The study of protein polymorphism in natural populations has stimulated heated controversy over the effects of various evolutionary forces on the observed patterns of genetic variation. One viewpoint is that a majority of the mutations at a locus are selectively equivalent and that variations in gene frequencies in time and space are primarily a result of nonselective evolutionary forces. The opposing view is that most mutations have sufficient effect on individual fitness that variations in gene frequencies are adaptations resulting from the action of natural selection. I compared gene frequency distributions among various loci to assess the roles of selective and nonselective evolutionary forces in determining patterns of allozyme variation in populations of rodents. I used two versions of the Lewontin-Krakauer test on temporal variation in allozyme frequencies reported for populations of the prairie vole, Microtus ochrogaster. The tests revealed that the changes in gene frequency were homogeneous among loci which suggests that nonselective forces such as genetic drift and migration were the primary cause of gene frequency change within populations. I also compared the spatial gene frequency distributions reported for 17 species of rodents to assess which evolutionary factors account for the genetic differentiation of populations within each species. Most loci showed similar degrees of differentiation, a pattern expected if nonselective forces operated in population differentiation. I found a positive relationship between the amount of differentiation of populations and the magnitude of positive association among rare alleles. This result suggests an active role of genetic drift in population differentiation within rodent species. The analysis of allozyme distributions in populations of rodents indicates that nonselective evolutionary forces play a substantial role in determining patterns of genetic variation. According to Wright's Shifting Balance Theory, the random differentiation of populations may actually accelerate adaptive evolution, which may account for the rapid evolutionary rates found in rodents.

Thesis (Ph. D.)--University of Hong Kong, 2003. / Includes bibliographical references (leaves 136-161) Also available in print.

No description available.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

Frequency-dependent selection has long been a popular heuristic explanation for the maintenance of genetic diversity in natural populations. Indeed, a large body of theoretical and empirical work has already gone into elucidating the causes and consequences of frequency-dependent selection. Most theoretical work, to date, has focused either on the diallelic case, or dealt with only very specific forms of frequency-dependence. A general model of the maintenance of multiallelic genetic diversity has been lacking. Here we extend a flexible general model of frequency-dependent selection, the pairwise interaction model, to the case of multiple alleles. First, we investigate the potential for genetic variation under the pairwise interaction model using a parameter-space approach. This approach involves taking a large random sample of all possible fitness sets and initial allele-frequency vectors of the model, iterating each to equilibrium from each set of random initial conditions, and measuring how often variation is maintained, and by which parameter combinations. We find that frequency- dependent selection maintains full polymorphism more often than classic constant-selection models and produces more skewed equilibrium allele frequencies. Fitness sets with some degree of rare advantage maintained full polymorphism most often, but a variety of non-obvious fitness patterns were also found to have positive potential for polymorphism. Second, we further investigate some unusual dynamics uncovered by the parameter-space approach above. Long-period allele-frequency cycles and a small number of aperiodic trajectories were detected. We measured the number, length and domains of attraction of the various attractors produced by the model. The genetic cycles produced by the model did not have periods short enough to be observable on an ecological time scale. In a real world system, allele-frequency cycling is likely to be indistinguishable from stable equilibrium when observed over short time scales. Third, we use a construction approach to model frequency-dependent selection with mutation under the pairwise interaction model. This approach involves the construction of an allelic polymorphism by bombarding an initial monomorphism with mutant alleles over many generations. We find that frequency-dependent selection is able to generate large numbers of alleles at a single locus. The construction process generates a wide range of allele- frequency distributions and genotypic fitness relationships. We find that constructed polymorphisms remain permanently invasible to new mutants. Analysis of constructed fitness sets may even reveal a signature of positive frequency dependence. Finally, we examine the numbers and distributions of fitnesses and alleles produced by construction under the pairwise interaction model with mutation from existing alleles, using several different methods of generating mutant fitnesses. We find that, relative to more general construction models, generating mutants from existing alleles lowers the average number of alleles maintained by frequency-dependent selection. Nevertheless, while the overall numbers of alleles are lower, the polymorphisms produced are more stable, with more natural allele-frequency distributions. Overall, frequency-dependent selection remains a powerful mechanism for the maintenance of genetic variation, although it does not always work in intuitively obvious ways.

