Conservation weighting functions enable covariance analyses to detect functionally important amino acids.
The explosive growth in the number of protein sequences gives rise to the possibility of using the natural variation in sequences of homologous proteins to find residues that control different protein phenotypes. Because in many cases different phenotypes are each controlled by a group of residues, the mutations that separate one version of a phenotype from another will be correlated. Here we incorporate biological knowledge about protein phenotypes and their variability in the sequence alignment of interest into algorithms that detect correlated mutations, improving their ability to detect the residues that control those phenotypes. We demonstrate the power of this approach using simulations and recent experimental data. Applying these principles to the protein families encoded by Dscam and Protocadherin allows us to make testable predictions about the residues that dictate the specificity of molecular interactions.
University Chemical Laboratory, Cambridge University, Cambridge, United Kingdom.
Lucy J
LJ
Colwell
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
Michael P
MP
Brenner
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America.
Andrew W
AW
Murray
D000465:Algorithms; D000596:Amino Acids / Q000032:analysis* / Q000378:metabolism*; D000704:Analysis of Variance; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence; D008958:Models, Molecular; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
D000596:Amino Acids; D011506:Proteins