Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

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Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Thesis (Ph. D., Bioinformatics and Computational Biology)--University of Idaho, May 2009. / Major professor: Paul Joyce. Includes bibliographical references (leaves 58-63). Also available online (PDF file) by subscription or by purchasing the individual file.

Thesis (doctoral)--University of Turku. / Includes reprints of 6 articles on which thesis is based.

Orientador: Sergio Roberto Peres Line / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-09T20:16:25Z (GMT). No. of bitstreams: 1 Santos_MariaCristinaLemeGodoydos_D.pdf: 2829764 bytes, checksum: 6b12dbb6ac70704425ca20c5664c1884 (MD5) Previous issue date: 2007 / Resumo: Amelogênese imperfeita (AI) representa um grupo de doenças hereditárias que causa defeito na formação do esmalte dental. Esse distúrbio afeta o esmalte em diferentes intensidades, promovendo desde a deficiência na formação do esmalte até defeitos no conteúdo mineral e protéico. O desenvolvimento do esmalte envolve a expressão de múltiplos genes necessários para controlar o complexo processo de mineralização. Distintos tipos de amelogênese imperfeita apresentam diferentes padrões de herança, incluindo autossômicos dominante, autossômicos recessivo e ligados ao X. Mutações nos genes de proteínas e proteases do esmalte são associadas à AI. O objetivo desse trabalho foi investigar a ocorrência de mutações nos seis principais genes candidatos à AI em duas famílias brasileiras com AI autossômica recessiva e AI ligada ao X. O DNA obtido de cada paciente foi amplificado e seqüenciado para os exons da AMELX, AMBN, ENAM, MMP- 20, KLK-4 e Amelotin. Também foi realizada a técnica de genotipagem em regiões conhecidas por conter importantes genes para o desenvolvimento do esmalte. O presente trabalho mostrou que a AI nas duas famílias estudadas não é causada por mutações nos conhecidos loci relacionados à AI, nem nos principais genes candidatos propostos na literatura / Abstract: Amelogenesis imperfecta (AI) is a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Enamel findings in AI are highly variable, ranging from deficient enamel formation to defects in the mineral and protein content. Enamel formation requires the expression of multiple genes needed to control the complex process of crystal growth and mineralization. Different inheritance patterns such as autosomal dominant, autosomal recessive and X-linked types have been reported. Mutations in genes coding for enamel structural proteins and proteases have been associated with AI. The object of this study was to evaluate evidence for linkage of the six major candidate gene loci in two Brazilian families with AI. DNA was obtained from normal and affected family members and exons of AMELX, AMBN, ENAM, MMP-20, KLK-4 and Amelotin were amplified and sequenced. Each family was evaluated for linkage to chromosome regions known to contain genes important in enamel development. The present study indicates that the autosomal recessive and X-linked hypomineralized form of AI in these two families is not caused by any of the known loci for AI or any of the candidate genes proposed in the literature / Doutorado / Histologia e Embriologia / Doutor em Biologia Buco-Dental

The subject of this study is a new dominant suppressor mutation Su(pr) which acts on the purple eye-colour mutant (pr) of Drosophila a melanogaster. The Induction of Su (pr) was originally associated with the synthesis of a compound-2R chromosome In SD72/cn bw females. The suppression of p_ was first observed in combination with a homologous pr bearing compound-2L chromosome. Suppressed-pr flies appeared to have a fully wild eye phenotype. The intention of this study was to determine the chromosomal constitution necessary for Su(pr) induction, and to map the suppressor site. To do this, many compound-2R chromosomes were synthesized from several combinations of standard seconds. It was found that SD72 must be present to produce a suppressing compound-2R. The SD72 second carries a pericentric inversion that results in a duplication of 2L heterochromatIn, and an associated deficiency of 2R heterochromatin in the compound-2R S u (p r) chromosome. Suppression, therefore, Is associated with the pericentric inversion found only on SD72. The role of this segmental aneuploidy was studied by detaching several C(2L)pr: C(2R)SD72/,cn bw suppressed strains such that both arms of the Su(pr) compound autosome were recovered independently and established in standard strains. Suppressing and non-suppressing detachment products were recovered with a frequency that varied according to the compound-2R Su(pr) strain from which they were derived. The chromosome mechanics involved in the process of C(2R)SD72/cn bw formation and subsequent detachment implicates alterations to a segment of proxlmial 2R heterochromatin from SD72 in Su(pr) Induction. Loss of Su(pr) in the detachment process correlates predominantly with deletions generated In 2R heterochromatIn. Recombination mapping relative to the two visible heterochromatic markers, Iight and rolled, revealed that Su(pr) Iies to the left of rolIed. SpectrophotometrIc measurements of eye pigments revealed that suppressed-pr and suppressed-pru bw flies had pigment levels that exceeded the wild type. The lethal allele prc4. was not found to be suppressible. / Science, Faculty of / Zoology, Department of / Graduate