Diss. (sammanfattning) Umeå : Umeå universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Miami University, Dept. of Microbiology, 2004. / Title from second page of PDF document. Includes bibliographical references (p. 133-140).

Orientador: Hercílio Martelli Júnior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-18T03:14:48Z (GMT). No. of bitstreams: 1 Aquino_SibeleNascimentode_M.pdf: 1254396 bytes, checksum: 23d834d1395b6d0cfe104c6231785589 (MD5) Previous issue date: 2011 / Resumo: Fissuras do lábio e/ou palato (FL/P) representam uma das anomalias congênitas mais comuns em humanos. A etiologia das FL/PNS é complexa e envolve a participação de inúmeros genes e fatores ambientais. Diversos estudos têm investigado genes relacionados a síndromes, que apresentam FL/P em seu espectro clínico, e/ou que são expressos durante o desenvolvimento do lábio e/ou palato. O objetivo deste estudo foi verificar se novos polimorfismos contidos nos genes relacionados ao desenvolvimento do lábio e palato, incluindo TGF?3, MSX1, MYH9 e JAG2, podem contribuir para a etiologia das FL/PNS. Seis regiões polimórficas foram genotipadas por PCR-RFLP (reação em cadeia da polimerase associada à análise de polimorfismo de fragmentos de restrição enzimática) em amostras de DNA proveniente de 367 pacientes com FL/PNS (grupo caso) e de 413 indivíduos não afetados (grupo controle). No grupo caso, 54% foram do gênero masculino e 46% do feminino, com idade média de 19,1 ± 14,9 anos e prevalência de indivíduos feodermas (42,5%) e leucodermas (42%). As fissuras lábio-palatinas (FLP) foram predominantes (54%), seguidas pela fissura labial (FL) (24%) e fissura palatina (FP) (22%). Do total de seis polimorfismos analisados neste estudo, apenas um foi confirmado nessa população: rs1057744 do gene JAG2. Para este locus polimórfico, o alelo A e o genótipo GA foi mais comum, no grupo controle e caso, não sendo encontrada diferença estatística significante. Para esse polimorfismo, a análise em um modo dominante ou recessivo também não mostrou diferenças estatísticas significantes. Assim, demonstrou-se que os polimorfismos rs34019007 e rs4252315, do gene TGF?3, rs62636562, do gene MSX1, rs11549910 e rs11549909, do gene MYH9 não foram confirmados. O polimorfismo rs1057744 do gene JAG2, embora confirmado, não apresentou associação significante com FL/PNS na população avaliada / Abstract: Cleft lip and/or cleft palate (CL/P) is one of the most common congenital anomaly in humans. NSCL/P etiology is complex and involves the participation of numerous genes and environmental factors. Several studies have investigated genes related to syndromes that have CL/P in their clinical and/or which are expressed during the development of lip and palate. The aim of this study was to determine whether polymorphisms contained genes related to the development of lip and/or palate, including TGF?3, MSX1, MYH9 and JAG2 can contribute to the etiology of NSCL/P. Six polymorphic regions were genotyped by PCR-RFLP (restriction fragment length polymorphism-polymerase chain reaction) in DNA samples from 367 patients affected by NSCL/P (experimental group) and 413 clinically normal subjects (control group). In the affected group, 54% were male and 46% female, mean age 19.1 ± 14.9 years and the prevalence of mixed black individuals (42.5%) and Caucasian (42%). The clefts of the lip with or without cleft palate (CLP) were predominant (54%), followed by cleft lip (FL) (24%) and cleft palate FP (22%). Out of 6 probable polymorphisms, only one was confirmed in this population: rs1057744 gene JAG2. For this polymorphic locus, the A allele and the genotype was slightly more common in the contr ol and experimental, without statistically signific ant differences. For this polymorphism , the analysis in a dominant or recessive mode also showed no statistically significant difference s between the group. This study demonstrated that the polymorphisms rs34019007 and rs4252315, present in the gene TGF?3, rs62636562, in the MSX1 gene, rs11549910 and rs11549909, in the MYH9 gene we re not confirmed. The rs1057744 polymorphism in JAG2 gene was confirmed in this study but not significantly associated with NSCL/P in the Brazilian population / Mestrado / Patologia / Mestre em Estomatopatologia

