Disease Genetics
Permanent URI for this community
My scientific interests are concerned with the understanding of the genetic basis of resistance/susceptibility to disease. The vast majority of common diseases studied to date have been shown to depend on multiple genetic factors. This is the case of several autoimmune and infectious diseases where the main challenge is now to reveal the contribution of individual genetic factors to the disease process. I am proposing to develop a research program based on the systematic analysis of individual genetic factors involved in disease resistance or disease susceptibility both in humans and in murine models. The diseases under study are primarily type 1 diabetes and malaria. The research program is based in 4 distinct but convergent perspectives: (1) mouse genetics, (2) human genetics, (3) statistical genetics and (4) bio-informatics. This program is supported in a technological platform aiming to include all the steps involved in formal disease gene isolation namely fine genetic mapping and candidate gene analysis.
News
Collaborators
IMM
Maria Mota
Browse
Browsing Disease Genetics by Issue Date
Now showing 1 - 10 of 33
Results Per Page
Sort Options
- Modelos de interacção genética de dois genes em fenótiposPublication . Sepúlveda, Nuno; Paulino, C.D.; Penha-Gonçalves, CarlosEm trabalhos anteriores foram propostos diversos modelos estatísticos para a penetrância de forma a inferir a interacção de dois genes dial´elicos na construção de fenótipos binários complexos: modelos de acção independente, modelos de inibição e modelos de número mínimo de alelos. Estes modelos baseiam-se numa decomposição da penetrância através da abordagem por penetrâncias alélicas, que permitiu a inclusão dos conceitos mendelianos de dominância e recessividade alélica na sua modelação. Pretende-se aqui dar a conhecer os avanços mais recentes na parte da modelação da interacção genética, apresentando uma nova decomposição da penetrância e uma nova formulação matemática da dominância e da recessividade. Aplicam-se ainda ferramentas bayesianas para o ajustamento dos modelos de interacção genética a dados experimentais com recurso ao método de amostragem de Gibbs. Toda a metodologia é exemplificada num conjunto de dados de um estudo da susceptibilidade da malária cerebral em ratinhos.
- The multigenic structure of the MHC locus contributes to positive selection efficiency: A role for MHC class II gene-genespecificPublication . Monteiro, Miguel Caetano; Couceiro, Sofia; Penha-Gonçalves, CarlosThe study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of I-E molecule in the thymic cortex increases positive selection efficiency of CD4 cells by approximately 50%.We show that increments in positive selection attributable to either the I-A and I-E genes are not due to increased MHC class II expression in the thymic cortex and are not affected by the number of MHC alleles. Collectively, our findings imply that MHC class II generestricted TCR specificities significantly contribute to positive selection efficiency, introducing the notion that multigenic structure of the MHC locus serves to increase selection of non-overlapping TCR repertoires.
- Mapping of quantitative trait loci using the skew-normal distributionPublication . Fernandes, Elisabete; Pacheco, António; Penha-Gonçalves, CarlosIn standard interval mapping (IM) of quantitative trait loci (QTL), the QTL effect is described by a normal mixture model. When this assumption of normality is violated, the most commonly adopted strategy is to use the previous model after data transformation. However, an appropriate transformation may not exist or may be difficult to find. Also this approach can raise interpretation issues. An interesting alternative is to consider a skew-normal mixture model in standard IM, and the resulting method is here denoted as skew-normal IM. This flexible model that includes the usual symmetric normal distribution as a special case is important, allowing continuous variation from normality to non-normality. In this paper we briefly introduce the main peculiarities of the skew-normal distribution. The maximum likelihood estimates of parameters of the skew-normal distribution are obtained by the expectation-maximization (EM) algorithm. The proposed model is illustrated with real data from an intercross experiment that shows a significant departure from the normality assumption. The performance of the skew-normal IM is assessed via stochastic simulation. The results indicate that the skew-normal IM has higher power for QTL detection and better precision of QTL location as compared to standard IM and nonparametric IM.
- Allelic penetrance approach as a tool to model twolocusPublication . Sepúlveda, Nuno; Paulino, Carlos Daniel; Carneiro, Jorge; Penha-Gonçalves, CarlosMany binary phenotypes do not follow a classical Mendelian inheritance pattern. Interaction between genetic and environmental factors is thought to contribute to the incomplete penetrance phenomena often observed in these complex binary traits. Several two-locus models for penetrance have been proposed to aid the genetic dissection of binary traits. Such models assume linear genetic effects of both loci in different mathematical scales of penetrance, resembling the analytical framework of quantitative traits. However, changes in phenotypic scale are difficult to envisage in binary traits and limited genetic interpretation is extractable from current modeling of penetrance. To overcome this limitation, we derived an allelic penetrance approach that partitioned incomplete penetrance into the alleles controlling the phenotype and into the genetic background and environmental factors. We applied this approach to formulate dominance and recessiveness in a single biallelic locus and to model different genetic mechanisms for the joint action of two biallelic loci. We fit the models to data on the susceptibility of mice following infections with Listeria monocytogenes and Plasmodium berghei. These models gain in genetic interpretation, because they specify the alleles that are responsible for the genetic (inter)action and their genetic nature (dominant or recessive), and predict genotypic combinations determining the phenotype. Further, we show via computer simulations that the proposed models produce penetrance patterns not captured by traditional twolocus models. This approach provides a new analysis framework for dissecting mechanisms of interlocus joint action in binary traits using genetic crosses.
- Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mousePublication . Côrte-Real, J; Rodo, Joana; Almeida, P; Coutinho, António; Demengeot, Jocelyne; Penha-Gonçalves, CarlosNatural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation.
- Bayesian analysis of allelic penetrance models for complex binary traitsPublication . Sepúlveda, Nuno; Paulino, Carlos Daniel; Penha-Gonçalves, CarlosComplex binary traits result from an intricate network of genetic and environmental factors. To aid their genetic dissection, several generalized linear models have been described to detect interaction between genes. However, it is recognized that these models have limited genetic interpretation. To overcome this problem, the allelic penetrance approach was proposed to model the action of a dominant or a recessive allele at a single locus, and to describe two-locus independent, inhibition, and cumulative actions. Classically, a recessive inheritance requires the expression of both recessive alleles in homozygotes to obtain the phenotype (type I recessiveness). In previous work, recessiveness was defined alternatively as a situation where a recessive allele is able to express the phenotype when the dominant allele is not active (type II recessiveness). Both definitions of recessiveness are then discussed under the allelic penetrance models. Bayesian methods are applied to analyze two data sets: one regarding the effect of the haplotype [HLA-B8, SC01, DR3] on the inheritance of IgD and IgG4 immunoglobulin deficiencies in humans, and other related to two-locus action in the control of Listeria infection susceptibility in mice.
- The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected MicePublication . Sardinha, L. R.; Mosca, T.; Elias, R. M.; do Nascimento, R. S.; Goncalves, L. A.; Bucci, D. Z.; Marinho, C. R. F.; Penha-Goncalves, C.; Lima, M. R. D.; Alvarez, J. M.Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5x10(6) trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1(+), CD8(+) and CD4(+) cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4(+) and CD8(+) cells were activated, increased frequencies of CD69(+)CD8(+), CD69(+)CD4(+) and CD25(+)CD122(+)CD4(+) cells were observed at 24 and 48 h after challenge, and of CD25(-)CD122(+)CD4(+) cells at 48 h. The major role of CD4(+) cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-gamma-producing CD4(+) cells 24 h after challenge. In contrast, liver CD8(+) cells produced little IFN-gamma, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge.
- Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan ChildrenPublication . Sambo, Maria Rosário; Trovoada, Maria Jesus; Benchimol, Carla; Quinhentos, Vatúsia; Gonçalves, Lígia; Velosa, Rute; Marques, Maria Isabel; Sepúlveda, Nuno; Clark, Taane G.; Mustafa, Stefan; Wagner, Oswald; Coutinho, António; Penha-Gonçalves, Carlos; Rodrigues, Mauricio MartinsBACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012). CONCLUSIONS/SIGNIFICANCE: These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria.
- Early skin immunological disturbance after Plasmodium-infected mosquito bitesPublication . Silva, Henrique Borges da; Caetano, Susana S; Monteiro, Isadora; Gómez-Conde, Iván; Hanson, Kirsten; Penha-Gonçalves, Carlos; Olivieri, David N; Mota, Maria M; Marinho, Cláudio R.; D’Imperio Lima, Maria R.; Tadokoro, Carlos EAlthough the role of regulatory T cells (Tregs) during malaria infection has been studied extensively, such studies have focused exclusively on the role of Treg during the blood stage of infection; little is known about the detailed mechanisms of Tregs and sporozoite deposition in the dermis by mosquito bites. In this paper we show that sporozoites introduced into the skin by mosquito bites increase the mobility of skin Tregs and dendritic cells (DCs). We also show differences in MHC class II and/or CD86 expression on skin-resident dendritic cell subtypes and macrophages. From the observed decrease of the number of APCs into draining lymph nodes, suppression of CD28 expression in conventional CD4 T cells, and a low homeostatic proliferation of skin-migrated CD4 T found in nude mice indicate that Tregs may play a fundamental role during the initial phase of malaria parasite inoculation into the mammalian host
- Intravital placenta imaging reveals microcirculatory dynamics impact on sequestration and phagocytosis of Plasmodium-infected erythrocytesPublication . Moraes, Luciana Vieira de; Tadokoro, Carlos Eduardo; Gómez-Conde, Ivan; Olivieri, David N.; Penha-Gonçalves, CarlosMalaria in pregnancy is exquisitely aggressive, causing a range of adverse maternal and fetal outcomes prominently linked to Plasmodium-infected erythrocyte cytoadherence to fetal trophoblast. To elucidate the physiopathology of infected erythrocytes (IE) sequestration in the placenta we devised an experimental system for intravital placental examination of P. berghei-infected mice. BALB/c females were mated to C57Bl/6 CFP+ male mice and infected with GFP+ P. berghei IE, and at gestational day 18, placentas were exposed for time-lapse imaging acquisition under two-photon microscopy. Real-time images and quantitative measurements revealed that trophoblast conformational changes transiently restrain blood flow in the mouse placental labyrinth. The complex dynamics of placental microcirculation promotes IE accumulation in maternal blood spaces with low blood flow and allows the establishment of stable IE-trophoblast contacts. Further, we show that the fate of sequestered IE includes engulfment by both macrophagic and trophoblastic fetal-derived cells. These findings reinforce the current paradigm that IE interact with the trophoblast and provide definitive evidence on two novel pathogenesis mechanisms: (1) trophoblast layer controls placental microcirculation promoting IE sequestration; and (2) fetal-derived placental cells engulf sequestered IE.