Corrections pasted behind title page. / Bibliography: leaves 294-341. / xi, 341, [42] leaves, [42] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Involves the construction of a detailed physical map of the distal band of the long arm of human chromosome 16, 16q24. / Thesis (Ph.D.)--University of Adelaide, Dept. of Cytogenetics and Molecular Genetics, 1997

The striking similarity between Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes (T2D) in terms of the pathophysiologies and the risk factors has led to the hypothesis that GDM is an early manifestation of T2D, expressed under the stress of pregnancy, and therefore both diseases should share similar susceptibility genes. GDM patients may provide a more homogeneous sample for the genetic causes of the disease than T2D, and therefore make a useful group for the identification of the genes involved. Over 200 GDM affected sib-pairs from 178 families were investigated, with parents available in 40% of cases. Genomic regions from 4 different chromosomes, 6, 8, 14 and 18 were chosen from regions that showed clustering for positive linkage scores in previous linkage studies on T2D and one control region on 13, where no previous positive linkage was reported. A total of 19 microsatellite markers were analysed for linkage to GDM using sib-pair analysis. Subset analyses were performed by ranking sib-pairs on GDM-related variables, e.g. mean BMI of sibs, age at GDM episode, etc. GENEHUNTER was run multiple times, each time including the next highest ranked family in the analysis. This gave a continuous range of scores where increasing or decreasing NPL scores indicated heterogeneity associated with different environmental factors such as age and weight. To evaluate the significance of the subset analyses, the results were compared to 10,000 permutations generated by randomly ranking the sib-pairs. Using the entire dataset, the analysis showed no significant linkage to a disease locus. Positive evidence for linkage was found with the subset analysis on chromosomes 8 and 14, suggesting heterogeneity between sib-pairs in the dataset. Marker D8S1742 on 8p23 showed an NPL score of 3.01 (p=0.001) when age at GDM diagnosis was used as a covariate. Using waist-to-hip ratio (WHR), marker D14S275 on 14q12 showed an NPL score of 2.474 (p=0.006). When adjusted for multiple testing, the results were not statistically significant for linkage to a diabetes disease locus, but gave evidence that GDM and T2D share similar genetic determinants, and defined groups of siblings for follow-up analysis of both types of diabetes.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Cytogenetics and Molecular Genetics, 1999. / Copies of author's previously published articles inserted. Amendments pasted onto back-end paper. Bibliography: leaves 255-286.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [205]-219).

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 103-132). Also available in print.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 118-124).

Οι ρηξιγενείς ζώνες περιλαμβάνουν συνήθως ασυνεχή, υποπαράλληλα, κλιμακωτά ρηξιγενή τμήματα τα οποία χωρίζονται από ζώνες μεταβίβασης (relay zones). Καθώς οι ρηξιγενείς ζώνες εξελίσσονται, τα τμήματα των ζωνών αυτών, μπορούν να αλληλεπιδρούν μηχανικά και να ενώνονται σταδιακά, σχηματίζοντας έτσι δομές μεγαλύτερης κλίμακας με την αύξηση της παραμόρφωσης. Ο τρόπος με τον οποίο τα τμήματα αλληλεπιδρούν κατά τη διάρκεια της εξέλιξης των ζωνών, έχει γίνει αντικείμενο αρκετών ερευνών. Ωστόσο ακόμα και σήμερα οι γνώσεις μας για τις διεργασίες της αλληλεπίδρασης και της σύνδεσης των τμημάτων είναι περιορισμένες. Στην παρούσα εργασία, για τη μελέτη της τμηματοποίησης και του τρόπου σύνδεσης κανονικών ρηγμάτων, επιλέχτηκαν 3 περιοχές της Κεντρικής Ελλάδας: οι ρηξιγενείς ζώνες του Αιγίου και της Ελίκης στον Κορινθιακό κόλπο, οι ρηξιγενείς ζώνες της Αταλάντης και της Αρκίτσας στον Ευβοϊκό κόλπο και τέλος οι σύνθετες ρηξιγενείς ζώνες του Καπαρελλίου και της Δάφνης στην