Beaked whales (family Ziphiidae) are one of the least known of all mammalian groups. The majority of species have been described from only a handful of specimens. Found in deep ocean waters, these species are widespread and often sexually dimorphic. Little is known of intra-specific variation in morphology, and many species are very similar in external appearance. A reference database of mitochondrial DNA sequences was compiled for all 20 recognised ziphiid species to aid in species identification. All reference sequences were derived from validated specimens, which were often represented only by bone or teeth. DNA was obtained from this ‘historic’ material using ‘ancient’ DNA methods. For three species, holotypes were sampled. Phylogenetic analyses using this database led to the discovery of a new, previously unrecognised species of beaked whale (Mesoplodon perrini), new specimens of Longman's beaked whale (Indopacetus pacificus), a species known previously from only two partial skulls and the synonymy of a third (M. traversii = M. bahamondi). Phylogenetic reconstructions based on sequence data from three mitochondrial and two nuclear loci (total, 2815 bp) using neighbour joining, parsimony, and maximum likelihood methods, resolved many of the sister-species relationships in this group. Inferred relationships among Mesoplodon beaked whales indicated that cranial and tooth morphology may be far more variable between closely related species than previously assumed. No support was found for a linear-progression of tooth form as suggested by Moore (1968) in his phenetic evaluation of relationships among the Ziphiidae. The geographic distribution of Mesoplodon species with similar or divergent tooth morphology is likely due to a combination of sexual selection and selection for species recognition. Both hypotheses predict similar patterns, such as dissimilar tooth morphology among species with sympatric or parapatric distributions. However, only sexual selection appears to offer an explanation for why there are so many Mesoplodon beaked whales. Investigation of mtDNA diversity among a number of beaked whale species indicated that nucleotide diversity was generally lower in this group than in other wide-ranging oceanic cetaceans. The cause of this low diversity was not clear but may be indicative of overall low abundance. Particularly low levels of diversity were found in Baird's beaked whale Berardius bairdii , Arnoux's beaked whale B. arnuxii and the northern bottlenose whale Hyperoodon ampullatus. Strong geographic structure in haplotype frequencies was observed among a worldwide sample of Cuvier's beaked whales Ziphius cavirostris. / Subscription resource available via Digital Dissertations only.

The doctoral studies described in this thesis involve the phenotypic characterization of the tremor rat, an animal model of Canavan disease, and a proof of principle gene transfer study in this model. The phenotype of the tremor rat is examined at the genetic, molecular, cellular, neurochemical, physical and behavioural levels, and tremor mutants are described within the context of Canavan disease. Tremor mutants appear to share many phenotypes with both human patients and to the knock-out mouse model. The deletion of aspartoacylase results in a total loss of the capacity to metabolize N-acetyl-aspartate to acetate and aspartate in brain, leading to elevations in brain N-acetyl-aspartate levels, changes in cell and tissue morphology, and physical and behavioural deficits including mild akinesia and loss of normal motor coordination and balance. Parallel to this work was the development of a gene transfer approach to treat Canavan disease, involving Adeno-associated virus mediated delivery of aspartoacylase to the mammalian central nervous system. Gene transfer was undertaken in tremor rat mutants, and analysis was made of gene expression and function as well as the effect of aspartoacylase expression on improving the phenotypic deficits observed in mutant animals. Gene expression was observed at the RNA and protein level, with recombinant protein observed in cell soma and processes. Although not significant the data suggested a trend of decreased NAA levels after aspartoacylase transfer in comparison to animals injected with a vector encoding green fluorescent protein. Improvement was noted in the rotorod phenotype with mutant animals receiving aspartoacylase gene transfer performing better at tests of balance and coordinated locomotion than animals receiving a control vector. The study provided evidence that Adeno-associated virus mediated aspartoacylase gene transfer to the brain improves some of the deficits in tremor mutants, and supports the rationale of human gene transfer for Canavan disease. / Subscription resource available via Digital Dissertations only.

