[Truncated abstract] For the convenience of the reader, detailed figures and tables have been enlarged and compiled in Appendix 2, at the end of this thesis. This thesis is presented as an approach to identify, annotate and detect genomic duplication and polymorphism within large genomic regions. To demonstrate this, I have used as a model, the genomic region known as the Regulators of Complement Activation (RCA). The RCA complex is located on the long arm of chromosome 1 at position 1q32 and is a reservoir of complement regulatory proteins. The genes of the RCA share many similarities implying that all have arisen through multiple complex duplication events. My analysis of this region in the following chapters demonstrates the complexity of this duplication and identifies the many functional units within the RCA. It was my aim at the beginning of these studies to demonstrate an approach that could define the Ancestral Haplotypes (AHs) of the RCA gene cluster. To do this, extensive genomic analysis was required and the ever-increasing availability of genomic sequence has made this thesis possible. Each of the chapters serves to address the following aims set out at the beginning of this thesis: 1. Further characterise the relationship between the genes (Complement Control proteins-CCPs) and domains of the Regulators of Complement Activation (RCA). 2. Identify and examine the duplicated elements within the RCA. - 6 - 3. Examine the effects of retroviruses and other insertions and deletions (indels) in generating the divergence of duplicated genes. 4. Investigate the applicability of the Genomic Matching Technique (GMT) to define AH within the region. 5. Examine association of AHs with CCP implicated diseases. 6. Determine the GMT applicability in non-human species

Thesis equivalent (M.P.H.)--University of Michigan, 1947.

Thesis (M.P.H.)--University of Michigan, 1944.

Thesis equivalent (M.P.H.)--University of Michigan, 1947.

Thesis (M.P.H.)--University of Michigan, 1944.

Thesis (doctoral)--University of Göteborg, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--University of Göteborg, 1997. / Added t.p. with thesis statement inserted.

Made available in DSpace on 2014-06-11T19:30:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-18Bitstream added on 2014-06-13T19:19:19Z : No. of bitstreams: 1 santana_l_dr_sjrp.pdf: 1536697 bytes, checksum: 74eccec20298ad2fbce9e2f4cfd327a3 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O principal objetivo desta tese é o estudo da variação escalar entre construções verbais e nominais que figuram como complemento de orações hierarquicamente superiores, isto é, orações completivas finitas plenamente desenvolvidas e orações completivas não-finitas com um verbo infinitivo ou com uma nominalização como núcleo. Essas possibilidades de variação fornecem um conjunto de construções alternativas, cuja seleção pode depender de fatores funcionais, embora não exclusivamente. A variação entre construções mais nominais e construções mais verbais e as consequências dela decorrentes são razões que justificam plenamente uma investigação criteriosa das motivações semânticas que regem o funcionamento das construções encaixadas completivas, mediante a atuação dos princípios funcionais de iconicidade e economia (HAIMAN, 1983; CRISTOFARO, 2003) na relação entre a semântica do predicado encaixador de complemento e a codificação morfossintática do predicado encaixado. A principal proposição que conduz a investigação é a de que, para a seleção dos diferentes tipos de complemento, existe uma relação de integração semântica (GIVÓN, 1980, 1990) entre construções completivas e a categoria semântica do predicado encaixador, de modo que a semântica do predicado encaixador é altamente relevante para determinar a categoria morfossintática das predicações dependentes. A relação de gradação entre maior ou menor grau de sentencialidade (LEHMANN, 1988), que se correlaciona ao grau de nominalidade da construção dependente, está vinculada ao nível e à camada de organização estrutural definidos pela Gramática Discursivo-Funcional (HENGEVELD; MACKENZIE, 2008) nos seguintes termos: quanto mais baixa a camada de representação do complemento tanto maior o grau de integração semântica entre o predicado da oração encaixadora... / The aim of this thesis is to investigate the scalar variation between verbal and nominal constructions which function as complements of hierarchically higher clauses, i.e., finite complement clauses which are fully developed, and non-finite complement clauses which are headed by an infinitive verb or a nominalization. This range of variation provides a set of alternative constructions whose selection may, though not exclusively, depend on functional factors. The variation between more nominal and more verbal constructions and its consequences fully justifies a rigorous investigation of the semantic motivations which govern how embedded complement clauses actually function, by means of the functional principles of iconicity and economy (HAIMAN, 1983; CRISTOFARO, 2003) on the relationship between the semantics of the complement taking predicate and the morphosyntactic encoding of the embedded predicate. The main tenet underlying this investigation is that (i) sorting out different types of complement predicates requires a relation of semantic integration (GIVÓN, 1980, 1990) between complement clause and the semantic category of the complement taking predicate and (ii) such relation is, therefore, highly relevant to determine the morphosyntactic encoding of the dependent predications. The gradient relationship between balancing and deranking sentences, which is correlated to the degree of nominality or sentenciality of the dependent construction (LEHMANN, 1988), is associated with the structural organization of levels and layers defined by Functional Discourse Grammar (HENGEVELD; MACKENZIE, 2008) as follows: the lower the representation level of the complement the higher the degree of semantic integration between the complement taking predicate and the predicate of the embedded clause. Keywords: complement taking predicate; complement clause; semantic integration.

