Protein tertiary structure changes slowly during evolution. Nucleotide substitution rates are expected to be low if they result in an amino acid replacement that disrupts protein structure. The effect of an amino acid replacement on tertiary structure is determined not only by the residues involved in the replacement but also by the residues that are spatially nearby the site that experiences the replacement. This relationship between protein structure and protein change induces an evolutionary dependence among the positions in the protein-coding genes. Unfortunately, widely used models for the evolution of protein-coding genes ignore this dependence. The research in this project will build upon a newly developed statistical technique for making evolutionary inferences from sequence pairs. This new technique incorporates dependence among codons due to pain/vise amino acid interactions that are imposed by the protein tertiary structure. The initial focus will be to extend this model-based approach to the analysis of more than two phylogenetically-related sequences. The resulting method will be a powerful tool for characterizing the impact of protein structure on protein evolution. The Pandit database of aligned protein-coding DMA sequences will be mined to assess which protein families evolve under the most and least influence of tertiary structure. Evidence of positive selection in this database will be identified and the issue of whether the strength of the relationship between protein structure and protein evolution varies among taxonomic groups will be addressed. To complement the empirical studies and to further evaluate the new methodology, simulations will be performed. In addition, the possibility of allowing protein tertiary structure to change over time will be explored. Ancestral sequence inference that accounts for covarying positions and the potential for applying ancestral sequence inference to vaccine design is another topic of interest. Although the emphasis of this project is evolutionary dependence among codons due to protein structure, the statistical approach is quite general and could be applied to diverse cases of evolutionary dependence where surrogates for sequence fitness can be measured or modeled.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070806-03
Application #
7269344
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2005-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$142,794
Indirect Cost
Name
North Carolina State University Raleigh
Department
Genetics
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Lee, Hui-Jie; Kishino, Hirohisa; Rodrigue, Nicolas et al. (2016) Grouping substitution types into different relaxed molecular clocks. Philos Trans R Soc Lond B Biol Sci 371:
Ji, Xiang; Griffing, Alexander; Thorne, Jeffrey L (2016) A Phylogenetic Approach Finds Abundant Interlocus Gene Conversion in Yeast. Mol Biol Evol 33:2469-76
Lee, Hui-Jie; Rodrigue, Nicolas; Thorne, Jeffrey L (2015) Relaxing the Molecular Clock to Different Degrees for Different Substitution Types. Mol Biol Evol 32:1948-61
Wang, Kuangyu; Yu, Shuhui; Ji, Xiang et al. (2015) Roles of solvent accessibility and gene expression in modeling protein sequence evolution. Evol Bioinform Online 11:85-96
Lassiter, Erica S; Russ, Carsten; Nusbaum, Chad et al. (2015) Mitochondrial genome sequences reveal evolutionary relationships of the Phytophthora 1c clade species. Curr Genet 61:567-77
Vensko 2nd, Steven P; Stone, Eric A (2014) No evidence for a global male-specific lethal complex-mediated dosage compensation contribution to the demasculinization of the Drosophila melanogaster X chromosome. PLoS One 9:e103659
Griffing, Alexander R; Lynch, Benjamin R; Stone, Eric A (2014) Structural properties of the minimum cut of partially-supplied graphs. Discrete Appl Math 117:152-157
Griffing, Alexander R; Lynch, Benjamin R; Stone, Eric A (2013) An eigenvector interlacing property of graphs that arise from trees by Schur complementation of the Laplacian. Linear Algebra Appl 438:1078-1094
Nasrallah, Chris A (2013) The dynamics of alternative pathways to compensatory substitution. BMC Bioinformatics 14 Suppl 15:S2
Liberles, David A; Teichmann, Sarah A; Bahar, Ivet et al. (2012) The interface of protein structure, protein biophysics, and molecular evolution. Protein Sci 21:769-85

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