Beaked whales (family Ziphiidae) are one of the least known of all mammalian groups. The majority of species have been described from only a handful of specimens. Found in deep ocean waters, these species are widespread and often sexually dimorphic. Little is known of intra-specific variation in morphology, and many species are very similar in external appearance. A reference database of mitochondrial DNA sequences was compiled for all 20 recognised ziphiid species to aid in species identification. All reference sequences were derived from validated specimens, which were often represented only by bone or teeth. DNA was obtained from this ‘historic’ material using ‘ancient’ DNA methods. For three species, holotypes were sampled. Phylogenetic analyses using this database led to the discovery of a new, previously unrecognised species of beaked whale (Mesoplodon perrini), new specimens of Longman's beaked whale (Indopacetus pacificus), a species known previously from only two partial skulls and the synonymy of a third (M. traversii = M. bahamondi). Phylogenetic reconstructions based on sequence data from three mitochondrial and two nuclear loci (total, 2815 bp) using neighbour joining, parsimony, and maximum likelihood methods, resolved many of the sister-species relationships in this group. Inferred relationships among Mesoplodon beaked whales indicated that cranial and tooth morphology may be far more variable between closely related species than previously assumed. No support was found for a linear-progression of tooth form as suggested by Moore (1968) in his phenetic evaluation of relationships among the Ziphiidae. The geographic distribution of Mesoplodon species with similar or divergent tooth morphology is likely due to a combination of sexual selection and selection for species recognition. Both hypotheses predict similar patterns, such as dissimilar tooth morphology among species with sympatric or parapatric distributions. However, only sexual selection appears to offer an explanation for why there are so many Mesoplodon beaked whales. Investigation of mtDNA diversity among a number of beaked whale species indicated that nucleotide diversity was generally lower in this group than in other wide-ranging oceanic cetaceans. The cause of this low diversity was not clear but may be indicative of overall low abundance. Particularly low levels of diversity were found in Baird's beaked whale Berardius bairdii , Arnoux's beaked whale B. arnuxii and the northern bottlenose whale Hyperoodon ampullatus. Strong geographic structure in haplotype frequencies was observed among a worldwide sample of Cuvier's beaked whales Ziphius cavirostris. / Subscription resource available via Digital Dissertations only.

The doctoral studies described in this thesis involve the phenotypic characterization of the tremor rat, an animal model of Canavan disease, and a proof of principle gene transfer study in this model. The phenotype of the tremor rat is examined at the genetic, molecular, cellular, neurochemical, physical and behavioural levels, and tremor mutants are described within the context of Canavan disease. Tremor mutants appear to share many phenotypes with both human patients and to the knock-out mouse model. The deletion of aspartoacylase results in a total loss of the capacity to metabolize N-acetyl-aspartate to acetate and aspartate in brain, leading to elevations in brain N-acetyl-aspartate levels, changes in cell and tissue morphology, and physical and behavioural deficits including mild akinesia and loss of normal motor coordination and balance. Parallel to this work was the development of a gene transfer approach to treat Canavan disease, involving Adeno-associated virus mediated delivery of aspartoacylase to the mammalian central nervous system. Gene transfer was undertaken in tremor rat mutants, and analysis was made of gene expression and function as well as the effect of aspartoacylase expression on improving the phenotypic deficits observed in mutant animals. Gene expression was observed at the RNA and protein level, with recombinant protein observed in cell soma and processes. Although not significant the data suggested a trend of decreased NAA levels after aspartoacylase transfer in comparison to animals injected with a vector encoding green fluorescent protein. Improvement was noted in the rotorod phenotype with mutant animals receiving aspartoacylase gene transfer performing better at tests of balance and coordinated locomotion than animals receiving a control vector. The study provided evidence that Adeno-associated virus mediated aspartoacylase gene transfer to the brain improves some of the deficits in tremor mutants, and supports the rationale of human gene transfer for Canavan disease. / Subscription resource available via Digital Dissertations only.

