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Summary: Copy-number variants (CNVs) are genome-wide structural variations involving the duplication or deletion of large nucleotide sequences. While these types of variations can be commonly found in humans, large and rare CNVs are known to contribute to the development of various neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Nevertheless, given that these NDD-risk CNVs cover broad regions of the genome, it is particularly challenging to pinpoint the critical gene(s) responsible for the manifestation of the phenotype. In this study, we performed a meta-analysis of CNV data from 11,614 affected individuals with NDDs and 4,031 control individuals from SFARI database to identify 41 NDD-risk CNV loci, including 24 novel regions. We also found evidence for dosage-sensitive genes within these regions being significantly enriched for known NDD-risk genes and pathways. In addition, a significant proportion of these genes was found to (1) converge in protein-protein interaction networks, (2) be among most expressed genes in the brain across all developmental stages, and (3) be hit by deletions that are significantly over-transmitted to individuals with ASD within multiplex ASD families from the iHART cohort. Finally, we conducted a burden analysis using 4,281 NDD cases from Decipher and iHART cohorts, and 2,504 neurotypical control individuals from 1000 Genomes and iHART, which resulted in the validation of the association of 162 dosage-sensitive genes driving risk for NDDs, including 22 novel NDD-risk genes. Importantly, most NDD-risk CNV loci entail multiple NDD-risk genes in agreement with a polygenic model associated with the majority of NDD cases.

Inversions are a little-studied type of genomic variation that could contribute to phenotypic traits. Here the authors characterize 45 common polymorphic inversions in human populations and investigate their evolutionary and functional impact.

We determined the distribution and abundance of pelagic copepods in the eastern equatorial Pacific between the coast of Ecuador and the Galapagos Islands under oceanographic conditions associated with the weak La Niña event of 2001. In September-October 2001, negative anomalies of sea surface temperature from this event still remained in the eastern equatorial Pacific, mainly between Ecuador and the Galapagos Islands. The event allowed the incursion of the Humboldt Current farther north and of the Equatorial Undercurrent into the study area, favouring a strong Equatorial Front and upwelling processes. There was evidence of mesoscale eddies in the study area and of the presence of the South Equatorial Current going westward at about 1°N. We identified 107 copepod species and analyzed the distribution of the 10 most abundant ones: Oncaea venusta, Subeucalanus pileatus, S. crassus, S. subtenuis, Paraeucalanus attenuatus, Pleuromamma borealis, Scolecithrix danae, Clausocalanus farrani, Temora discaudata and Calanus chilensis. Copepod distribution and abundance exhibited marked latitudinal differences related to the oceanographic conditions; abundance was highest to the southeast of the Galapagos Islands. Oncaea venusta, Pleuromamma borealis, Calanus chilensis, and Subeucalanus subtenuis were the species that best defined the Equatorial Front and the upwelling process.

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.

El propósito de este artículo es hacer la descripción de un caso clínico donde se observa una convergencia entre el diagnóstico de TDAH e intento suicida, en ausencia de otras enfermedades psiquiátricas comórbidas, describiendo los antecedentes y el proceso de evaluación. Se trata de un paciente de 10 años de edad, con diagnóstico de TDAH (de acuerdo a los criterios clínicos del DSM IV TR), quien es hospitalizado al presentar intento suicida de alta letalidad por ahorcamiento en ausencia de comorbilidad psiquiátrica alguna, evaluado clínicamente, usando múltiples fuentes de información y por medio de escalas clinimétricas. A pesar de que la tasa de TDAH es alta en poblaciones con ideación, intentos y suicidio completado, (casi el doble que los controles)(1), son relativamente pocas las investigaciones que se han realizado de dicha asociación y además suelen intentar explicar la suicidalidad mediante la psicopatología comórbida (Trastornos afectivos, de ansiedad, de personalidad, abuso de sustancias), sin cuestionar la relación TDAH-riesgo suicida como mecanismo explicativo de forma independiente. La disfunción ejecutiva que se presenta en el TDAH, particularmente, la impulsividad, pudiera estudiarse como un posible mecanismo mediador en el riesgo suicida.

