The role of the interactome in the maintenance of deleterious variability in human populations

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish indi-viduals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observe

Bacillus thuringiensis Cry1A toxins are versatile proteins with multiple modes of action: two distinct pre-pores are involved in toxicity

Cry proteins from Bacillus thuringiensis are insecticidal PFTs (pore-forming toxins). In the present study, we show that two distinct functional pre-pores of Cry1Ab are formed after binding of the protoxin or the protease-activated toxin to the cadherin receptor, but before membrane insertion. Both pre-pores actively induce pore formation, although with different characteristics, and contribute to the insecticidal activity. We also analysed the oligomerization of the mutant Cry1AbMod protein. This mutant kills different insect populations that are resistant to Cry toxins, but lost potency against susceptible insects. We found that the Cry1AbMod-protoxin efficiently induces oligomerization, but not the activated Cry1AbMod-toxin, explaining the loss of potency of Cry1AbMod against susceptible insects. These data are relevant for the future control of insects resistant to Cry proteins. Our data support the pore-formation model involving sequential interaction with different midgut proteins, leading to pore formation in the target membrane. We propose that not only different insect targets could have different receptors, but also different midgut proteases that would influence the rate of protoxin/toxin activation. It is possible that the two pre-pore structures could have been selected for in evolution, since they have differential roles in toxicity against selected targets, increasing their range of action. These data assign a functional role for the protoxin fragment of Cry PFTs that was not understood previously. Most PFTs produced by other bacteria are secreted as protoxins that require activation before oligomerization, to finally form a pore. Thus different pre-pores could be also part of the general mechanism of action of other PFTs

Actualidad y prospectiva de la investigación científica en el Centro Universitario Amecameca de la Universidad Autónoma del Estado de México

Con responsabilidad, se organizó un programa cuya finalidad fuera publicitar con transparencia dichos avances, a través de un esfuerzo de rendición de cuentas a la comunidad inmediata, la universitaria, y a la comunidad abierta, la sociedad que la principal referencia para tal efecto. El programa se concretiza a través del presente libro, conformado con una inspiración de investigación multidisciplinaria; sin embargo, para llegar a tal fin, el reto es realizar el proceso de búsqueda y generación de conocimiento transitando hacia la colaboración de los cuerpos académicos, que puedan construir nuevos conocimientos fortalecidos por la convergencia de diferentes campos del saber. En consecuencia, la primera etapa de esta estrategia es la publicidad de los trabajos investigativos ejercidos, para hacer un balance al día, pero también proyectar el futuro de cada campo y área del conocimiento. La organización explicativa está organizada por tres bloques representativos del quehacer en la generación de conocimiento del Centro Universitario, un primer bloque centra el interés en las humanidades, educación y sustentabilidad; el segundo bloque lo integra la reflexión científica sobre la construcción democrática, derechos humanos y equidad de género; en el tercer segmento se destina a la seguridad alimentaria, salud pública y sistemas agropecuarios. La actualidad de la investigación eleva la producción lograda y lo que en el momento se encuentra en construcción y los alcances que produce para la docencia, la investigación misma, y para la sociedad en general. La prospectiva es un área que todos los capítulos desarrollan con el propósito de delinear los alcances innovadores por andar en teoría, metodología e incluso en los saberes mismo

OPHTHALMOLOGIC INVOLVEMENT IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS.

PURPOSE The aim of this study was to determine the ophthalmologic involvement in patients with hereditary transthyretin amyloidosis and its correlation with the mutations described in the literature. METHODS Cross-sectional, noninterventional study. Fifty-two eyes of 26 consecutive patients diagnosed with hereditary transthyretin amyloidosis who visited the Puerta de Hierro-Majadahonda University Hospital from September 2019 to March 2022. All patients underwent complete ophthalmologic examination and multimodal imaging. Cardiologic, neurologic, digestive, and renal examinations were also recorded. RESULTS Eighteen eyes of the total (34.61%) showed amyloid-related ocular involvement, vitreous amyloid deposits being the most common ocular manifestation (18/52). Statistically significant differences were found for the presence of vitreous amyloid deposits ( P < 0.01), crystalline amyloid deposits ( P < 0.05), parenchymal amyloid deposits ( P < 0.01), and vascular alterations ( P < 0.01) when comparing affected and unaffected eyes. Moreover, affected eyes showed worse best-corrected visual acuity ( P < 0.01). CONCLUSION Ocular manifestations are present in a substantial number of patients with ATTR that could potentially lead to devastating consequences to patients' best-corrected visual acuity and quality of life. Therefore, it is important to emphasize the importance of multidisciplinary management and ophthalmologic assessment, follow-up and surgical treatment when necessary. To the best of our knowledge, this represents the largest series in Spain of amyloidosis' ophthalmologic involvement.S

A map of human microRNA variation uncovers unexpectedly high levels of variability

Abstract Background MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in a healthy population seems an obvious requirement for future research on miRNA-related pathologies. Methods Data on 14 populations from the 1000 Genomes Project were analyzed, along with new data extracted from 60 exomes of healthy individuals from a population from southern Spain, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. Results Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. Conclusions Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.The Medical Genome Project is an initiative of the Consejería de Salud de la Junta de Andalucía and was supported by the "Programa Nacional de Proyectos de investigación Aplicada", I+D+i 2008, "Subprograma de actuaciones Científicas y Tecnológicas en Parques Científicos y Tecnológicos (ACTEPARQ 2009) and FEDER. This work is also partly supported by grants from projects BIO2008-04212 and BIO2011-27069 from the Spanish Ministry of Economy and Competitiveness, PI1001290 from the Fondo de Investigación Sanitaria, and PROMETEO/2010/001 from the GVA-FEDER. The CIBER de Enfermedades Raras is an initiative of the ISCIII. The RTICC is an initiative of the ISCIII. This work is also partly supported by a grant (RD06/0020/1019) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness. EA is supported by a fellowship from the FIS of the Spanish Ministry of Economy and Competitiveness (FI06/00027).Peer Reviewe

The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations

Network of significant gene co-occurrences.

<p>Genes are represented by nodes and their sizes defined from the number of significant co-occurrences they are implied. Edges represent co-occurrences between pairs of genes. Every edge is labelled with the number of samples that carries the mutated pair of genes as follows: higher than expected co-occurrences are coloured in green, while lower than expected (only one) in red. Edge width is proportional to the statistical p-value of chi-square test. Those genes co-occurring only at one single patient are painted in white. Seven co-occurrence subnetworks arise from the significant co-occurrence network, where remarkably a single component connected the half of represented genes. In contrast, 3 pairs are simultaneously mutated only in 2 different individuals, and 3 significant co-occurrence subnetworks, only in 1 patient.</p

Distribution of selected mutations along the different affected genes and their related functional categories.

<p>A) Number of mutated samples by gene according to the described mutation filtering protocol (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0148346#pone.0148346.s002" target="_blank">S2 Fig</a>). Only 33 recurrent genes were included. B) Number of mutated samples by gene category (bottom). The corresponding number of genes included in each functional category (top) is also represented in order to avoid any size bias. C) The functional categories are distributed depending on the observed mutated samples and the known number of belonging genes. Both transcription factor and ubiquitination categories shown and excess of mutated samples. D) The number of mutated samples per category in the haloplex cohort were compared against a reference population of healthy samples (1000 genomes). Here, while metabolism and signalling genes categories appear poorly mutated, ubiquitination appears remarkably more mutated than the reference population.</p

Mutated genes with a higher frequency in our cohort than expected in the 1000 genomes repository.

<p>Mutated genes with a higher frequency in our cohort than expected in the 1000 genomes repository.</p