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Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Schizophrenia has a heritability of 60–80%
1
, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit
GRIN2A
and transcription factor
SP4
, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.
Journal Article
A Comprehensive Classification and Evolutionary Analysis of Plant Homeobox Genes
The full complement of homeobox transcription factor sequences, including genes and pseudogenes, was determined from the analysis of 10 complete genomes from flowering plants, moss, Selaginella, unicellular green algae, and red algae. Our exhaustive genome-wide searches resulted in the discovery in each class of a greater number of homeobox genes than previously reported. All homeobox genes can be unambiguously classified by sequence evolutionary analysis into 14 distinct classes also characterized by conserved intron–exon structure and by unique codomain architectures. We identified many new genes belonging to previously defined classes (HD-ZIP I to IV, BEL, KNOX, PLINC, WOX). Other newly identified genes allowed us to characterize PHD, DDT, NDX, and LD genes as members of four new evolutionary classes and to define two additional classes, which we named SAWADEE and PINTOX. Our comprehensive analysis allowed us to identify several newly characterized conserved motifs, including novel zinc finger motifs in SAWADEE and DDT. Members of the BEL and KNOX classes were found in Chlorobionta (green plants) and in Rhodophyta. We found representatives of the DDT, WOX, and PINTOX classes only in green plants, including unicellular green algae, moss, and vascular plants. All 14 homeobox gene classes were represented in flowering plants, Selaginella, and moss, suggesting that they had already differentiated in the last common ancestor of moss and vascular plants.
Journal Article
Herding Hemingway's cats : understanding how our genes work
The language of genes has become common parlance. We know they make your eyes blue, your hair curly or your nose straight. The media tells us that our genes control the risk of cancer, heart disease, alcoholism or Alzheimer's. The cost of DNA sequencing has plummeted from billions of pounds to a few hundred, and gene-based advances in medicine hold huge promise. We've all heard of genes, but how do they actually work? Drawing on stories ranging from six toed cats and stickleback hips to Mickey Mouse mice and zombie genes - told by researchers working at the cutting edge of genetics - Kat Arney explores the mysteries in our genomes with clarity, flair and wit, creating a companion reader to the book of life itself.
Book
Efficient protein production by yeast requires global tuning of metabolism
The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find that many cellular processes have to be attuned to support efficient protein secretion. In particular, altered energy metabolism resulting in reduced respiration and increased fermentation, as well as balancing of amino-acid biosynthesis and reduced thiamine biosynthesis seem to be particularly important. We confirm our findings by inverse engineering and physiological characterization and show that by tuning metabolism cells are able to efficiently secrete recombinant proteins. Our findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion.
The contribution of metabolic pathways to protein secretion is largely unknown. Here, the authors find conserved metabolic patterns in yeast by examining genome-wide transcriptional responses in high protein secretion mutants and reveal critical factors that can be tuned for efficient protein secretion.
Journal Article
Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer
We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%-98.8%) and 80.9% (74.6%-81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%-98.5%), and 90.9% (50.8%-98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8-14.1; p = 0.0017) for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%-100%) and 80.3% (70.7%-89.9%, p = 0.06) in a Singapore dataset, and 89.5% (81.9%-94.1%) and 73.6% (67.2%-79.0%, p = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.
Journal Article
One-Step Inactivation of Chromosomal Genes in Escherichia coli K-12 Using PCR Products
We have developed a simple and highly efficient method to disrupt chromosomal genes in Escherichia coli in which PCR primers provide the homology to the targeted gene(s). In this procedure, recombination requires the phage λ Red recombinase, which is synthesized under the control of an inducible promoter on an easily curable, low copy number plasmid. To demonstrate the utility of this approach, we generated PCR products by using primers with 36- to 50-nt extensions that are homologous to regions adjacent to the gene to be inactivated and template plasmids carrying antibiotic resistance genes that are flanked by FRT (FLP recognition target) sites. By using the respective PCR products, we made 13 different disruptions of chromosomal genes. Mutants of the arcB, cyaA, lacZYA, ompR-envZ, phnR, pstB, pstCA, pstS, pstSCAB-phoU, recA, and torSTRCAD genes or operons were isolated as antibiotic-resistant colonies after the introduction into bacteria carrying a Red expression plasmid of synthetic (PCR-generated) DNA. The resistance genes were then eliminated by using a helper plasmid encoding the FLP recombinase which is also easily curable. This procedure should be widely useful, especially in genome analysis of E. coli and other bacteria because the procedure can be done in wild-type cells.
Journal Article