Date of Completion

12-7-2015

Embargo Period

12-5-2016

Keywords

Genetics, Genomics, BIoinformatics Molecular Biology, Evolution, Gene Duplication, Mammals, Retrotransposition, RIbosomal Proteins, CRISPR-Cas9

Major Advisor

Dr. Craig Nelson

Associate Advisor

Dr. Victoria Robinson

Associate Advisor

Dr. Peter Gogarten

Associate Advisor

Dr. Charlie Giardina

Associate Advisor

Dr. Leighton Core

Field of Study

Genetics and Genomics

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Since Susumu Ohno’s seminal work in 1970, gene duplication has been widely recognized as the origin of multi-gene families and a major mechanism of evolutionary change. Understanding forces that govern the evolution of gene families through retention or loss of duplicated genes has been the subject of much inquiry and debate. The key challenge in this debate is accounting for retention of duplicate genes when, in the absence of some countervailing selective pressure leading to their retention, population genetics predicts that the overwhelming majority of duplicated genes should be lost. In an attempt to investigate the generation and retention of duplicate genes in mammals, the Nelson lab undertook annotation of duplication events in five mammalian genomes. We classified each event by duplication mechanism and duplicate gene fate. This led to two important and unexpected findings: First, half of all conserved duplicates are generated by RNA-based duplication (Retroduplication) events; second, ribosomal protein genes constitute one of the largest classes of conserved duplicated genes in mammals with majority of these duplicates being RNA-based.

The work in this thesis begins with identifying and characterizing all gene duplicates of mammalian ribosomal protein gene (RPG) families. We found an unexpected large amount of intact retroduplicates (RTs) which cannot be readily explained by Ohno’s classic gene duplication trajectories. Hence, we propose a novel gene duplication model, Duplication Purification and Inactivation (DPI) that would be able to account for this phenomenon and ultimately serve in conjunction with other established models. Specifically, we hypothesize that dominant negative phenotypes prevent fixation of missense mutations in duplicated genes, thereby extending the survival of intact copies in the genome.

Together, this thesis work provides a comprehensive history of ribosomal protein evolution in mammals, comprises a body of evidence that meets or exceeds that available for any other model of duplicate retention, and establishes the impact of forces that could influence the fate of every gene duplication event. Thus, the work described here has the potential to provide one of the most rigorously tested and widely applicable models of duplicate gene retention since Ohno first articulated the problem in the 1970’s.

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