Beaked whales (family Ziphiidae) are one of the least known of all mammalian groups. The majority of species have been described from only a handful of specimens. Found in deep ocean waters, these species are widespread and often sexually dimorphic. Little is known of intra-specific variation in morphology, and many species are very similar in external appearance. A reference database of mitochondrial DNA sequences was compiled for all 20 recognised ziphiid species to aid in species identification. All reference sequences were derived from validated specimens, which were often represented only by bone or teeth. DNA was obtained from this ‘historic’ material using ‘ancient’ DNA methods. For three species, holotypes were sampled. Phylogenetic analyses using this database led to the discovery of a new, previously unrecognised species of beaked whale (Mesoplodon perrini), new specimens of Longman's beaked whale (Indopacetus pacificus), a species known previously from only two partial skulls and the synonymy of a third (M. traversii = M. bahamondi). Phylogenetic reconstructions based on sequence data from three mitochondrial and two nuclear loci (total, 2815 bp) using neighbour joining, parsimony, and maximum likelihood methods, resolved many of the sister-species relationships in this group. Inferred relationships among Mesoplodon beaked whales indicated that cranial and tooth morphology may be far more variable between closely related species than previously assumed. No support was found for a linear-progression of tooth form as suggested by Moore (1968) in his phenetic evaluation of relationships among the Ziphiidae. The geographic distribution of Mesoplodon species with similar or divergent tooth morphology is likely due to a combination of sexual selection and selection for species recognition. Both hypotheses predict similar patterns, such as dissimilar tooth morphology among species with sympatric or parapatric distributions. However, only sexual selection appears to offer an explanation for why there are so many Mesoplodon beaked whales. Investigation of mtDNA diversity among a number of beaked whale species indicated that nucleotide diversity was generally lower in this group than in other wide-ranging oceanic cetaceans. The cause of this low diversity was not clear but may be indicative of overall low abundance. Particularly low levels of diversity were found in Baird's beaked whale Berardius bairdii , Arnoux's beaked whale B. arnuxii and the northern bottlenose whale Hyperoodon ampullatus. Strong geographic structure in haplotype frequencies was observed among a worldwide sample of Cuvier's beaked whales Ziphius cavirostris. / Subscription resource available via Digital Dissertations only.

The doctoral studies described in this thesis involve the phenotypic characterization of the tremor rat, an animal model of Canavan disease, and a proof of principle gene transfer study in this model. The phenotype of the tremor rat is examined at the genetic, molecular, cellular, neurochemical, physical and behavioural levels, and tremor mutants are described within the context of Canavan disease. Tremor mutants appear to share many phenotypes with both human patients and to the knock-out mouse model. The deletion of aspartoacylase results in a total loss of the capacity to metabolize N-acetyl-aspartate to acetate and aspartate in brain, leading to elevations in brain N-acetyl-aspartate levels, changes in cell and tissue morphology, and physical and behavioural deficits including mild akinesia and loss of normal motor coordination and balance. Parallel to this work was the development of a gene transfer approach to treat Canavan disease, involving Adeno-associated virus mediated delivery of aspartoacylase to the mammalian central nervous system. Gene transfer was undertaken in tremor rat mutants, and analysis was made of gene expression and function as well as the effect of aspartoacylase expression on improving the phenotypic deficits observed in mutant animals. Gene expression was observed at the RNA and protein level, with recombinant protein observed in cell soma and processes. Although not significant the data suggested a trend of decreased NAA levels after aspartoacylase transfer in comparison to animals injected with a vector encoding green fluorescent protein. Improvement was noted in the rotorod phenotype with mutant animals receiving aspartoacylase gene transfer performing better at tests of balance and coordinated locomotion than animals receiving a control vector. The study provided evidence that Adeno-associated virus mediated aspartoacylase gene transfer to the brain improves some of the deficits in tremor mutants, and supports the rationale of human gene transfer for Canavan disease. / Subscription resource available via Digital Dissertations only.

