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Determinants of genomic diversity in the collared flycatcher (Ficedula albicollis)Dutoit, Ludovic January 2017 (has links)
Individuals vary from each other in their genetic content. Genetic diversity is at the core of the evolutionary theory. Rooted in a solid theoretical framework developed as early as the 1930s, current empirical observations of genomic diversity became possible due to technological advances. These measurements, originally based on a few gene sequences from several individuals, are becoming possible at the genome scale for entire populations. We can now explore how evolutionary forces shape diversity levels along different parts of the genome. In this thesis, I focus on the variation in levels of diversity within genomes using avian systems and in particular that of the collared flycatcher (Ficedula albicollis). First, I describe the variation in genetic diversity along the genome of the collared flycatcher and compare it to the amount of variation in diversity across individuals within the population. I provide guidelines on how a small number of makers can capture the extent of variability in a population. Second, I investigate the stability of the local levels of diversity in the genome across evolutionary time scales by comparing collared flycatcher to the hooded crow (Corvus (corone) corone). Third, I study how selection can maintain variation through pervasive evolutionary conflict between sexes. Lastly, I explore how shifts in genome-wide variant frequencies across few generations can be utilised to estimate the effective size of population.
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Prevenção primária da síndrome de Down e da doença de Alzheimer: Investigação de polimorfismos gênicos acentuadores da deposição cerebral de beta amilóide / Primary prevention of Dow's Syndrome and Alzheimer disease: Investigation of genetic polymorphisms enhacer of brain deposition of beta amyloidJuliana da Cruz Corrêa 17 February 2009 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O desenvolvimento de mudanças neuropatológicas características da doença de Alzheimer (DA) nos portadores de síndrome de Down (SD) a partir dos 40 anos de idade e a alta taxa de indivíduos com SD em famílias nas quais a DA está presente sugerem uma susceptibilidade comum entre as duas doenças. Além disso, mulheres jovens (<35 anos na concepção) que tiveram filhos com a SD têm um risco cinco vezes maior de desenvolverem DA do que a população em geral. Esta alta suscetibilidade compartilhada poderia envolver um processo de envelhecimento acelerado, que levaria à SD em filhos de mães jovens e a um risco aumentado de demência nestas mães. Até o momento, os genes APOE, PSEN1 e TNF-α, envolvidos direta ou indiretamente na deposição cerebral de beta amilóide e reconhecidos dentre os determinantes genéticos para a DA, parecem também intervir na patogênese da demência na SD. Neste estudo, analisamos a freqüência dos alelos ε2, ε3 e ε4 do gene APOE e dos polimorfismos -48C>T no gene PSEN1 e -850C>T no gene TNF-α em mães de portadores da SD em comparação com mães de indivíduos cromossomicamente normais. Para isto, amostras de DNA foram extraídas a partir do sangue periférico de 114 mães de portadores da trissomia livre do cromossomo 21 com idade inferior a 35 anos no momento da concepção e de 110 mães controle. Para a triagem dos polimorfismos dos alelos do gene APOE e dos polimorfismos PSEN1 -48C>T e TNF-α -850C>T foi realizada a técnica de PCR seguida da digestão dos produtos amplificados com as endonucleases de restrição HhaI, HgaI e HincII, respectivamente. Os produtos digeridos foram analisados através de eletroforese em géis de poliacrilamida corados por prata. A análise estatística através do teste exato de Fisher revelou que não houve diferenças significativas entre as distribuições genotípicas observadas nas amostras caso e controle tanto para os alelos do gene APOE, quanto para os polimorfismos PSEN1-48C>T e TNF-α -850C>T (c2 =4,26; g.l. = 4; P =0,37; c2 =0,22; g.l. = 2; P =0,89; c2 = 4,24; g.l. = 2; P = 0,12, respectivamente). Diferenças significativas também não foram observadas tanto na análise da interação gênica multiplicativa entre os alelos dos genes APOE, PSEN1 e TNF-α como na interação entre estes alelos e polimorfismos participantes do metabolismo do folato (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, RFC-1 80G>A, TC 776C>G e CBS 844ins68). No Brasil, este é o primeiro relato da investigação destes genes entre as mães de indivíduos com SD. Nossos resultados sugerem que os alelos APOE e4, PSEN1-48 C e TNF-α -850T não são fatores de risco independentes para a DA nestas mães. Entretanto, em virtude da complexidade