R Package for the analysis of epistatic networks

Las mutaciones o cambios en la dotación genética de los organismos, son uno de los mecanismos básicos de la evolución de las especies. Estas pueden encontrarse en zonas codificantes o zonas no codificantes del genoma, siendo las primeras -las encontradas en zonas codificantes- las que suscitan más interés ya que en muchos casos pueden tener efectos negativos asociados con la prevalencia de enfermedades en el organismo. Entre estos efectos negativos, las mutaciones también pueden estar relacionadas con la aparición de enfermedades asumiendo que dichos cambios aumentan la propensión del individuo a padecer una enfermedad. Hoy en día se acepta que muchas de las enfermedades con origen en mutaciones son causadas por mecanismos epistáticos, esto es una interacción entre varias mutaciones que tienen efecto en su conjunto sobre una enfermedad. Estas relaciones epistáticas o de alto orden presentan dificultades para ser estudiadas debido a la complejidad computacional que presentan. Por lo tanto, es necesario diseñar nuevos métodos software de estudio de relaciones Genotipo-Fenotipo que permitan un análisis exhaustivo epistático, en este caso por parejas, complementando el análisis con teoría de grafos. Este trabajo pretende contribuir a la investigación actual identificando relaciones Genotipo-Fenotipo, especialmente las que requieren análisis epistático, creando un paquete de software para R, uno de los lenguajes de programación más usados en biología computacional y en biomedicina, ofreciendo una interfaz de uso simplificada para completar el análisis de redes epistáticas creando un grafo de Polimorfismos de Nucleótidos Únicos o SNPs según sus siglas en inglés. A partir de dichos grafos el usuario puede obtener un grafo de genes y permitiendo al usuario obtener los genes o SNPs con mayor centralidad. La herramienta a desarrollar también permite al usuario almacenar sus resultados intermedios y finales para poderlos procesar posteriormente con otros programas externos. La herramienta a desarrollar permite su gestión con programas externos como Galaxy, un WMS (Workflow Management System) que permite la gestión de flujos de trabajo, y Cytoscape, un software especializado en la visualización y gestión de grafos. Ambas herramientas son comúnmente utilizada por el público objetivo. El resultado de este trabajo pretende hacer posible la mejora en los estudios de esta área de investigación, permitiendo a más usuarios con menor conocimiento tecnológico realizar estudios GWAS expandiendo su uso y favoreciendo el incremento de resultados y conocimiento

Crop to wild introgression in lettuce: following the fate of crop genome segments in backcross populations

Background: After crop-wild hybridization, some of the crop genomic segments may become established in wild populations through selfing of the hybrids or through backcrosses to the wild parent. This constitutes a possible route through which crop (trans)genes could become established in natural populations. The likelihood of introgression of transgenes will not only be determined by fitness effects from the transgene itself but also by the crop genes linked to it. Although lettuce is generally regarded as self-pollinating, outbreeding does occur at a low frequency. Backcrossing to wild lettuce is a likely pathway to introgression along with selfing, due to the high frequency of wild individuals relative to the rarely occurring crop-wild hybrids. To test the effect of backcrossing on the vigour of inter-specific hybrids, Lactuca serriola, the closest wild relative of cultivated lettuce, was crossed with L. sativa and the F1 hybrid was backcrossed to L. serriola to generate BC1 and BC2 populations. Experiments were conducted on progeny from selfed plants of the backcrossing families (BC1S1 and BC2S1). Plant vigour of these two backcrossing populations was determined in the greenhouse under non-stress and abiotic stress conditions (salinity, drought, and nutrient deficiency). Results: Despite the decreasing contribution of crop genomic blocks in the backcross populations, the BC1S1 and BC2S1 hybrids were characterized by a substantial genetic variation under both non-stress and stress conditions. Hybrids were identified that performed equally or better than the wild genotypes, indicating that two backcrossing events did not eliminate the effect of the crop genomic segments that contributed to the vigour of the BC1 and BC2 hybrids. QTLs for plant vigour under non-stress and the various stress conditions were detected in the two populations with positive as well as negative effects from the crop. Conclusion: As it was shown that the crop contributed QTLs with either a positive or a negative effect on plant vigour, we hypothesize that genomic regions exist where transgenes could preferentially be located in order to mitigate their persistence in natural populations through genetic hitchhiking

Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish

BACKGROUND: Population heterogeneity may be a significant confounding factor hampering detection and verification of late onset Alzheimer's disease (LOAD) susceptibility genes. The Amish communities located in Indiana and Ohio are relatively isolated populations that may have increased power to detect disease susceptibility genes. METHODS: We recently performed a genome scan of dementia in this population that detected several potential loci. However, analyses of these data are complicated by the highly consanguineous nature of these Amish pedigrees. Therefore we applied the Combinatorial Mismatch Scanning (CMS) method that compares identity by state (IBS) (under the presumption of identity by descent (IBD)) sharing in distantly related individuals from such populations where standard linkage and association analyses are difficult to implement. CMS compares allele sharing between individuals in affected and unaffected groups from founder populations. Comparisons between cases and controls were done using two Fisher's exact tests, one testing for excess in IBS allele frequency and the other testing for excess in IBS genotype frequency for 407 microsatellite markers. RESULTS: In all, 13 dementia cases and 14 normal controls were identified who were not related at least through the grandparental generation. The examination of allele frequencies identified 24 markers (6%) nominally (p ≤ 0.05) associated with dementia; the most interesting (empiric p ≤ 0.005) markers were D3S1262, D5S211, and D19S1165. The examination of genotype frequencies identified 21 markers (5%) nominally (p ≤ 0.05) associated with dementia; the most significant markers were both located on chromosome 5 (D5S1480 and D5S211). Notably, one of these markers (D5S211) demonstrated differences (empiric p ≤ 0.005) under both tests. CONCLUSION: Our results provide the initial groundwork for identifying genes involved in late-onset Alzheimer's disease within the Amish community. Genes identified within this isolated population will likely play a role in a subset of late-onset AD cases across more general populations. Regions highlighted by markers demonstrating suggestive allelic and/or genotypic differences will be the focus of more detailed examination to characterize their involvement in dementia

SLAM Family Receptors and Autoimmunity

The immune system is responsible for the defense against a wide array of pathogens but without responding to each individual’s (self) antigens. Autoimmune diseases are characterized by a loss of tolerance to self antigens that leads to the appearance of autoreactive lymphocytes. The main factors that contribute to the development of autoimmunity are genetic susceptibility and infection. Disease susceptibility is the result of the combined action of multiple genes. It has been shown that certain gene polymorphisms can influence the establishment of self-tolerance. The human immune system is a complex machinery involving numerous proteins. Cell-surface proteins expressed by leukocytes are of particular relevance due not only to their participation in the network of interactions that regulate the innate and adaptive immune responses, but also to their potential as excellent targets for diagnostic and therapeutic interventions (Diaz-Ramos et al., 2011). These molecules deliver signals that modulate leukocyte development, activation, survival, clonal expansion, and important effector functions. Some of these cell-surface signaling molecules have the capacity to activate lymphocytes and other leukocytes, while others function as downmodulators of immune responses, playing a key role in the establishment of tolerance to self antigens. Thus, it is not surprising that many of the allelic variants associated with autoimmunity identified, to date, correspond to leukocyte cell-surface molecules (Maier & Hafler, 2009). In this review we will discuss recent observations that point to a key role of signaling lymphocyte activation molecule family (SLAMF) receptors in the development of autoimmunity