Orientadores: Claudio Saddy Rodrigues Coy, Carmen Silvia Passos Lima / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T01:34:06Z (GMT). No. of bitstreams: 1 Credidio_Laura_M.pdf: 7330672 bytes, checksum: 03e0aafb86a0b4df9c88c89f064490e2 (MD5) Previous issue date: 2012 / Resumo: O papel da angiogênese para o desenvolvimento do câncer colorretal (CCR) ainda não é totalmente conhecido. Uma das principais glicoproteínas responsáveis pela angiogênese é o fator de crescimento endotelial vascular (VEGF), acredita-se que o polimorfismo C936T, localizado no gene VEGF, esteja correlacionado com a suscetibilidade para o desenvolvimento do CCR. Objetivos: Identificar as freqüências dos genótipos do polimorfismo C936T do gene VEGF em pacientes portadores de adenocarcinoma colorretal esporádico (ACE) e controles e correlacionar a ocorrência do mesmo com as seguintes variáveis: sexo, idade, localização tumoral, acometimento de linfonodos (N) e infiltração tumoral (T) em pacientes. Material e método: No período compreendido entre outubro de 2008 a dezembro de 2009 foram coletadas amostras de sangue periférico de pacientes com ACE, no ambulatório de Coloproctologia do HC UNICAMP (G1). O grupo controle (G2) foi constituído por doadores de sangue. Foram excluídos do estudo portadores de polipose familiar, síndrome de Lynch, doenças inflamatórias intestinais e com antecedente familiar de CCR. A extração do DNA genômico se deu por cloreto de lítio e por kit de extração de DNA. Os genótipos do polimorfismo C936T foi avaliado por meio da reação em cadeia da polimerase e digestão enzimática. Resultados : O G1 constou de 261 pacientes, sendo 52,1% do sexo masculino com média de idade de 64,9 (32-97) anos. O G2 foi formado por 261 doadores de sangue, com idade media de 52,9 anos (25-62) sendo 52,1% do sexo masculino. A ocorrência do genótipo selvagem (CC) foi de 80,5%, do heterozigoto (CT) foi de 18,4% e do homozigoto (TT) de 1,1% em pacientes. No G2 a ocorrência dos genótipos foram 78,5% (CC), 20,7% (CT) e 0,8% (TT), indivíduos com genótipos distintos do gene estiveram sob riscos similares do ACE. Com relação á localização do tumor, 51,5% encontravam-se no reto, 16,4% cólon direito, 31,1% em cólon esquerdo. Em relação ao grau de invasão tumoral, 0,7% foram classificados como Tis, 1,5% T0, 8,1% T1, 19,3% T2, 65,2% T3 e 7,4% como T4. Quanto ao acometimento de linfonodos, 53,9% foram classificados como N0, 33,6% como N1 e 12,5% como N2. Não se observou diferenças em relação ao grau de invasão tumoral, acometimento de linfonodos ou ocorrência de metástases (p = 0,2996) em relação à ocorrência do polimorfismo C936T. Conclusão: O polimorfismo C936T do gene VEGF não correlaciona-se com o risco de ocorrência do tumor e com o sexo, idade, localização da lesão, acometimento de linfonodos e infiltração tumoral / Abstract: Background: The role of angiogenesis for the development of Colorectal Cancer (CC) is not yet fully known. One of the major glycoprotein responsible for pro-angiogenesis is vascular endothelial growth factor (VEGF). It is believed that the C936T polymorphism located in the VEGF gene is correlated with less susceptibility to the development of CC. Objectives: To identify