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- Helleday, Thomas, 1971-
(författare)
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Environmental Contaminants, Recombination and Cancer : Investigations on the molecular mechanisms of spontaneous and induced recombination in the hprt gene of Chinese hamster cells
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recombination results in rearrangement of the genetic material contained in the chromosomes inherited from the mother and father and this process is also involved in repairing damage to the genome. Occasionally, the machinery that performs recombination malfunctions and this may lead to illegitimate recombination events which inactivate tumor suppressor genes or activate protooncogenes. Recent studies have demonstrated that certain carcinogens (designated recombinogens) can induce genetic recombination without giving rise to mutations in mutation assays. PCBs and heavy metals are examples of recombinogens which are often stable, non-reactive and unable to bind covalently to DNA.The aim of this thesis has been to elucidate basic mechanisms involved in genetic recombination and to investigate how foreign compounds might affect these mechanisms. V79 Chinese hamster cell lines with well-characterized mutations in the hprt gene were used for this purpose. These cell lines exhibit partial gene duplications, including extra exons, in the hprt gene. The two cell lines employed here can revert to the wild-type phenotype by loss of these exons either by homologous or non-homologous recombination. Using this experimental system, these two types of recombination were found to be affected differently by exposure to various agents and, thus, that distinguishing between these two pathways was shown to be important for proper evaluation of recombinogenic effects.A novel finding presented here is that genetic recombination can be induced by brominated flame retardants, indicating that these compounds may be human carcinogens. Several heavy metals and arsenic are recognized as human carcinogens, but the mechanisms underlying their carcinogenicity is not yet fully understood. We show here that arsenic and certain heavy metals induce genetic recombination, which might be of importance in this connection.The basic mechanisms involved in genetic recombination in the hprt gene of V79 Chinese hamster cells were also investigated here. It was found that homologous in contrast to non-homologous recombination is coupled to DNA replication. A model for how recombination can be induced in the vicinity of replication forks is presented.In conclusion, this thesis suggests that investigation of genetic recombination may provide a valuable tool for identifying human carcinogens.
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- Lyrholm, Thomas, 1958-
(författare)
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Sperm Whales : Social Organization and Global Genetic Structure
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The social organization of most mammals is characterised by female philopatry and male dispersal. This thesis examines the social organization of sperm whales, Physeter macrocephalus, using a combination of field observations and molecular genetic techniques. A major conclusion is that widely dispersing males sometimes may move between oceans, whereas this is probably less common in females.Analyses of re-sightings of recognisable female and immature sperm whales in the Galápagos islands indicated that they live in stable social groups of about 13 whales, which may represent family units, and that these units associated with each other for periods of days. There was a high turnover by movements of groups in and out of the study area, and the groups seemed to be part of a larger population which may be geographically localised.These observations, together with previous knowledge that males disperse from their natal groups to higher latitudes, while females and juveniles are limited to low latitudes, led to the hypothesis that breeding dispersal between oceans may be more common among males than among females. If so, one might expect less differentiation in the bi-parental nuclear genome than in the maternally inherited mitochondrial DNA (mtDNA) on a global scale. This hypothesis was examined by genetic analyses of samples from the North Atlantic, North Pacific and Southern Hemisphere, representing a substantial part of the global range of the species.Global variation in mtDNA control region sequences revealed an unusually low diversity, and an evolutionarily recent common ancestry of less than 100,000 years, perhaps even less than 25,000 years. This implies a young global population structure of sperm whales. There was highly significant heterogeneity in mtDNA haplotype frequencies between oceans, indicating that female dispersal between oceans has been limited during the period since mtDNA ancestry, allowing some global differentiation to develop. In contrast, analysis of variation in allele frequencies at nine nuclear microsatellite loci did not indicate significant genetic heterogeneity between oceans. Taken together, these patterns suggest that movements between oceans have been more prevalent among males than among females. This is also consistent with observations of females being the philopatric sex and having a more limited latitudinal distribution than males. Consequently, the typical mammalian dispersal pattern may have operated on a global scale in sperm whales.Analysis of genetic differentiation between potential social groups of females within oceanic areas indicated significant heterogeneity in both mtDNA and microsatellites, and the amount of differentiation in mtDNA was estimated to be an order of magnitude higher than that between oceans. These results thus seem to support the notion of groups of females at least partly being composed of matrilineally related individuals, which may be of importance for an understanding of the evolution of sociality in this species.
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