Beaked whales (family Ziphiidae) are one of the least known of all mammalian groups. The majority of species have been described from only a handful of specimens. Found in deep ocean waters, these species are widespread and often sexually dimorphic. Little is known of intra-specific variation in morphology, and many species are very similar in external appearance. A reference database of mitochondrial DNA sequences was compiled for all 20 recognised ziphiid species to aid in species identification. All reference sequences were derived from validated specimens, which were often represented only by bone or teeth. DNA was obtained from this ‘historic’ material using ‘ancient’ DNA methods. For three species, holotypes were sampled. Phylogenetic analyses using this database led to the discovery of a new, previously unrecognised species of beaked whale (Mesoplodon perrini), new specimens of Longman's beaked whale (Indopacetus pacificus), a species known previously from only two partial skulls and the synonymy of a third (M. traversii = M. bahamondi). Phylogenetic reconstructions based on sequence data from three mitochondrial and two nuclear loci (total, 2815 bp) using neighbour joining, parsimony, and maximum likelihood methods, resolved many of the sister-species relationships in this group. Inferred relationships among Mesoplodon beaked whales indicated that cranial and tooth morphology may be far more variable between closely related species than previously assumed. No support was found for a linear-progression of tooth form as suggested by Moore (1968) in his phenetic evaluation of relationships among the Ziphiidae. The geographic distribution of Mesoplodon species with similar or divergent tooth morphology is likely due to a combination of sexual selection and selection for species recognition. Both hypotheses predict similar patterns, such as dissimilar tooth morphology among species with sympatric or parapatric distributions. However, only sexual selection appears to offer an explanation for why there are so many Mesoplodon beaked whales. Investigation of mtDNA diversity among a number of beaked whale species indicated that nucleotide diversity was generally lower in this group than in other wide-ranging oceanic cetaceans. The cause of this low diversity was not clear but may be indicative of overall low abundance. Particularly low levels of diversity were found in Baird's beaked whale Berardius bairdii , Arnoux's beaked whale B. arnuxii and the northern bottlenose whale Hyperoodon ampullatus. Strong geographic structure in haplotype frequencies was observed among a worldwide sample of Cuvier's beaked whales Ziphius cavirostris. / Subscription resource available via Digital Dissertations only.

The doctoral studies described in this thesis involve the phenotypic characterization of the tremor rat, an animal model of Canavan disease, and a proof of principle gene transfer study in this model. The phenotype of the tremor rat is examined at the genetic, molecular, cellular, neurochemical, physical and behavioural levels, and tremor mutants are described within the context of Canavan disease. Tremor mutants appear to share many phenotypes with both human patients and to the knock-out mouse model. The deletion of aspartoacylase results in a total loss of the capacity to metabolize N-acetyl-aspartate to acetate and aspartate in brain, leading to elevations in brain N-acetyl-aspartate levels, changes in cell and tissue morphology, and physical and behavioural deficits including mild akinesia and loss of normal motor coordination and balance. Parallel to this work was the development of a gene transfer approach to treat Canavan disease, involving Adeno-associated virus mediated delivery of aspartoacylase to the mammalian central nervous system. Gene transfer was undertaken in tremor rat mutants, and analysis was made of gene expression and function as well as the effect of aspartoacylase expression on improving the phenotypic deficits observed in mutant animals. Gene expression was observed at the RNA and protein level, with recombinant protein observed in cell soma and processes. Although not significant the data suggested a trend of decreased NAA levels after aspartoacylase transfer in comparison to animals injected with a vector encoding green fluorescent protein. Improvement was noted in the rotorod phenotype with mutant animals receiving aspartoacylase gene transfer performing better at tests of balance and coordinated locomotion than animals receiving a control vector. The study provided evidence that Adeno-associated virus mediated aspartoacylase gene transfer to the brain improves some of the deficits in tremor mutants, and supports the rationale of human gene transfer for Canavan disease. / Subscription resource available via Digital Dissertations only.

