attributes (polarity, secondary structure propensity, volume, codon composition, charge) influencing sequence variability.
Conclusions:
- Amino acid variability in bHLH domains is structurally constrained by alpha-helix periodicity.
- Physicochemical properties play a significant role in driving observed sequence variation patterns.
- This research provides insights into the relationship between protein sequence, structure, and evolutionary constraints.
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