περιοχή της Βοιωτίας. Οι δύο πρώτες έχουν ΔΒΔ διεύθυνση, ενώ η τελευταία έχει σχεδόν Α-Δ διεύθυνση και αντιπροσωπεύει τη ζώνη παραμόρφωσης μεταξύ των δύο κύριων ζωνών rift. Η επιλογή των περιοχών αυτών έγινε με βάση την σημαντική τεκτονική τους δραστηριότητα τα τελευταία 1.5 εκατομμύρια χρόνια και την σπουδαιότητα τους στη νεοτεκτονική εξέλιξη της Κεντρικής Ελλάδας. Στην παρούσα διατριβή υπολογίστηκαν παράμετροι που αντανακλούν έμμεσα την κατανομή της τάσης γύρω από τα ρήγματα, όπως είναι η κατακόρυφη μετατόπιση (D), το μήκος των ρηγμάτων (L), ο αριθμός των ρηξιγενών τμημάτων κάθε ζώνης (n), η επικάλυψη (OL), η κλιμάκωση (S), και το μήκος της ζώνης μεταβίβασης (Lr). Οι παράμετροι αυτοί αποτελούν δείκτες του βαθμού σύνδεσης μεταξύ των ρηξιγενών τμημάτων καθώς και του βαθμού ωριμότητας μιας ενεργού ζώνης. Έτσι, χρησιμοποιήθηκαν αρχικά Ψηφιακά Μοντέλα Αναγλύφου (DEM) από τα οποία κατασκευάστηκαν τοπογραφικά προφίλ σε κάθε ρηξιγενή ζώνη, με σκοπό τον υπολογισμό της κατακόρυφης μετατόπισης των ρηγμάτων τόσο στα επι μέρους τμήματα όσο και στις ζώνες μεταβίβασης καθώς και η κατανομή της μετατόπισης κατά μήκος οροφής-βάσης των ρηγμάτων. Επίσης προσδιορίστηκε η γεωμετρία των ζωνών μεταβίβασης μεταξύ των ρηξιγενών τμημάτων, με σκοπό να εξετασθούν οι τρόποι σύνδεσης των τμημάτων με υπολογισμό του μήκους των μη επικαλυπτόμενων ζωνών (underlapping zone), των ζωνών επικάλυψης (overlap zone) και των κλιμακώσεων (separation/spacing). Τα μήκη των τμημάτων των ρηξιγενών ζωνών προβλήθηκαν σε διαγράμματα αθροιστικής συχνότητας με σκοπό την περιγραφή των πληθυσμών των ρηγμάτων στις τρεις περιοχές μελέτης. Τα διαγράμματα δηλώνουν μια πολυκλασματική κατανομή, που αντιπροσωπεύει διαφορετικούς πληθυσμούς ρηγμάτων που αλληλεπιδρούν ή μια εκθετική κατανομή που δείχνει ένα πρώιμο στάδιο κορεσμού των ρηγμάτων. Στη συνέχεια, κατασκευάστηκαν διαγράμματα της μέγιστης κατακόρυφης μετατόπισης των τμημάτων με το μήκος (D-L), με σκοπό να προσδιοριστεί σε ποιο στάδιο σύνδεσης βρίσκονται οι συγκεκριμένες ζώνες και να προταθούν μοντέλα εξέλιξης αυτών. Τέλος εξετάστηκαν και συσχετίστηκαν τα γεωμετρικά χαρακτηριστικά των ζωνών μεταβίβασης (μήκος κλιμάκωσης, μήκος επικαλυπτόμενων ή μη τμημάτων), με σκοπό την εξαγωγή συμπερασμάτων για την ικανοποίηση ή μη κριτηρίων αλληλεπίδρασης των τμημάτων και της πιθανής σύνδεσης αυτών. Η κατανόηση του ρόλου της τμηματοποίησης και του τρόπου σύνδεσης των τμημάτων των ρηξιγενών ζωνών μπορεί να βοηθήσει σημαντικά στην εκτίμηση της σεισμικής επικινδυνότητας μιας περιοχής, στην κατανόηση των ιζηματογενών διαδικασιών μπροστά από τα ρήγματα καθώς και στον προσδιορισμό παγίδων ρευστής φάσης και της μετανάστευσή τους, μιας και οι ζώνες μεταβίβασης δύναται να αποτελούν περιοχές διαφυγής ή εμπόδια στη ροή των ρευστών. / Fault zones are commonly composed of discontinuous, sub-parallel, stepping fault segments, separated by relay zones. During the growth of a fault zone, its segments interact mechanically and link up into gradually larger segments that eventually may form large structures, due to strain accommodation. The way that segments interact during the growth of a fault zone, has been the subject of several studies. Yet, present understanding of interaction and linkage of segments, continues to be shrouded by considerable uncertainty. Three areas in central Greece were chosen, to investigate the role of segmentation and linkage of normal faults: the Aigio and Eliki fault zones in the Gulf of Corinth, the Atalanti and Arkitsa fault zones in the Northern Gulf of Evoia and the composite fault zones of Kaparelli and Dafnes in Beotia area. The Gulf of Corinth and the Northern Gulf of Evia are WNW-trending grabens, while Beotia area represents the deformed zone between the two main rift zones. These areas have been chosen due to their significant tectonic activity in the last 1.5Ma and their great importance in the neotectonic evolution of central Greece. In this study, several parameters reflecting the stress distribution around faults, have been measured, such