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J Mol Biol. 2017 Feb 3;429(3):435-445. doi: 10.1016/j.jmb.2016.12.003. Epub 2016 Dec 7.

Intensification: A Resource for Amplifying Population-Genetic Signals with Protein Repeats.

Author information

1
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
2
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
3
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA.
4
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA. Electronic address: mark@gersteinlab.org.

Abstract

Large-scale genome sequencing holds great promise for the interpretation of protein structures through the discovery of many, rare functional variants in the human population. However, because protein-coding regions are under high selective constraints, these variants occur at low frequencies, such that there is often insufficient statistics for downstream calculations. To address this problem, we develop the Intensification approach, which uses the modular structure of repeat protein domains to amplify signals of selection from population genetics and traditional interspecies conservation. In particular, we are able to aggregate variants at the codon level to identify important positions in repeat domains that show strong conservation signals. This allows us to compare conservation over different evolutionary timescales. It also enables us to visualize population-genetic measures on protein structures. We make available the Intensification results as an online resource (http://intensification.gersteinlab.org) and illustrate the approach through a case study on the tetratricopeptide repeat.

KEYWORDS:

database; exome sequencing; population genetics; protein repeat domain; protein structure

PMID:
27939289
PMCID:
PMC5420328
DOI:
10.1016/j.jmb.2016.12.003
[Indexed for MEDLINE]
Free PMC Article

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