All ETDs from UAB

Advisory Committee Chair

Eric J Sorscher

Advisory Committee Members

Steven N Austad

Trenton R Schoeb

Thane Wibbels

Stephen A Watts

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Progress in whole genome sequencing in multiple species has provided new knowledge regarding the origins and evolution of large, disease associated genes such as the cystic fibrosis conductance regulator (CFTR). In this context, mechanisms that underlie human mutation, sequence fault tolerance, and maintenance of DNA integrity from the perspective of protein plasticity represent areas of considerable interest. The common occurrence of mutations within CFTR, including the F508del allele, provide a powerful system for studies of this sort. In this project, we consider the stability and persistence of CFTR in terms of longevity, accumulation of single nucleotide polymorphisms (SNPs), and effects on fitness. We describe an analysis of SNP categories most likely to occur within CFTR over an evolutionary timeframe. Our findings include data showing a strong predisposition towards accumulation of both synonymous and noncoding SNPs in a manner suggesting not only the established role of natural selection, but also a significant bias at the time these SNPs were originally produced. Further, we provide evidence for the same process in other eukaryotic genes- as well as confirmatory data indicating the same mechanism in yeast (in addition to human and mouse). We have also cloned, expressed and characterized the most ancient CFTR identified to date (from sea lamprey, Petromyzon marinus) which encodes a CF gene >550 million years old, and conducted initial studies supporting synonymous and transition SNP bias in this species, as well. Finally, because our findings can be interpreted to suggest a significant phenotypic effect on higher organisms carrying loss of function in one CFTR allele, we used a new CF rat model to perform the first comprehensive analysis of cystic fibrosis-related infertility (congenital bilateral absence of the vas deferens, CBAVD) as a potential contributor to CFTR evolution and fitness. Our studies provide a framework for evaluating aspects of genomic evolution using CFTR as a model, and with implications for other genes among higher eukaryotes.

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