The expression level of BAALC -associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (⩾60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P =0.0025), shorter leukemia-free survival (P =0.026) and higher cumulative incidence of relapse (P =0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P =0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (>= 60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P = 0.0025), shorter leukemia-free survival (P = 0.026) and higher cumulative incidence of relapse (P = 0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P = 0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

Contains fulltext : 140075.pdf (Publisher’s version ) (Open Access

Estimación de la huella de la selección natural y el efecto Hill- Robertson a lo largo del genoma de Drosophila melanogaster

La presente tesis es un estudio exhaustivo de genómica de poblaciones en la especie modelo Drosophila melanogaster la cual combina aproximaciones bioinformáticas y teórico-estadísticas. El objetivo de este estudio es doble, queremos estimar la importancia relativa de distintos regímenes de selección natural y el impacto del efecto Hill-Robertson a lo largo del genoma de D. melanogaster. Hemos dividido los resultados y discusión en tres partes distintas. En la primera parte hemos desarrollado dos estimadores puntuales de la acción de la selección purificadora basados en el polimorfismo nucleotídico. En la segunda parte hemos aplicado nuestros nuevos estimadores, junto con estimadores existentes de la distribución de coeficientes de selección de nuevas mutaciones deletéreas y la tasa de evolución adaptativa, sobre secuencias genómicas de D. melanogaster provenientes del proyecto Drosophila Genetic Reference Panel (DGRP). Este trabajo de tesis se inició como parte de un gran proyecto internacional el cual fue publicado en 2012 (Mackay et al. 2012). En la tercera y última parte hemos estudiado el efecto de la tasa de recombinación, la densidad génica y la tasa de mutación sobre el número de substituciones de cambio de amino ácido adaptativas ocurridas desde la separación de D. melanogaster y D. yakuba. Además, hemos estimado por primera vez cuantas substituciones adaptativas dejan de fijarse como consecuencia del efecto Hill-Robertson en el genoma codificador de D. melanogaster. Este trabajo ha sido publicado recientemente en 2016 (Castellano et al. 2016).The present thesis is a comprehensive population genomic study in the model species Drosophila melanogaster which combines bioinformatic and theoretical-statistical approaches. The purpose of this study is two-fold, we want to estimate the relative importance of different regimes of natural selection and the impact of the Hill-Robertson effect along the genome of D. melanogaster. We have divided the results and discussion sections in three distinct parts. In the first part we have designed two new point estimators of the action of purifying selection using nucleotide polymorphism data. In the second part we have applied our new estimators together with existing methods to estimate the distribution of fitness effects (DFE) of new deleterious mutations and the rate of adaptive evolution using genomic sequences of D. melanogaster coming from the Drosophila Genetic Reference Panel (DGRP) project. This thesis work has started as part of a large international project which was published in 2012 (Mackay et al. 2012). In the third and last part we have studied the effect of the rate of recombination, the mutation rate and gene density upon the number of adaptive amino acid substitutions that have occurred since the split between D. melanogaster and D. yakuba. Moreover, we have estimated for the first time how much the Hill-Robertson interference impedes the rate of adaptive evolution in the coding genome of D. melanogaster. This work has been recently published in 2016 (Castellano et al. 2016)

Estimación de la huella de la selección natural y el efecto Hill- Robertson a lo largo del genoma de Drosophila melanogaster