Surface features of the hydrodynamics at the mouth of Aysen Fjord, in the Chilean Inland Sea, were described using Landsat and ERS-SAR images in combination with field data. A set of seventeen radar images from ERS, along with one Landsat (ETM) were analyzed to study the surface features observed in this region, where fresh water input is an important contributor to the dynamics of the estuarine system. Field data were provided by current measurements obtained with an Acoustic Doppler Current Profiler (ADCP) mounted in a catamaran looking downward, which was towed from a boat during two semidiurnal cycles to obtain repetitions over two transverse transects. There were also density measurements obtained from CTD (Conductivity, Temperature and Depth) vertical profiles in the water column and from a surface termosalinograph (Conductivity, Temperature) mounted onboard of a research vessel. The results of this campaign in Aysen Fjord were associated to the surface features observed in satellite images. The results show the main features of the circulation at the mouth of this fjord and other phenomena of interest for physical oceanography. Noteworthy is a frontal structure suggested on both types of images. This feature is partially supported by ADCP measurements and strongly suggested by density measurements. Packages of internal waves in Costa Channel are also suggested in radar images, while the distribution of the fresh water plume is supported by the Landsat image. Satellite images provided valuable guidance to focus the research in a selected area and phenomena

In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6-24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ∼ 12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.

UNLABELLED: Next-generation sequencing technologies expedited research to develop efficient computational tools for the identification of structural variants (SVs) and their use to study human diseases. As deeper data is obtained, the existence of higher complexity SVs in some genomes becomes more evident, but the detection and definition of most of these complex rearrangements is still in its infancy. The full characterization of SVs is a key aspect for discovering their biological implications. Here we present a pipeline (PeSV-Fisher) for the detection of deletions, gains, intra- and inter-chromosomal translocations, and inversions, at very reasonable computational costs. We further provide comprehensive information on co-localization of SVs in the genome, a crucial aspect for studying their biological consequences. The algorithm uses a combination of methods based on paired-reads and read-depth strategies. PeSV-Fisher has been designed with the aim to facilitate identification of somatic variation, and, as such, it is capable of analysing two or more samples simultaneously, producing a list of non-shared variants between samples. We tested PeSV-Fisher on available sequencing data, and compared its behaviour to that of frequently deployed tools (BreakDancer and VariationHunter). We have also tested this algorithm on our own sequencing data, obtained from a tumour and a normal blood sample of a patient with chronic lymphocytic leukaemia, on which we have also validated the results by targeted re-sequencing of different kinds of predictions. This allowed us to determine confidence parameters that influence the reliability of breakpoint predictions. AVAILABILITY: PeSV-Fisher is available at http://gd.crg.eu/tools.

One of the most used techniques to study structural variation at a genome level is paired-end mapping (PEM). PEM has the advantage of being able to detect balanced events, such as inversions and translocations. However, inversions are still quite difficult to predict reliably, especially from high-throughput sequencing data. We simulated realistic PEM experiments with different combinations of read and library fragment lengths, including sequencing errors and meaningful base-qualities, to quantify and track down the origin of false positives and negatives along sequencing, mapping, and downstream analysis. We show that PEM is very appropriate to detect a wide range of inversions, even with low coverage data. However, ≥% of inversions located between segmental duplications are expected to go undetected by the most common sequencing strategies. In general, longer DNA libraries improve the detectability of inversions far better than increments of the coverage depth or the read length. Finally, we review the performance of three algorithms to detect inversions--SVDetect, GRIAL, and VariationHunter--, identify common pitfalls, and reveal important differences in their breakpoint precisions. These results stress the importance of the sequencing strategy for the detection of structural variants, especially inversions, and offer guidelines for the design of future genome sequencing projects.

BACKGROUND:Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations. METHODOLOGY/PRINCIPAL FINDINGS:We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level. CONCLUSIONS:Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

El trabajo analiza la expansión del monocultivo extractivista en Costa Rica y la Argentina en detrimento del capital natural y las poblaciones campesinas. La metodologí­a incluyó entrevistas realizadas a campo en ambos paí­ses y consultas a fuentes documentales, periodí­sticas y bibliográficas. Se concluye que los conflictos ecosociales son provocados por la ausencia de un ordenamiento territorial, la escasa fiscalización estatal en materia ambiental y la alianza de los gobiernos con el capital concentrado. En este contexto, también se evidencian estrategias de resistencia de los campesinos que luchan por la justicia ambiental y la concreción de una institucionalidad socioambiental acorde con sus intereses.