Facilitating a culture of responsible and effective sharing of cancer genome data

Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance the diagnosis, prognostication and treatment of cancer. A critical point has now been reached at which the analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers to data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data-aggregation challenges faced by the field, suggests potential collaborative solutions and describes how GA4GH can catalyze a harmonized data-sharing culture.

Cellular responses to genome mistranslation

Low level protein synthesis errors can have profound effects on normal cell physiology and disease development, namely neurodegeneration, cancer and aging. The biology of errors introduced into proteins during mRNA translation, herein referred as mistranslation, is not yet fully understood. In order to shed new light into this biological phenomenon, we have engineered constitutive codon misreading in S. cerevisiae, using a mutant tRNA that misreads leucine CUG codons as serine, representing a 240 fold increase in mRNA translational error relative to typical physiological error (0.0001%). Our studies show that mistranslation induces autophagic activity, increases accumulation of insoluble proteins, production of reactive oxygen species, and morphological disruption of the mitochondrial network. Mistranslation also up-regulates the expression of the longevity gene PNC1, which is a regulator of Sir2p deacetylase activity. We show here that both PNC1 and SIR2 are involved in the regulation of autophagy induced by mistranslation, but not by starvation-induced autophagy. Mistranslation leads to P-body but not stress-granule assembly, down-regulates the expression of ribosomal protein genes and increases slightly the selective degradation of ribosomes (ribophagy). The study also indicates that yeast cells are much more resistant to mistranslation than expected and highlights the importance of autophagy in the cellular response to mistranslation. Morpho-functional alterations of the mitochondrial network are the most visible phenotype of mistranslation. Since most of the basic cellular processes are conserved between yeast and humans, this study reinforces the importance of yeast as a model system to study mistranslation and suggests that oxidative stress and accumulation of misfolded proteins arising from aberrant protein synthesis are important causes of the cellular degeneration observed in human diseases associated to mRNA mistranslation.

Phenotypic consequences of genome mistranslation in Candida albicans

Várias espécies do género Candida traduzem o codão CUG de leucine como serina. Em C. albicans este codão é traduzido pelo tRNACAG Ser de serina que é reconhecido por leucil- e seril-tRNA sintetases (LeuRS e SerRS), permitindo a incorporação de leucina ou serina em posições com CUG. Em condições padrão de crescimento os codões CUG é incorporam 3% de leucina e 97% de serina, no entanto estes valores são flexíveis uma vez que a incorporação de serina pode variar entre 0.6% e 5% em resposta a condições de stress. Estudos anteriores realizados in vivo em Escherichia coli sugeriram que a ambiguidade em codões CUG é regulada pela SerRS. De facto, o gene da SerRS de C. albicans tem um codão CUG na posição 197 (Ser197) cuja descodificação ambígua resulta na produção de duas isoformas de SerRS. A isoforma SerRS_Leu197 é mais ativa, apesar de menos estável, que a isoforma SerRS_Ser197, suportando a ideia da existência de um feedback loop negativo, envolvendo estas duas isoformas de SerRS, a enzima LeuRS e o tRNACAG Ser, que mantem os níveis de incorporação de leucina no codões CUG baixos. Nesta tese demonstramos que tal mecanismo não é operacional nas células de C. albicans. De facto, os níveis de incorporação de leucina em codões CUG flutuam drasticamente em resposta a alterações ambientais. Por exemplo, a incorporação de leucina pode chegar a níveis de 49.33% na presença de macrófagos e anfotericina B, mostrando a notória tolerância de C. albicans à ambiguidade. Para compreender a relevância biológica da ambiguidade do código genético em C. albicans construímos estirpes que incorporam serina em vários codões. Apesar da taxa crescimento ter sido negativamente afetada em condições padrão de crescimento, as estirpes construídas crescem favoravelmente em várias condições de stresse, sugerindo que a ambiguidade desempenha um papel importante na adaptação a novos nichos ecológicos. O transcriptoma das estirpes construídas de C. albicans e Saccharomyces. cerevisiae mostram que as leveduras respondem à ambiguidade dos codões de modo distinto. A ambiguidade induziu uma desregulação moderada da expressão génica de C. albicans, mas ativou uma resposta comum ao stresse em S. cerevisiae. O único processo celular que foi induzido na maioria das estirpes foi a oxidação redução. De salientar, que enriquecimento em elementos cis de fatores de transcrição que regulam a resposta à ambiguidade em ambas as leveduras foi distinta, sugerindo que ambas respondem ao stresse de modo diferente. Na globalidade, o nosso estudo aprofunda o conhecimento da elevada tolerância à ambiguidade de codões em C. albicans. Os resultados sugerem que este fungo usa a ambiguidade do codão CUG durante infeção, possivelmente para modular a sua interação com o hospedeiro e a resposta a drogas antifúngicas.

Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

Rethinking the capsid proteins of enveloped viruses: multifunctionality from genome packaging to genome transfection

© 2015 FEBS

Macroinvertebrados bentônicos como bioindicadores de qualidade de água na produção de jundiara (Leiarius marmoratus macho x P. reticulatum fêmea) em reservatório do rio Sorriso, MT.

Resumo: O objetivo deste estudo foi avaliar grupos de organismos bentônicos como bioindicadores de qualidade de água em tanques-rede com criação de jundiara (Leiarius marmoratus macho x P. reticulatum fêmea) no estado do Mato Grosso. Observou-se ue, no período inicial de 15 dias, em pontos de coleta próximos dos tanques-rede a diversidade de espécies e o número de indivíduos de macroinvertebrados foi maior do que nos pontos distantes dos tanques-rede. A elevada densidade de macroinvertebrados colonizadores e a dominância de táxons reconhecidamente tolerantes à poluição orgânica podem demonstrar uma provável piora na qualidade da água relacionada com a aquicultura. Por outro lado, a maior riqueza observada em locais próximos aos tanques sugere que houve uma maior diversificação do nicho alimentar agindo positivamente para aumentar a biodiversidade bentônica.

Histogram-based DNA analysis for the visualization of chromosome, genome and species information

We describe a novel approach to explore DNA nucleotide sequence data, aiming to produce high-level categorical and structural information about the underlying chromosomes, genomes and species. The article starts by analyzing chromosomal data through histograms using fixed length DNA sequences. After creating the DNA-related histograms, a correlation between pairs of histograms is computed, producing a global correlation matrix. These data are then used as input to several data processing methods for information extraction and tabular/graphical output generation. A set of 18 species is processed and the extensive results reveal that the proposed method is able to generate significant and diversified outputs, in good accordance with current scientific knowledge in domains such as genomics and phylogenetics.

Accessing complexity from genome information

This paper studies the information content of the chromosomes of 24 species. In a first phase, a scheme inspired in dynamical system state space representation is developed. For each chromosome the state space dynamical evolution is shed into a two dimensional chart. The plots are then analyzed and characterized in the perspective of fractal dimension. This information is integrated in two measures of the species’ complexity addressing its average and variability. The results are in close accordance with phylogenetics pointing quantitative aspects of the species’ genomic complexity.

Genome-wide association studies reveal genomic windows and candidate genes related to fat deposition in chickens.

2016

Identification of CNVs on the genome of Brazilian chicken lines.

2016

Deciphering the genome of Desulfovibrio gigas: the role of the hydrogenases

The work presented in this thesis describes the functional characterization of hydrogenases in the overall energy metabolism of the sulfate reducing bacterium Desulfovibrio gigas. With the complete annotation of the D. gigas genome, we were able to verify that only the two previously described hydrogenases are present in this organism, the periplasmic [NiFe] HynAB and the cytoplasmic membrane-bound [NiFe] Ech.(...)