Beaked whales (family Ziphiidae) are one of the least known of all mammalian groups. The majority of species have been described from only a handful of specimens. Found in deep ocean waters, these species are widespread and often sexually dimorphic. Little is known of intra-specific variation in morphology, and many species are very similar in external appearance. A reference database of mitochondrial DNA sequences was compiled for all 20 recognised ziphiid species to aid in species identification. All reference sequences were derived from validated specimens, which were often represented only by bone or teeth. DNA was obtained from this ‘historic’ material using ‘ancient’ DNA methods. For three species, holotypes were sampled. Phylogenetic analyses using this database led to the discovery of a new, previously unrecognised species of beaked whale (Mesoplodon perrini), new specimens of Longman's beaked whale (Indopacetus pacificus), a species known previously from only two partial skulls and the synonymy of a third (M. traversii = M. bahamondi). Phylogenetic reconstructions based on sequence data from three mitochondrial and two nuclear loci (total, 2815 bp) using neighbour joining, parsimony, and maximum likelihood methods, resolved many of the sister-species relationships in this group. Inferred relationships among Mesoplodon beaked whales indicated that cranial and tooth morphology may be far more variable between closely related species than previously assumed. No support was found for a linear-progression of tooth form as suggested by Moore (1968) in his phenetic evaluation of relationships among the Ziphiidae. The geographic distribution of Mesoplodon species with similar or divergent tooth morphology is likely due to a combination of sexual selection and selection for species recognition. Both hypotheses predict similar patterns, such as dissimilar tooth morphology among species with sympatric or parapatric distributions. However, only sexual selection appears to offer an explanation for why there are so many Mesoplodon beaked whales. Investigation of mtDNA diversity among a number of beaked whale species indicated that nucleotide diversity was generally lower in this group than in other wide-ranging oceanic cetaceans. The cause of this low diversity was not clear but may be indicative of overall low abundance. Particularly low levels of diversity were found in Baird's beaked whale Berardius bairdii , Arnoux's beaked whale B. arnuxii and the northern bottlenose whale Hyperoodon ampullatus. Strong geographic structure in haplotype frequencies was observed among a worldwide sample of Cuvier's beaked whales Ziphius cavirostris. / Subscription resource available via Digital Dissertations only.

The doctoral studies described in this thesis involve the phenotypic characterization of the tremor rat, an animal model of Canavan disease, and a proof of principle gene transfer study in this model. The phenotype of the tremor rat is examined at the genetic, molecular, cellular, neurochemical, physical and behavioural levels, and tremor mutants are described within the context of Canavan disease. Tremor mutants appear to share many phenotypes with both human patients and to the knock-out mouse model. The deletion of aspartoacylase results in a total loss of the capacity to metabolize N-acetyl-aspartate to acetate and aspartate in brain, leading to elevations in brain N-acetyl-aspartate levels, changes in cell and tissue morphology, and physical and behavioural deficits including mild akinesia and loss of normal motor coordination and balance. Parallel to this work was the development of a gene transfer approach to treat Canavan disease, involving Adeno-associated virus mediated delivery of aspartoacylase to the mammalian central nervous system. Gene transfer was undertaken in tremor rat mutants, and analysis was made of gene expression and function as well as the effect of aspartoacylase expression on improving the phenotypic deficits observed in mutant animals. Gene expression was observed at the RNA and protein level, with recombinant protein observed in cell soma and processes. Although not significant the data suggested a trend of decreased NAA levels after aspartoacylase transfer in comparison to animals injected with a vector encoding green fluorescent protein. Improvement was noted in the rotorod phenotype with mutant animals receiving aspartoacylase gene transfer performing better at tests of balance and coordinated locomotion than animals receiving a control vector. The study provided evidence that Adeno-associated virus mediated aspartoacylase gene transfer to the brain improves some of the deficits in tremor mutants, and supports the rationale of human gene transfer for Canavan disease. / Subscription resource available via Digital Dissertations only.