Evolutionary Analysis of the Histone Deacetylase Family: Biomedical Research

Summary

Principal Investigator: JOSEPH LEWIS GRAVES
Abstract: DESCRIPTION (provided by applicant): This proposal seeks to utilize evolutionary methods to examine molecular signatures of positive in the histone deacetylase family (HDAC's.) The HDAC's reverse the regulatory acetylation of histone proteins thereby influencing nucleosome structure and altering gene transcription. The HDAC's are also associated with gene activation. Acetylation of core histones has been correlated with cellular processes including chromatin assembly, DNA repair, and recombination. The fact that HDACs interact with various partners through complex molecular mechanisms leading to the control of gene expression means that they have become an active area of research. This possibility has important biomedical research implications, in that the HDAC's have been implicated in a number of disease systems including general aging, age- dependent memory impairment, developmental abnormalities, HIV infection, various cancers, GPI deficiency, ulcerative colitis, sickle cell disease, and chronic obstructive pulmonary disease among others. The analysis of adaptive evolution in the HDAC family will require the acquisition and alignment of the sequences of HDAC's from all fully sequenced organisms. Since it is important that the alignment process does not introduce frameshifts and preserves codons, the alignment will go from translated protein sequences and then map backward to codons. Once these sequences are aligned, phylogenetic trees shall be drawn and their reliability estimated by various methods (Maximum Likelihood, Bayesian Analysis.) Once these steps have been achieved, the trees will be used to detect adaptive evolution via dN/dS ratios. To achieve these ends I must receive training and become competent in the existing phylogenetic and computational software: CLUSTAL &MUSCLE (for alignments), PAUP*, PHYML, MrBayes, BEAST, RaxML (for phylogenetic reconstruction), PAML (for selection analysis). In addition, I shall need to further develop my understanding of the theory behind computational methods applied to phylogeny and elucidating adaptive evolution at the molecular level. Thus the specific aims of this project are to update the phylogeny of all recognizable HDAC relatives in all fully sequenced organisms (prokaryotic and eukaryotic) and to apply appropriate computational methods for identifying adaptive evolution in the new HDAC phylogeny. Targets of adaptive evolution will help to identify functionality amongst these proteins that may not have been previously demonstrated. This in turn has the potential to inform drug development efforts impacting a breadth of specific diseases, as well as general senescence itself. PUBLIC HEALTH RELEVANCE: The histone deacetylases are proteins that play an important role in gene expression. For this reason these proteins are involved in a number of diseases, such as general aging, age-dependent memory impairment, developmental abnormalities, HIV infection, various cancers, GPI deficiency, ulcerative colitis, sickle cell disease, and chronic obstructive pulmonary . This proposal seeks to utilize evolutionary methods to examine molecular signatures of positive adaptation in the histone deacetylase family (HDAC's.) This in turn has the potential to inform drug development efforts impacting a breadth of specific diseases, as well as general aging itself.
Funding Period: 2011-09-01 - 2012-08-31
more information: NIH RePORT