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|Title:||A comparative study of beta-globin pseudogenes in man and the primates.|
|Presented at:||University of Leicester|
|Abstract:||The human beta-globin gene family, situated on chromosome 11, consists of five functional genes (epsilon Ggamma, Agamma, delta and beta) and a non-processed pseudogene, Psibeta1. The major work undertaken in this thesis consisted of a phylogenetic analysis of the non-processed pseudogene of the human globin cluster in order to establish the tempo and mode of evolution of such sequences, their suitability as examples of more general non-coding DNA sequence evolution and their possible influences on eukaryotic multigene family evolution. This study of contemporary Psibeta1 pseudogene sequences has shown that this gene has been a stable component of the beta-globin gene cluster during the evolution of the primate, and other, mammalian orders. The pseudogene was probably functional early in primate evolution and silenced probably before the basal primate radiation -70 million years ago. The presence of a functional orthologue to the human Psibeta1 gene in the goat (the ?II gene) supports the view that the human Psibeta1 gene was functional prior to its silencing early in primate evolution. After silencing, the primate Psibeta1 pseudogene has evolved randomly in terms of base substitution and insertion/deletion at a mean rate thought to be representative of non-functional non-coding DNA sequences throughout the primates. These conclusions are supported by the mode and tempo of non-coding DNA sequence evolution observed within the functional brown lemur beta-globin gene. However, the tempo of primate Psibeta1 gene evolution conflicts with views concerning the universal constant rate of neutral evolution, the rate of non-coding DNA evolution having apparently decreased to varying extents within the different lineages of this mammalian order. The consequences for primate beta-globin gene cluster evolution of the presence of a non-processed pseudogene are discussed. The distinct nature of the gene in the human beta-globin gene cluster, the history of the Psibeta1 gene in the primates and the presence of sequences related to Psibeta1 in various other mammalian orders suggests an additional ancient genetic locus was present in the ancestral beta-globin gene cluster prior to the mammalian radiation. In order to acknowledge the distinct nature of this locus the human Psibeta1 gene has therefore been renamed n and other contemporary n-related sequences renamed accordingly. The evolution and gene orthologies of the other non-primate beta-globin gene families are discussed in the light of the phylogenetic analysis of the human Psin pseudogene. The simplest interpretation of the evolution of contemporary mammalian beta-globin gene clusters is that they resulted from a common minimal ancestral cluster composed of proto epsilon-, gamma-, eta-, delta- and beta- like sequences. The generality of the conclusions drawn from this work concerning pseudogene longevity and sequence evolution after silencing await the phylogenetic analysis of other pseudogene sequences. It is apparent however that pseudogenes may constitute another potential source of genetic variation on which the processes of natural selection can act in the evolution of both eukaryotic multigene families and the genome in general.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Genetics|
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