tanto da SD como da DA, a análise de variantes em outros genes é de fundamental importância para melhor elucidar o aparecimento insidioso de DA em mães jovens que tiveram filhos com SD. / The development of neuropathological changes of Alzheimer's disease (AD) in patients with Down syndrome (DS) from 40 years old and the high rate of DS births in families of DA individuals suggest a common susceptibility between the two diseases. Besides a five-fold higher risk for AD has been reported in young mothers of DS individuals. This shared genetic susceptibility involving DS and AD could be due to an accelerated ageing process, leading to the birth of a DS child in the offspring of young mothers and to an increased risk of dementia among them. Between the genetic risk factors for AD, APOE, PSEN1 and TNF-α genes are directly or indirectly involved in cerebral amyloid deposition and seem to play a role in the pathogenesis of dementia in DS. In this study, we analyzed the frequency of APOE alleles ε2, ε3 e ε4 and the polymorphisms -48C>T in the PSEN1 gene and -850C>T in the TNF-α gene in DS young mothers in comparison to mothers who had had chromosomicaly normal children. With this purpose, DNA samples were extracted from 114 mothers of DS individuals (full trisomy 21) with less than 35 years-old at conception, and from 110 control mothers. For the screening of the APOE alleles, PSEN1 -48C>T and TNF-α -850C>T polymorphisms, polymerase chain reaction (PCR) was accomplished, followed by the digestion of the amplification products with the restriction endonucleases HhaI, HgaI and HincII, respectively. The digested products were analysed by polyacrilamide gels electrophoresis followed by silver staining. No significant differences were observed between the genotype distributions observed in control and case samples with respect APOE alleles, PSEN1 -48C>T and TNF-α -850C>T polymorphisms (Fisher exact test: c2 =4,26; g.l. = 4; P =0,37; c2 =0,22; g.l. = 2; P =0,89; c2 = 4,24; g.l. = 2; P = 0,12, respectively). No differences were also observed in the gene multiplicative interaction analysis for APOE, PSEN1 and TNF-α alleles and in the interaction of these alleles with folate pathway polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, RFC-1 80G>A, TC 776C>G e CBS 844ins68). This is the first study reporting the investigation of these genes in Brazilian DS mothers. Our findings suggest that APOE ε4, PSEN1 -48C and TNF-α -850T alleles are not independent risk factors for AD in young DS mothers. However, considering the complexity of both DS and AD, polymorphisms in other genes should be investigated to evaluate the actual relationship between the genetic risk factors and AD in DS young mothers.
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Prevenção primária da síndrome de Down e da doença de Alzheimer: Investigação de polimorfismos gênicos acentuadores da deposição cerebral de beta amilóide / Primary prevention of Dow's Syndrome and Alzheimer disease: Investigation of genetic polymorphisms enhacer of brain deposition of beta amyloidJuliana da Cruz Corrêa 17 February 2009 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O desenvolvimento de mudanças neuropatológicas características da doença de Alzheimer (DA) nos portadores de síndrome de Down (SD) a partir dos 40 anos de idade e a alta taxa de indivíduos com SD em famílias nas quais a DA está presente sugerem uma susceptibilidade comum entre as duas doenças. Além disso, mulheres jovens (<35 anos na concepção) que tiveram filhos com a SD têm um risco cinco vezes maior de desenvolverem DA do que a população em geral. Esta alta suscetibilidade compartilhada poderia envolver um processo de envelhecimento acelerado, que levaria à SD em filhos de mães jovens e a um risco aumentado de demência nestas mães. Até o momento, os genes APOE, PSEN1 e TNF-α, envolvidos direta ou indiretamente na deposição cerebral de beta amilóide e reconhecidos dentre os determinantes genéticos para a DA, parecem também intervir na patogênese da demência na SD. Neste estudo, analisamos a freqüência dos alelos ε2, ε3 e ε4 do gene APOE e dos polimorfismos -48C>T no gene PSEN1 e -850C>T no gene TNF-α em mães de portadores da SD em comparação com mães de indivíduos cromossomicamente normais. Para isto, amostras de DNA foram extraídas a partir do sangue periférico de 114 mães de portadores da trissomia livre do cromossomo 21 com idade inferior a 35 anos no momento da concepção e de 110 mães controle. Para a triagem dos polimorfismos dos alelos do gene APOE e dos polimorfismos PSEN1 -48C>T e TNF-α -850C>T foi realizada a técnica de PCR seguida da digestão dos produtos amplificados com as endonucleases de restrição HhaI, HgaI e HincII, respectivamente. Os