Dependence among sites in protein and RNA evolution

by 1976- Yu, Jiaye

YU, JIAYE. Dependence among sites in protein and RNA evolution. (Under the direction of Dr. Jeffrey L. Thorne) Widely used models of molecular evolution assume independent change among sequence sites. This assumption facilitates computation but it is biologically unrealistic. RNA secondary structure and protein tertiary structure both change more slowly over time than do the encoding DNA sequences. The constraints upon sequence evolution that serve to maintain structure induce dependent change among molecular sequence positions. The object of this thesis is to characterize the impact of structure on sequence evolution. The dependence among sites in protein evolution is first studied. Two simple and not very parametric hypothesis tests are introduced to study the spatial clustering of amino acid replacements within protein tertiary structure. Results of applying these tests to 273 protein families support the expectation that spatial clustering of amino acid replacements within tertiary structure is a ubiquitous phenomenon. More importantly, patterns of amino acid replacements do not seem to be solely attributable to spatial clustering of sequence positions that are independently evolving and have high rates of change. Instead, application of the newly introduced simple hypothesis tests yields evidence for dependent change among spatially clustered protein positions. This portion of the thesis work thereby casts doubt upon widely used methods for phylogeny inference. The second focus of this thesis is the impact of RNA secondary structure on RNA evolution. A model of RNA evolution incorporating RNA secondary structure is developed. The model introduces dependence among sites in RNA evolution via the effects of sequence changes on the approximate free energy of the resulting RNA secondary structure. This approximate free energy information can be thought as surrogate of fitness that serves as a link between genotype and phenotype in the model. Analysis of eukaryotic 5S ribosomal RNA sequences with this model shows the importance of RNA secondary structure on evolution. This analysis also confirms the value of the new model for studying adaptive evolution and for inferring ancestral sequences. Dependence among sites in protein and RNA evolution by Jiaye Yu a dissertation submitted to the graduate faculty of north carolina state university in partial fulfillment of the requirements for the degree of doctor of philosophy bioinformatics raleigh 2005 approved by: William R. Atchley Carla Mattos Jeffrey L. Thorne chair of advisory committee Bruce S. Weir  To my parents and my wife ii Biography Jiaye Yu was born as the only child to his parents Zhi Yu and Jianhua Zhou in Wenshan, Yunnan Province, China in November 1976. He was admitted to Shanghai JiaoTong University (SJTU) in 1993 and received a Bachelor of Engineering degree in Biochemical Engineering in July 1997. He then received a Master of Science degree in Biochemistry and Molecular Biology in March 2000 from SJTU. In August 2000, Jiaye came to North Carolina State University (NCSU) to pursue a PhD degree in Bioinformatics. Under the direction of Dr. Jeffrey L. Thorne, Jiaye studied dependence among sites in evolution of protein and RNA sequences. He will continue to work in the area of molecular evolution as a postdoc in University of Copenhagen, Denmark. iii