the genotype frequencies of the C936T polymorphism of the VEGF gene in patients with sporadic colorectal adenocarcinoma (ACE) and controls and to correlate the occurrence of the same with following variables: gender, age, tumor location, lymph node (N) and tumor infiltration (T). Methods: Between October 2008 and December 2009 samples were collected from peripheral blood of patients with colorectal cancer in the clinic of Coloproctology of HC UNICAMP (G1). The control group (G2) comprised blood donors. We excluded patients with familial polyposis, Lynch syndrome, inflammatory bowel diseases and family history of CC. The genomic DNA extraction was done by lithium chloride and by DNA extraction kit. The genotypes of the C936T polymorphism were assessed by polymerase chain reaction and enzymatic digestion. Results: G1 consisted of 261 patients, 52.1% male with a mean age of 64.9 (32-97) years. The G2 is composed of 261 blood donors, with a mean age of 52.9 years (25-62) 52.1% male. The occurrence of wild genotype (CC) was 80.5%, the heterozygous (CT) was 18.4% and the homozygous (TT) of 1.1% in patients. In G2 the occurrence of genotypes were 78.5% (CC), 20.7% (CT) and 0.8% (TT); individuals with different genotypes of the gene were under similar risks of ACE. Regarding the location of the tumor, 51.5% were in the rectum, right colon 16.4%, 31.1% in the left colon. Regarding the degree of tumor invasion, 0.7% was classified as Tis, T0 1.5%, 8.1% T1, 19.3% T2, T3 65.2% and 7.4% as T4. As for the involvement of lymph nodes, 53.9% were classified as N0, 33.6% N1 and 12.5% N2. There were no significant differences in the degree of tumor invasion, lymph nodes or occurrence of metastases (p = 0.2996) in relation to the occurrence of the C936T polymorphism. Conclusion: The C936T polymorphism of the VEGF gene did not correlate with the risk of tumor occurrence and sex, age, lesion location, lymph nodes and tumor infiltration / Mestrado / Ciências da Cirurgia / Mestre em Ciências

A paraoxonase sérica humana (PON) vem sendo amplamente estudada. Além da capacidade de PON1 em hidrolisar compostos organofosfatados, sabe-se, atualmente, que toda a família PON (composta por PON1, PON2 e PON3) promove a proteção de lípides, incluindo-se a lipoproteína de baixa densidade (LDL) contra a oxidação. O gene da PON1 sérica apresenta dois sítios polimórficos bem determinados: a troca Gln192Arg (Q/R) e Met55Leu, os quais estão associados com diferenças na atividade e concentrações séricas da enzima, respectivamente. Também o polimorfismo Cys311Ser parece contribuir sinergisticamente com o alelo PON1-192R quanto ao risco cardiovascular em algumas populações. Já foi demonstrado, por sua vez, que pacientes infectados pelo vírus HIV podem desenvolver dislipidemia e que tanto a atividade como a concentração de PON1 podem ser influenciadas por esta infecção. O objetivo deste estudo foi determinar as freqüências alélicas dos polimorfismos genéticos PON1-192QR, PON1-55LM, PON2-311SC e PON2-148AG, bem como avaliar a atividade de PON1 e a peroxidação lipídica no plasma de indivíduos portadores de HIV. Materiais e Métodos após aprovação pela comissão de ética e da aplicação do termo de consentimento pós-esclarecido, 350 (264 homens e 86 mulheres) pacientes infectados pelo HIV foram incluídos no estudo. Foi avaliado ainda um grupo de 32 (23 homens e 9 mulheres) indivíduos recentemente diagnosticados como portadores do vírus. Uma população saudável composta por 179 doadores de sangue, todos de sexo masculino, foi avaliada como controle. Após a extração do DNA, procedeu-se à genotipagem para os polimorfismos de PON1 e PON2 através de PCR-RFLP. A atividade paraoxonase de PON1 foi avaliada por espectrofotometria empregando-se