produtos digeridos foram analisados através de eletroforese em géis de poliacrilamida corados por prata. A análise estatística através do teste exato de Fisher revelou que não houve diferenças significativas entre as distribuições genotípicas observadas nas amostras caso e controle tanto para os alelos do gene APOE, quanto para os polimorfismos PSEN1-48C>T e TNF-α -850C>T (c2 =4,26; g.l. = 4; P =0,37; c2 =0,22; g.l. = 2; P =0,89; c2 = 4,24; g.l. = 2; P = 0,12, respectivamente). Diferenças significativas também não foram observadas tanto na análise da interação gênica multiplicativa entre os alelos dos genes APOE, PSEN1 e TNF-α como na interação entre estes alelos e polimorfismos participantes do metabolismo do folato (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, RFC-1 80G>A, TC 776C>G e CBS 844ins68). No Brasil, este é o primeiro relato da investigação destes genes entre as mães de indivíduos com SD. Nossos resultados sugerem que os alelos APOE e4, PSEN1-48 C e TNF-α -850T não são fatores de risco independentes para a DA nestas mães. Entretanto, em virtude da complexidade tanto da SD como da DA, a análise de variantes em outros genes é de fundamental importância para melhor elucidar o aparecimento insidioso de DA em mães jovens que tiveram filhos com SD. / The development of neuropathological changes of Alzheimer's disease (AD) in patients with Down syndrome (DS) from 40 years old and the high rate of DS births in families of DA individuals suggest a common susceptibility between the two diseases. Besides a five-fold higher risk for AD has been reported in young mothers of DS individuals. This shared genetic susceptibility involving DS and AD could be due to an accelerated ageing process, leading to the birth of a DS child in the offspring of young mothers and to an increased risk of dementia among them. Between the genetic risk factors for AD, APOE, PSEN1 and TNF-α genes are directly or indirectly involved in cerebral amyloid deposition and seem to play a role in the pathogenesis of dementia in DS. In this study, we analyzed the frequency of APOE alleles ε2, ε3 e ε4 and the polymorphisms -48C>T in the PSEN1 gene and -850C>T in the TNF-α gene in DS young mothers in comparison to mothers who had had chromosomicaly normal children. With this purpose, DNA samples were extracted from 114 mothers of DS individuals (full trisomy 21) with less than 35 years-old at conception, and from 110 control mothers. For the screening of the APOE alleles, PSEN1 -48C>T and TNF-α -850C>T polymorphisms, polymerase chain reaction (PCR) was accomplished, followed by the digestion of the amplification products with the restriction endonucleases HhaI, HgaI and HincII, respectively. The digested products were analysed by polyacrilamide gels electrophoresis followed by silver staining. No significant differences were observed between the genotype distributions observed in control and case samples with respect APOE alleles, PSEN1 -48C>T and TNF-α -850C>T polymorphisms (Fisher exact test: c2 =4,26; g.l. = 4; P =0,37; c2 =0,22; g.l. = 2; P =0,89; c2 = 4,24; g.l. = 2; P = 0,12, respectively). No differences were also observed in the gene multiplicative interaction analysis for APOE, PSEN1 and TNF-α alleles and in the interaction of these alleles with folate pathway polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, RFC-1 80G>A, TC 776C>G e CBS 844ins68). This is the first study reporting the investigation of these genes in Brazilian DS mothers. Our findings suggest that APOE ε4, PSEN1 -48C and TNF-α -850T alleles are not independent risk factors for AD in young DS mothers. However, considering the complexity of both DS and AD, polymorphisms in other genes should be investigated to evaluate the actual relationship between the genetic risk factors and AD in DS young mothers.
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Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control studyBuch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U., Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Matthias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Corradini, Stefano Ginanni, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Müller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-François, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, Stickel, Felix 22 February 2024 (has links)
Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. - Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). - Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10⁻⁹, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10⁻⁵, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10⁻⁴⁴). - Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
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