La presente tesis es un estudio exhaustivo de genómica de poblaciones en la especie modelo Drosophila melanogaster la cual combina aproximaciones bioinformáticas y teórico-estadísticas. El objetivo de este estudio es doble, queremos estimar la importancia relativa de distintos regímenes de selección natural y el impacto del efecto Hill-Robertson a lo largo del genoma de D. melanogaster. Hemos dividido los resultados y discusión en tres partes distintas. En la primera parte hemos desarrollado dos estimadores puntuales de la acción de la selección purificadora basados en el polimorfismo nucleotídico. En la segunda parte hemos aplicado nuestros nuevos estimadores, junto con estimadores existentes de la distribución de coeficientes de selección de nuevas mutaciones deletéreas y la tasa de evolución adaptativa, sobre secuencias genómicas de D. melanogaster provenientes del proyecto Drosophila Genetic Reference Panel (DGRP). Este trabajo de tesis se inició como parte de un gran proyecto internacional el cual fue publicado en 2012 (Mackay et al. 2012). En la tercera y última parte hemos estudiado el efecto de la tasa de recombinación, la densidad génica y la tasa de mutación sobre el número de substituciones de cambio de amino ácido adaptativas ocurridas desde la separación de D. melanogaster y D. yakuba. Además, hemos estimado por primera vez cuantas substituciones adaptativas dejan de fijarse como consecuencia del efecto Hill-Robertson en el genoma codificador de D. melanogaster. Este trabajo ha sido publicado recientemente en 2016 (Castellano et al. 2016).The present thesis is a comprehensive population genomic study in the model species Drosophila melanogaster which combines bioinformatic and theoretical-statistical approaches. The purpose of this study is two-fold, we want to estimate the relative importance of different regimes of natural selection and the impact of the Hill-Robertson effect along the genome of D. melanogaster. We have divided the results and discussion sections in three distinct parts. In the first part we have designed two new point estimators of the action of purifying selection using nucleotide polymorphism data. In the second part we have applied our new estimators together with existing methods to estimate the distribution of fitness effects (DFE) of new deleterious mutations and the rate of adaptive evolution using genomic sequences of D. melanogaster coming from the Drosophila Genetic Reference Panel (DGRP) project. This thesis work has started as part of a large international project which was published in 2012 (Mackay et al. 2012). In the third and last part we have studied the effect of the rate of recombination, the mutation rate and gene density upon the number of adaptive amino acid substitutions that have occurred since the split between D. melanogaster and D. yakuba. Moreover, we have estimated for the first time how much the Hill-Robertson interference impedes the rate of adaptive evolution in the coding genome of D. melanogaster. This work has been recently published in 2016 (Castellano et al. 2016)

Estimación de la huella de la selección natural y el efecto Hill-Robertson a lo largo del genoma de Drosophila melanogaster

La presente tesis es un estudio exhaustivo de genómica de poblaciones en la especie modelo Drosophila melanogaster la cual combina aproximaciones bioinformáticas y teórico-estadísticas. El objetivo de este estudio es doble, queremos estimar la importancia relativa de distintos regímenes de selección natural y el impacto del efecto Hill-Robertson a lo largo del genoma de D. melanogaster. Hemos dividido los resultados y discusión en tres partes distintas. En la primera parte hemos desarrollado dos estimadores puntuales de la acción de la selección purificadora basados en el polimorfismo nucleotídico. En la segunda parte hemos aplicado nuestros nuevos estimadores, junto con estimadores existentes de la distribución de coeficientes de selección de nuevas mutaciones deletéreas y la tasa de evolución adaptativa, sobre secuencias genómicas de D. melanogaster provenientes del proyecto Drosophila Genetic Reference Panel (DGRP). Este trabajo de tesis se inició como parte de un gran proyecto internacional el cual fue publicado en 2012 (Mackay et al. 2012). En la tercera y última parte hemos estudiado el efecto de la tasa de recombinación, la densidad génica y la tasa de mutación sobre el número de substituciones de cambio de amino ácido adaptativas ocurridas desde la separación de D. melanogaster y D. yakuba. Además, hemos estimado por primera vez cuantas substituciones adaptativas dejan de fijarse como consecuencia del efecto Hill-Robertson en el genoma codificador de D. melanogaster. Este trabajo ha sido publicado recientemente en 2016 (Castellano et al. 2016).The present thesis is a comprehensive population genomic study in the model species Drosophila melanogaster which combines bioinformatic and theoretical-statistical approaches. The purpose of this study is two-fold, we want to estimate the relative importance of different regimes of natural selection and the impact of the Hill-Robertson effect along the genome of D. melanogaster. We have divided the results and discussion sections in three distinct parts. In the first part we have designed two new point estimators of the action of purifying selection using nucleotide polymorphism data. In the second part we have applied our new estimators together with existing methods to estimate the distribution of fitness effects (DFE) of new deleterious mutations and the rate of adaptive evolution using genomic sequences of D. melanogaster coming from the Drosophila Genetic Reference Panel (DGRP) project. This thesis work has started as part of a large international project which was published in 2012 (Mackay et al. 2012). In the third and last part we have studied the effect of the rate of recombination, the mutation rate and gene density upon the number of adaptive amino acid substitutions that have occurred since the split between D. melanogaster and D. yakuba. Moreover, we have estimated for the first time how much the Hill-Robertson interference impedes the rate of adaptive evolution in the coding genome of D. melanogaster. This work has been recently published in 2016 (Castellano et al. 2016)