as the vertical displacement (D), the number of segments (n), the overlap (OL), the spacing (S) and the length of relay zone (Lr). These parameters are indicators of the degree of linkage between fault segments and the degree of maturity of an active fault zone. Digital Elevation Models (DEM) have been used to construct elevation profiles in every fault zone, in order to measure the vertical throw of each segment, and in the relay zones as well as the distribution of displacement in footwall and hanging wall blocks. In addition, the geometry of the relay zones between fault segments is defined by calculating the length of underlapping zone, the length of overlapping zone and the length of spacing, in order to examine the segment linkage. The lengths of fault zones’ segments have been illustrated in plots of cumulative frequency, in order to describe the fault population in the three study areas. The plots indicate either multifractal distribution that represents fault population with different characteristics that interact or exponential distribution that shows an early stage of fault saturation. The relationship between maximum vertical displacement and length is illustrated in d-L plots, in order to determine the linkage stage of the particular fault zones and to propose evolutionary models. Finally the geometric characteristics of relay zones (spacing, length of underlapping or overlapping segments) were examined, in order to investigate whether or not the segments satisfy the interaction criteria and their possible linkage. Segmentation and fault segment linkage plays an important role in evaluating seismic hazard of an area, the architecture of sedimentary deposits, as well as in fluid flow in faulted reservoirs since relay zones can act as leakage zones or barriers from the hanging wall to the footwall blocks.

Abstract Genetic factors have been shown to have an important role in intervertebral disc disease. The associations of known genetic risk factors and whole-body vibration, a proposed environmental risk factor, for intervertebral disc disease (IDD) were evaluated. Eleven variations in eight genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3 and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no occupational exposure to vibration. The number of individuals belonging to the IDD group was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; p = 0.005). In addition, the IL1A-889T allele represented a risk factor for the IDD-phenotype. In order to clarify the role of genetic variations in the genes coding for several proinflammatory mediators, hundred fifty-five Finnish individuals with IDD were analyzed for mutations in the genes coding for inflammatory mediators IL-1α, IL-1β, IL-6 and TNF-α. In addition, sixteen single nucleotide polymorphisms (SNPs) in inflammatory mediator genes were genotyped. An association was identified between IDD and IL6 polymorphism +15T>A in exon 5 (p = 0.007). In addition, IL6 haplotype GGGA of -597G>A, -572G>C, -174G>C and +15T>A in exon 5 associated with IDD (p = 0.0033). A functional SNP in the CILP gene has been suggested to cause IDD in the Japanese population. This functional variation was analyzed in 243 Finnish IDD patients and 259 controls, and in 348 Chinese individuals with degenerative MRI findings and 343 Chinese individuals with normal MRI. No association was found in the Finnish and Chinese study populations. In order to reveal chromosomal susceptibility loci and new candidate gene(s) for IDD a genome-wide scan was performed on 14 Finnish families with 186 individuals. Genome-wide and fine mapping analysis provided maximum two-point LOD scores of 2.71, 2.36 and 2.04 for chromosomes 21, 4, and 6, respectively. Second fine mapping confirmed the susceptibility of chromosome 21. Two candidate genes, ADAMTS-1 and ADAMTS-5, were analyzed in the region suggesting linkage, leading to the identification of thirteen sequence variations. However, none of the variations were disease causing.

