Fmrp targets or not: Long, highly brain-expressed genes tend to be implicated in autism and brain disorders

BACKGROUND: Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. FINDINGS: We tested whether Fmrp binding may be a proxy for some other features of these transcripts. Reviewing recent literature on the cross-linking and immunoprecipitation (CLIP)-derived targets of Fmrp in the brain, and the literature on identifying genes thought to mediate autism and other psychiatric disorders, reveals that both appear to be disproportionately made up of highly brain-expressed genes. This suggests a parsimonious explanation—that the overlap between Fmrp targets and neuropsychiatric candidate genes might be secondary to simple features such as transcript length and robust expression in the brain. Indeed, reanalyzing Fmrp high-throughput sequencing of RNAs isolated by CLIP (HITS-CLIP) data suggests that approximately 60% of CLIP tag depth can be predicted by gene expression, coding sequence length, and transcript length. Furthermore, there is a statistically significant overlap between autism candidate genes and random samples of long, highly brain-expressed genes, whether they are Fmrp targets or not. CONCLUSIONS: Comparison of known Fmrp-binding targets to candidate gene lists should be informed by both of these features. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-015-0008-1) contains supplementary material, which is available to authorized users

Psychiatric gene discoveries shape evidence on ADHD's biology

The Wellcome Trust, MRC and Action Medical Research have provided ADHD research support for AT, PH, JM, NW, MJO, MCO; we also acknowledge support from NIH grants R1 3MH059126, R0 1MH62873 and R0 1MH081803 to Dr SV Faraone. Dr E Mick received funding through the UMass Center for Clinical and Translational Science (P30HD004147) supported by the NIH.A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10-4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.Publisher PDFPeer reviewe

Regulation of Local Translation in Neuronal Processes of Specific Cell Types

Local translation in distal processes of the neuron was discovered over 35 years ago, but only with the recent advancements in microscopy, molecular techniques, and high throughput sequencing have we been able to identify which mRNAs are locally translated. Previous methods were unable to harvest cell specific RNA from neurites in vivo from a variety of cell types; however, building on these advancements, we developed SynapTRAP to examine localized translation in specific cell types. The diversity of arbors and functions of neurons across the central nervous system suggests different proteins localized to the periphery of cells for neurite growth and regulation, although it is unknown which of these proteins are synthesized locally. To determine if these different proteins are produced locally or if they are shuttled to the synapse post-translationally, we profiled two different cell types: GABAergic interneurons and layer V pyramidal neurons, using SynapTRAP. From these results we determined that not only do local translatomes differ between types of neurons, but that mRNA localization to neurites is regulated by both baseline cellular differences and post transcriptional pathways

The Role of Pelvic Lymphadenectomy in the Management of Prostate and Bladder Cancer

A pelvic lymph node dissection is commonly performed by urologists in the surgical management of prostate and bladder cancer. Identification of lymph node metastases provides important prognostic information for both diseases. Despite advances in radiographic imaging, a pelvic lymphadenectomy remains the most accurate method to stage lymph node involvement. In the past two decades, there has been an increase in the diagnosis of early stage prostate cancer, which has led some to omit a pelvic lymphadenectomy in patients thought to have low probability of positive lymph nodes. There is little debate, however, over the inclusion of a lymph node dissection in bladder cancer given the approximately 25% incidence of unsuspected nodal disease at the time of surgery. Controversy exists over the extent of an appropriate lymphadenectomy and its therapeutic efficacy. This review will examine the need, extent, and the potential prognostic and therapeutic benefits of a pelvic lymphadenectomy in prostate and bladder cancer

A Population-Based Study of Autosomal-Recessive Disease-Causing Mutations in a Founder Population

The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal-recessive (AR) mutations known to be present in members of a founder population and revealed surprisingly high carrier frequencies for many of these mutations. By utilizing the rich demographic, genetic, and phenotypic data available on these subjects and simulations in the exact pedigree that these individuals belong to, we show that the majority of mutations were most likely introduced into the population by a single founder and then drifted to the high carrier frequencies observed. We further show that although there is an increased incidence of AR diseases overall, the mean carrier burden is likely to be lower in the Hutterites than in the general population. Finally, on the basis of simulations, we predict the presence of 30 or more undiscovered recessive mutations among these subjects, and this would at least double the number of AR diseases that have been reported in this isolated population