The sex-linked vermilion (v) locus is probably the structural gene for the enzyme tryptophan pyrrolase. Mutations at the locus invariably are recessive and result in a bright-red eye colour phenotype accompanied by a loss of tryptophan pyrrolase activity. Extensive genetic, biochemical and developmental studies of v mutations have shown that the gene is a relatively small cistron controlling the catalytic activity of tryptophan pyrrolase which gives rise to kynure-nine, a brown eye pigment precursor, in the larval fat body during a defined developmental period. Alleles of the locus can be broadly grouped into two classes: 1) spontaneous v mutations, the majority of which are suppressible by mutation at the non-allelic suppressor of sable [su(s)] locus, 2) induced v mutations which are all unsuppressible by su(s) alleles. Alleles of both classes behave nonautonomously during development and all map within the definable limits of the v cistron. This investigation was initiated to recover conditional (temperature-sensitive) v alleles which could be used to study further the regulation of the activity of the v gene during development, and to extend our knowledge of the genetic functioning of the locus. A temperature-sensitive (ts) allele of a known structural gene, affecting the catalytic activity of an assayable enzyme, could also enable a determination of the factors responsible for temperature-sensitivity in Drosophila in terms of changes in the gene product. The temperature-sensitive period (TSP) of a ts mutant in Drosophila is defined as that period during development when exposure to the restrictive temperature commits the organism to a mutant phenotype. With a ts v allele, a correlation can be made between the TSP determined phenotypically and the variation in tryptophan pyrrolase activity during development, and thus contribute to a molecular understanding of the TSP. This study has consisted mainly of the following approaches: 1) mutagenesis and genetic screening to recover ts v alleles, 2) an examination of the phenogenetics of one ts v allele, including fine structure mapping, complementation properties, nonautonomous expression in gynandromorphs, and suppressibility, and a comparison of these properties with those exhibited by some non-ts v mutations, 3) a biochemical analysis of the effect of a ts v mutation on the properties of tryptophan pyrrolase, a deter-mination of the TSP of a ts v allele based on the eye phenotype. Both ts v alleles, v[sup ts1] and v[sup ts2], recovered in this investigation cause a vermilion phenotype if v flies are raised at the restrictive temperature (29°C), whereas v[sup ts] flies raised at the permissive temperature (17° or 22°C) have almost normal eye colour. The activity of tryptophan pyrrolase, extracted from [sup ts1] flies raised at 29°G and 22°C respectively, parallels the temperature-dependent phenotypic properties; enzyme activity is markedly reduced in flies raised at 29°C but is almost normal in flies raised at the permissive temperature. The v[sup ts1] mutation behaves like non-ts,induced v alleles at 29°C in its complementation, suppressibility and nonautonomy. Thus, it fails to complement any other v point mutant, is unsuppressible by su(s)² and is developmentally nonautonomous when present with v* tissue in gynandromorphs raised at 29°C. Since the v[sup ts1] allele is viable when heterozygous with deletions removing the v locus and maps within the v cistron as a point, it is assumed to be a point mutation in the v structural gene. Furthermore, the tryptophan pyrrolase controlled by the v[sup ts1] mutant has different in vitro kinetic and temperature-dependent properties when v[sup ts1] flies are raised at 29 C compared to either wild type or tryptophan pyrrolase extracted from v[sup ts1] flies raised at 22°C. The v[sup ts1] mutant demonstrates different phenotypic and enzyme properties between males and females raised at 29°C; hemizygous males are more mutant in phenotype and have lower tryptophan pyrrolase activity than their homozygous sibs. This result apparently is the reverse of the dosage compensation nor-mally demonstrated by wild type tryptophan pyrrolase in which males with one dose of the v⁺ gene have at least the enzyme activity obtained from females with two doses of the v⁺ gene. How-ever, the TSP for the v[sup ts1] mutant is the same for males and females and falls between the early third instar larva and early pupa stages of development. This period corresponds to the maximum pre-adult activity of tryptophan pyrrolase and also correlates with the formation of kynurenine in the cells of the fat bffidy. These results are discussed in relation to a molecular model explaining the genetic and molecular functioning of the v locus during development. The results are consistent with the hypothesis that v[sup ts] and nonconditional v mutations affect different aspects of active tryptophan pyrrolase structure rather than regulation of the rate of synthesis of the enzyme. Thus, suppressible v mutations affect allosteric or regulatory sites of the enzyme which interact with metabolic and develop-mental cofactors, whereas the nonconditional, unsuppressible, induced v mutations probably affect the catalytic sites of t tryptophan pyrrolase. The ts v mutation, v[sup ts1] , has genetic and biochemical properties which are compatible with an effect on the aggregation of enzyme subunits due to conformational changes during enzyme synthesis at the restrictive temperature. / Science, Faculty of / Zoology, Department of / Graduate