Orientador: Roberto Gomes Camacho / Banca: Sebastião Carlos Leite Gonçalves / Banca: Cláudia Nívea Roncarati de Souza / Banca: Flávia Bezerra de Menzes Hirata-Vale / Banca: Vânia Cristina Casseb Galvão / Resumo: O principal objetivo desta tese é o estudo da variação escalar entre construções verbais e nominais que figuram como complemento de orações hierarquicamente superiores, isto é, orações completivas finitas plenamente desenvolvidas e orações completivas não-finitas com um verbo infinitivo ou com uma nominalização como núcleo. Essas possibilidades de variação fornecem um conjunto de construções alternativas, cuja seleção pode depender de fatores funcionais, embora não exclusivamente. A variação entre construções mais nominais e construções mais verbais e as consequências dela decorrentes são razões que justificam plenamente uma investigação criteriosa das motivações semânticas que regem o funcionamento das construções encaixadas completivas, mediante a atuação dos princípios funcionais de iconicidade e economia (HAIMAN, 1983; CRISTOFARO, 2003) na relação entre a semântica do predicado encaixador de complemento e a codificação morfossintática do predicado encaixado. A principal proposição que conduz a investigação é a de que, para a seleção dos diferentes tipos de complemento, existe uma relação de integração semântica (GIVÓN, 1980, 1990) entre construções completivas e a categoria semântica do predicado encaixador, de modo que a semântica do predicado encaixador é altamente relevante para determinar a categoria morfossintática das predicações dependentes. A relação de gradação entre maior ou menor grau de sentencialidade (LEHMANN, 1988), que se correlaciona ao grau de nominalidade da construção dependente, está vinculada ao nível e à camada de organização estrutural definidos pela Gramática Discursivo-Funcional (HENGEVELD; MACKENZIE, 2008) nos seguintes termos: quanto mais baixa a camada de representação do complemento tanto maior o grau de integração semântica entre o predicado da oração encaixadora... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this thesis is to investigate the scalar variation between verbal and nominal constructions which function as complements of hierarchically higher clauses, i.e., finite complement clauses which are fully developed, and non-finite complement clauses which are headed by an infinitive verb or a nominalization. This range of variation provides a set of alternative constructions whose selection may, though not exclusively, depend on functional factors. The variation between more nominal and more verbal constructions and its consequences fully justifies a rigorous investigation of the semantic motivations which govern how embedded complement clauses actually function, by means of the functional principles of iconicity and economy (HAIMAN, 1983; CRISTOFARO, 2003) on the relationship between the semantics of the complement taking predicate and the morphosyntactic encoding of the embedded predicate. The main tenet underlying this investigation is that (i) sorting out different types of complement predicates requires a relation of semantic integration (GIVÓN, 1980, 1990) between complement clause and the semantic category of the complement taking predicate and (ii) such relation is, therefore, highly relevant to determine the morphosyntactic encoding of the dependent predications. The gradient relationship between balancing and deranking sentences, which is correlated to the degree of nominality or sentenciality of the dependent construction (LEHMANN, 1988), is associated with the structural organization of levels and layers defined by Functional Discourse Grammar (HENGEVELD; MACKENZIE, 2008) as follows: the lower the representation level of the complement the higher the degree of semantic integration between the complement taking predicate and the predicate of the embedded clause. Keywords: complement taking predicate; complement clause; semantic integration. / Doutor

Dense Deposit Disease (DDD) causes chronic renal dysfunction which progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in complement Factor H (CFH) are associated with the development of DDD, suggesting that dysregulation of the alternative pathway (AP) of the complement cascade is important in disease pathophysiology. Patients with DDD are studied to determine whether specific allele variants of the genes of the alternative pathway of the complement system segregate preferentially with the DDD. We have screened coding and intronic regions of genes of the complement system in DDD cases and controls using PCR, restriction digest and bidirectional sequencing. We have been able to identify novel mutations, allele variants and haplotypes in several genes of the complement system which are associated with the DDD phenotype based on statistical analyses. Since we have identified several genes associated with DDD, we have determined possible gene-gene interactions using computational analyses. We have found a strong synergistic interaction between polymorphisms in CFH and C3. To ascertain if the associated allele variants had a functional impact in the complement activity of an individual, we have obtained blood samples from normal individuals and measured AP complement activity and genotyped CFH and C3 for these samples. Association between AP activity and genotypes is analyzed using statistical methods. Significant association of CFH and C3 variants with AP complement activity has been observed. We also have generated a mice deficient of CFH and Factor D (CFD). CFH deficient mice develop renal pathology similar to DDD in humans. Renal function and complement activity have been determined in the double knockout in comparison to CFH deficient and CFD deficient mice. Results have shown that absence of Factor D can inhibit complement activation in CFH mice. Our data imply that DDD is a complex genetic disease and that genes of the AP complement system contribute to level of complement activity and the pathogenesis of DDD. With this study, we hope to develop an effective diagnosis and treatment plan for DDD patients.