Evolutionary dynamics of Chlamydia trachomatis genome and identification of molecular patterns of hypothetical protein coding genes

The obligate intracellular bacterium Chlamydia trachomatis is a human pathogen of major public health significance. Strains can be classified into 15 main serovars (A to L3) that preferentially cause ocular infections (A-C), genital infections (D-K) or lymphogranuloma venereum (LGV) (L1-L3), but the molecular basis behind their distinct tropism, ecological success and pathogenicity is not welldefined. Most chlamydial research demands culture in eukaryotic cell lines, but it is not known if stains become laboratory adapted. By essentially using genomics and transcriptomics, we aimed to investigate the evolutionary patterns underlying the adaptation of C. trachomatis to the different human tissues, given emphasis to the identification of molecular patterns of genes encoding hypothetical proteins, and to understand the adaptive process behind the C. trachomatis in vivo to in vitro transition. Our results highlight a positive selection-driven evolution of C. trachomatis towards nichespecific adaptation, essentially targeting host-interacting proteins, namely effectors and inclusion membrane proteins, where some of them also displayed niche-specific expression patterns. We also identified potential "ocular-specific" pseudogenes, and pointed out the major gene targets of adaptive mutations associated with LGV infections. We further observed that the in vivo-derived genetic makeup of C. trachomatis is not significantly compromised by its long-term laboratory propagation. In opposition, its introduction in vitro has the potential to affect the phenotype, likely yielding virulence attenuation. In fact, we observed a "genital-specific" rampant inactivation of the virulence gene CT135, which may impact the interpretation of data derived from studies requiring culture. Globally, the findings presented in this Ph.D. thesis contribute for the understanding of C.trachomatis adaptive evolution and provides new insights into the biological role of C. trachomatishypothetical proteins. They also launch research questions for future functional studies aiming toclarify the determinants of tissue tropism, virulence or pathogenic dissimilarities among C. trachomatisstrains.

Side effects of genome structural changes.

The first extensive catalog of structural human variation was recently released. It showed that large stretches of genomic DNA that vary considerably in copy number were extremely abundant. Thus it is conceivable that they play a major role in functional variation. Consistently, genomic insertions and deletions were shown to contribute to phenotypic differences by modifying not only the expression levels of genes within the aneuploid segments but also of normal copy-number neighboring genes. In this report, we review the possible mechanisms behind this latter effect.

Genome of an arbuscular mycorrhizal fungus provides insight into the oldest plant symbiosis.

The mutualistic symbiosis involving Glomeromycota, a distinctive phylum of early diverging Fungi, is widely hypothesized to have promoted the evolution of land plants during the middle Paleozoic. These arbuscular mycorrhizal fungi (AMF) perform vital functions in the phosphorus cycle that are fundamental to sustainable crop plant productivity. The unusual biological features of AMF have long fascinated evolutionary biologists. The coenocytic hyphae host a community of hundreds of nuclei and reproduce clonally through large multinucleated spores. It has been suggested that the AMF maintain a stable assemblage of several different genomes during the life cycle, but this genomic organization has been questioned. Here we introduce the 153-Mb haploid genome of Rhizophagus irregularis and its repertoire of 28,232 genes. The observed low level of genome polymorphism (0.43 SNP per kb) is not consistent with the occurrence of multiple, highly diverged genomes. The expansion of mating-related genes suggests the existence of cryptic sex-related processes. A comparison of gene categories confirms that R. irregularis is close to the Mucoromycotina. The AMF obligate biotrophy is not explained by genome erosion or any related loss of metabolic complexity in central metabolism, but is marked by a lack of genes encoding plant cell wall-degrading enzymes and of genes involved in toxin and thiamine synthesis. A battery of mycorrhiza-induced secreted proteins is expressed in symbiotic tissues. The present comprehensive repertoire of R. irregularis genes provides a basis for future research on symbiosis-related mechanisms in Glomeromycota.