paraoxon como substrato. O colesterol total, VLDL-colesterol, HDL-colesterol e triglicérides foram determinados por métodos padrão. A fração LDL-colesterol foi calculada pela fórmula de Friedwald. Resultados As freqüências alélicas para os polimorfimos de PON1 nos pacientes foram: 36,43% para o alelo PON1-192R, 57,86% para PON1-55L, 65,57% para PON2-311S e 76,43% para o alelo PON2-148A. No grupo de indivíduos recentemente diagnosticados como portadores de HIV estas freqüências foram 37,50%, 51,56%, 81,25% e 68,75, respectivamente. No grupo composto pelos saudáveis, a freqüência alélica de PON1-192R foi 43,02%, a de PON1-55L foi 68,99%, a do alelo PON2-311S foi 67,60% e, por fim, a freqüência do alelo PON2-148A foi 75,14%. Conclusões As distribuições alélicas dos polimorfimos em PON1 e PON2 foram similares dentre os portadores de HIV e os controles. A relação entre os genótipos PON1-192QR e/ou PON1-55LM e a atividade de PON1 em pacientes não diferiu daquela observada nos controles. Observou-se ainda, aumento do colesterol, dos triglicérides e da peroxidação lipídica no plasma dos infectados pelo vírus e, nos pacientes, uma maior atividade enzimática dentre os possuidores de contagem de linfócitos CD4+ acima de 500 células por mm3. / Human serum paraoxonase (PON) has been the subject of a number of studies. Beside the capacity of PON1 in hydrolyzing organophosphate compounds, it is known now that the entire PON family (which comprises PON1, PON2 and PON3) protects lipids, including low-density lipoprotein (LDL), from oxidation. Serum PON1 gene presents two well-determined genetic polymorphic sites: a Gln192 Arg (Q/R) and Met55 Leu, which are associated with differences in enzymatic activity and serum concentrations, respectively. Moreover, PON2 Cys311 Ser polymorphism seems to contribute synergistically with PON-192R allele to cardiovascular risk in some populations. It has been shown that HIV infected patients may develop dyslipidemia and that PON1 activity and concentration may be influenced by this infection. The aim of this study was to determine allelic frequencies of PON1-192QR, PON1-55LM, PON2-311SC and PON2-148AG genetic polymorphisms, evaluate PON1 activity and lipid peroxidation in plasma of HIV patients. Methods and Subjects after ethical committee approval and written consent, 350 (264 men and 86 women) HIV infected patients were included in the study. It was also evaluated a group of 32 recently diagnosed HIV individuals (23 men and 9 women). As controls, a healthy population formed by 179 men, blood donors, was studied. After DNA extraction PON1 and PON2 genotyping were performed by PCR-RFLP. Paraoxonase activity of PON1 was evaluated spectrofotometrically using paraoxon as substrate. Serum cholesterol, VLDL-cholesterol, HDL-cholesterol and triglycerides were analyzed by standard methods. LDL-cholesterol was calculated by Friedewald formula. Results: Allelic frequencies for PON1 polymorphisms in patients were: 36,43% for PON1-192R, 57,86% for PON1-55L, 65,57% for PON2-311S and 76,43% for PON2-148A. In recently diagnosed individuals these frequencies were 37,50%, 51,56%, 81,25% and 68,75% respectively. In controls, PON1-192R allelic frequency was 43,02%, PON1-55L was 68,99%, PON2-311S was 67,60% and PON2-148A was 75,14%. Conclusion: Allelic distributions of PON1 and PON2 polymorphisms were similar in HIV patients and controls. The relationship between PON1-192 QR and/or PON1-55LM genotypes and enzyme activity in patients were not different from controls. It was also observed an elevation of cholesterol, tryglicerides and lipid peroxidation levels in plasma of infected patients and, in this group, a higher activity in those which CD4+ cells counting was more than 500 cell/mm3.