Living on the edge: stress and activation of stress responses promote lifespan extension

Oxidative stress constitutes the basis of physio-pathological situations such as neurodegenerative diseases and aging. However, sublethal exposure to toxic molecules such as reactive oxygen species can induce cellular responses that result in stress fitness. Studies in Schizosaccharomyces pombe have recently showed that the Sty1 MAP kinase, known to be activated by hydrogen peroxide and other cellular stressors, plays a pivotal role in promoting fitness and longevity when it becomes activated by calorie restriction, a situation which induces oxidative metabolism and reactive oxygen species production. Activation of the MAP kinase by calorie restriction during logarithmic growth induces a transcriptional anti-stress response including genes essential to promote lifespan extension. Importantly enough, the lifespan promotion exerted by deletion of the pka1 or sck2 genes, inactivating the two main nutrient-responsive pathways, is dependent on the presence of a functional Sty1 stress pathway, since double mutants also lacking Sty1 or its main substrate Atf1 do not display extended viability. In this Research Perspective, we review these findings in relation to previous reports and extend important aspects of the original study. We propose that moderate stress levels that are not harmful for cells can make them stronger.This work was supported by Dirección General de Investigación of Spain Grants BFU2006-02610 and BFU2009-06933, Plan E and FEDER, and by the Spanish program Consolider-Ingenio 2010 Grant /nCSD 2007-0020 to E.

Adaptation and Conservation throughout the Drosophila melanogaster Life-Cycle

Altres ajuts: FI-DGR-2015Previous studies of the evolution of genes expressed at different life-cycle stages of Drosophila melanogaster have not been able to disentangle adaptive from nonadaptive substitutions when using nonsynonymous sites. Here, we overcome this limitation by combining whole-genome polymorphism data from D. melanogaster and divergence data between D. melanogaster and Drosophila yakuba. For the set of genes expressed at different life-cycle stages of D. melanogaster, as reported in modENCODE, we estimate the ratio of substitutions relative to polymorphism between nonsynonymous and synonymous sites (α) and then α is discomposed into the ratio of adaptive (ω ) and nonadaptive (ω ) substitutions to synonymous substitutions. We find that the genes expressed in mid- and late-embryonic development are the most conserved, whereas those expressed in early development and postembryonic stages are the least conserved. Importantly, we found that low conservation in early development is due to high rates of nonadaptive substitutions (high ω ), whereas in postembryonic stages it is due, instead, to high rates of adaptive substitutions (high ω ). By using estimates of different genomic features (codon bias, average intron length, exon number, recombination rate, among others), we also find that genes expressed in mid- and late-embryonic development show the most complex architecture: they are larger, have more exons, more transcripts, and longer introns. In addition, these genes are broadly expressed among all stages. We suggest that all these genomic features are related to the conservation of mid- and late-embryonic development. Globally, our study supports the hourglass pattern of conservation and adaptation over the life-cycle

Functional impact and evolution of a novel human polymorphic inversion that disrupts a gene and creates a fusion transcript

Altres ajuts: a PIF PhD fellowship from the Universitat Autònoma de Barcelona (Spain) to CGD, and a Beatriu de Pinós Postdoctoral fellowship by the Commission for Universities and Research of the Ministry of Innovation, Universities and Enterprise of the Autonomous Government of Catalonia and the Cofund programme of the Marie Curie Actions of the FP7 to JILL.Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far