Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Maternal sensitivity and mother-infant attachment are associated with antibiotic uptake in infancy.

Attachment security has been associated with health status and symptom reporting. In this longitudinal study, we investigated the association between antibiotics uptake by infants at 9-months and mother-infant attachment at 12-months. Logistic regression analyses indicated that lower maternal sensitivity was associated with increased odds of antibiotic uptake. Furthermore, 89.7% of insecure-ambivalent infants consumed antibiotics, which contrasted with 32.5% of avoidant infants and 21.5% of secure infants. This study suggests that maternal behavior and mother-infant attachment impact on antibiotic consumption, which is worrying because antibiotics may lead to several health problems later in life and antibiotic-resistance.

Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure.

OBJECTIVE: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson's disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. MATERIALS AND METHODS: To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. RESULTS: Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. CONCLUSION: Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains.

Attitudes of the autism community to early autism research.

Investigation into the earliest signs of autism in infants has become a significant sub-field of autism research. This work invokes specific ethical concerns such as use of 'at-risk' language, communicating study findings to parents and the future perspective of enrolled infants when they reach adulthood. This study aimed to ground this research field in an understanding of the perspectives of members of the autism community. Following focus groups to identify topics, an online survey was distributed to autistic adults, parents of children with autism and practitioners in health and education settings across 11 European countries. Survey respondents (n = 2317) were positively disposed towards early autism research, and there was significant overlap in their priorities for the field and preferred language to describe infant research participants. However, there were also differences including overall less favourable endorsement of early autism research by autistic adults relative to other groups and a dislike of the phrase 'at-risk' to describe infant participants, in all groups except healthcare practitioners. The findings overall indicate that the autism community in Europe is supportive of early autism research. Researchers should endeavour to maintain this by continuing to take community perspectives into account.

Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders.

BACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. RESULTS: The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.

CNVs leading to fusion transcripts in individuals with autism spectrum disorder.

There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies.

Genomic sequence around butterfly wing development genes: annotation and comparative analysis.

BACKGROUND: Analysis of genomic sequence allows characterization of genome content and organization, and access beyond gene-coding regions for identification of functional elements. BAC libraries, where relatively large genomic regions are made readily available, are especially useful for species without a fully sequenced genome and can increase genomic coverage of phylogenetic and biological diversity. For example, no butterfly genome is yet available despite the unique genetic and biological properties of this group, such as diversified wing color patterns. The evolution and development of these patterns is being studied in a few target species, including Bicyclus anynana, where a whole-genome BAC library allows targeted access to large genomic regions. METHODOLOGY/PRINCIPAL FINDINGS: We characterize ∼1.3 Mb of genomic sequence around 11 selected genes expressed in B. anynana developing wings. Extensive manual curation of in silico predictions, also making use of a large dataset of expressed genes for this species, identified repetitive elements and protein coding sequence, and highlighted an expansion of Alcohol dehydrogenase genes. Comparative analysis with orthologous regions of the lepidopteran reference genome allowed assessment of conservation of fine-scale synteny (with detection of new inversions and translocations) and of DNA sequence (with detection of high levels of conservation of non-coding regions around some, but not all, developmental genes). CONCLUSIONS: The general properties and organization of the available B. anynana genomic sequence are similar to the lepidopteran reference, despite the more than 140 MY divergence. Our results lay the groundwork for further studies of new interesting findings in relation to both coding and non-coding sequence: 1) the Alcohol dehydrogenase expansion with higher similarity between the five tandemly-repeated B. anynana paralogs than with the corresponding B. mori orthologs, and 2) the high conservation of non-coding sequence around the genes wingless and Ecdysone receptor, both involved in multiple developmental processes including wing pattern formation.

Odorant receptor (Or) genes: polymorphism and divergence in the D. melanogaster and D. pseudoobscura lineages.

BACKGROUND: In insects, like in most invertebrates, olfaction is the principal sensory modality, which provides animals with essential information for survival and reproduction. Odorant receptors are involved in this response, mediating interactions between an individual and its environment, as well as between individuals of the same or different species. The adaptive importance of odorant receptors renders them good candidates for having their variation shaped by natural selection. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed nucleotide variation in a subset of eight Or genes located on the 3L chromosomal arm of Drosophila melanogaster in a derived population of this species and also in a population of Drosophila pseudoobscura. Some heterogeneity in the silent polymorphism to divergence ratio was detected in the D. melanogaster/D. simulans comparison, with a single gene (Or67b) contributing ∼37% to the test statistic. However, no other signals of a very recent selective event were detected at this gene. In contrast, at the speciation timescale, the MK test uncovered the footprint of positive selection driving the evolution of two of the encoded proteins in both D. melanogaster--OR65c and OR67a--and D. pseudoobscura--OR65b1 and OR67c. CONCLUSIONS: The powerful polymorphism/divergence approach provided evidence for adaptive evolution at a rather high proportion of the Or genes studied after relatively recent speciation events. It did not provide, however, clear evidence for very recent selective events in either D. melanogaster or D. pseudoobscura.

High incidence of interchromosomal transpositions in the evolutionary history of a subset of or genes in Drosophila.

In insects, the odorant receptor (Or) multigene family is an intermediate-sized family with genes present in all chromosomes, indicating that duplication followed by interchromosomal transposition played an important role in the early stages of the family evolution. Here, we have explored the occurrence of interchromosomal transpositions in more recent stages through the comparative analysis of a subset of Or genes in Drosophila, where the gene content of chromosomal arms is highly conserved. The studied subset consisted of 11 Or genes located on the left arm of chromosome 3 (Muller's D element) in D. melanogaster. Our study focused on the number and chromosomal arm location of these members of the family across the 12 Drosophila species with complete genome sequences. In contrast to previous results from in situ hybridization comparative mapping that were mainly based on single-copy genes, our study, based on members of a multigene family of moderate size, revealed repeated interchromosomal transposition events and a complex history of some of the studied genes.