During the screening process 5,20 8 X chromosomes of -Drosophila melanogaster were analyzed for the presence of temperature-sensitive (ts) lethal mutations (i.e. mutants which die at 29°C but are viable at 22°C) in short proximal and distal segments of the chromosome. Seven ts and 16 non-ts lethals were recovered in both regions combined. A new class of mutations (class-3), which failed to survive at 29°C with either proximal or distal duplication and showed ts lethality with one, was found and extensively analyzed. These mutants were initially interpreted to be dominant ts's, although the heterozygotes of each mutant showed this not to be so. It was decided that these might more probably be chromosomes carrying a lethal mutation covered by the duplication, and a ts lethal mapping elsewhere. By masking the non-conditional lethal with a duplication, developmental studies of the ts mutant were made. The temperature-sensitive period (TSP) and lethal phase (LP) were characterized for each. All TSP’s spanned the early pupal interval, though an individual TSP might extend to either side of this interval. The pattern of temperature-sensitivity of C3-3 suggested that once formed at permissive temperature, its product was not affected by 29°C. The experiments suggest that the temperature-sensitive process occurs at transcription or translation. A lethal allele of the dor locus was recovered, and, in analysis of this mutant with other dor alleles and several variegating duplications, dor itself was found to be a ts lethal. "Warped" wing, a new phenotype of the dor locus which occurred only with the variegating duplications, was described. This paper further describes a method for developmental analysis of non-ts lethal mutations, involving the use of variegating rearrangements. / Science, Faculty of / Zoology, Department of / Graduate

La Polyarthrite Rhumatoïde, une des maladies auto-immunes les plus répandues, est caractérisée par une destruction progressive des articulations, conduisant à des déformations et handicaps. La nature multifactorielle de la PR fournit une hétérogénéité élevée avec des combinaisons spécifiques entre un profil génétique et des facteurs environnementaux qui influencent la susceptibilité, la gravité et le développement de la maladie. L’objectif de cette thèse est l’identification et la caractérisation de gènes candidats dans la PR. Nous avons confirmé l’association ainsi que la liaison des régions TRAF1-C5 et 6q23, et démontré une tendance pour une association et liaison entre la région génique 4q27 et la PR dans la population européenne. De plus, nous avons fourni des résultats concluants qui s’opposent à une implication des gènes PRKCH, CASP7, RANK, RANKL et PTPN22-1123G dans la susceptibilité génétique à la PR dans la population européenne. Nous avons effectué une étude d’expression génique utilisant 48.701 ADNc des PBMC de patients et contrôles sains. Une expression différentielle de 339 gènes entre les deux groupes a été observée. Nous avons identifié une expression élevée d’un spectre de nouveaux gènes impliqués dans différents mécanismes immunitaires de la PR. Nous avons aussi identifié une association entre les allèles HLA EP et le tabac au sein des patients ACPA positifs avec une PR familiale ou sporadique. Ces différentes approches complémentaires ont permis l’identification de nouveaux gènes et la mise en évidence d’interactions gène-autoanticorps-environnement, contribuant ainsi à une meilleure compréhension des mécanismes pathologiques de la PR. / Rheumatoid Arthritis, one of the most common autoimmune diseases, is characterized by progressive articular damage leading to joint deformities and disability. The multifactorial nature of RA provides high disease heterogeneity with specific combinations of a genetic background and environmental factors that influence the susceptibility, severity and outcome of the disease. The aim of this thesis was the identification and characterization of candidate genes in RA. We have confirmed the association and linkage of TRAF1-C5 and 6q23 gene regions, and demonstrated a trend for the association and linkage of the 4q27 gene region with RA in European descent populations. Furthermore, we provided evidence against the involvement of the PRKCH, CASP7, RANK and RANKL genes and the PTPN22–1123G allele in RA genetic susceptibility in the European population. We performed a large-scale gene expression profiling study using 48.701 cDNAs in PBMCs of RA patients and healthy controls. A differentially expression of 339 genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of new genes involved in immunity and defense mechanisms. Finally, we identified an association between HLA SE alleles and tobacco smoking for anti-CCP positivity in French population with familial and sporadic RA. All these complementary approaches that allowed the identification of new genes and gene-autoantibodies-environment interactions contribute to a better understanding of RA disease mechanisms and could lead to the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions.