Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility ...complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number ...from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples during collection and sequencing. We present a statistical tool (exome hidden Markov model XHMM) that uses principal-component analysis (PCA) to normalize exome read depth and a hidden Markov model (HMM) to discover exon-resolution CNV and genotype variation across samples. We evaluate performance on 90 schizophrenia trios and 1,017 case-control samples. XHMM detects a median of two rare (<1%) CNVs per individual (one deletion and one duplication) and has 79% sensitivity to similarly rare CNVs overlapping three or more exons discovered with microarrays. With sensitivity similar to state-of-the-art methods, XHMM achieves higher specificity by assigning quality metrics to the CNV calls to filter out bad ones, as well as to statistically genotype the discovered CNV in all individuals, yielding a trio call set with Mendelian-inheritance properties highly consistent with expectation. We also show that XHMM breakpoint quality scores enable researchers to explicitly search for novel classes of structural variation. For example, we apply XHMM to extract those CNVs that are highly likely to disrupt (delete or duplicate) only a portion of a gene.
Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and ...whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.
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•iPSC-derived motor neurons harboring SOD1 mutations exhibit cell survival deficits•Genetic correction rescues ALS-related phenotypes•RNA-seq reveals expression changes and mitochondrial and ER stress disturbances•Motor neurons exhibit inherent ER stress linked to electrical activity
Motor neurons differentiated from human-ALS-patient-derived iPSCs were used to define transcriptional and functional changes arising from SOD1 mutations, which could be reversed by genome engineering of the SOD1 locus.
Many human proteins contain domains that vary in size or copy number because of variable numbers of tandem repeats (VNTRs) in protein-coding exons. However, the relationships of VNTRs to most ...phenotypes are unknown because of difficulties in measuring such repetitive elements. We developed methods to estimate VNTR lengths from whole-exome sequencing data and impute VNTR alleles into single-nucleotide polymorphism haplotypes. Analyzing 118 protein-altering VNTRs in 415,280 UK Biobank participants for association with 786 phenotypes identified some of the strongest associations of common variants with human phenotypes, including height, hair morphology, and biomarkers of health. Accounting for large-effect VNTRs further enabled fine-mapping of associations to many more protein-coding mutations in the same genes. These results point to cryptic effects of highly polymorphic common structural variants that have eluded molecular analyses to date.
Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show here that DNA replication timing is shaped by genetic polymorphisms that ...act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, read depth along chromosomes reflected DNA replication activity in those cells. We used this relationship to analyze variation in replication timing among 161 individuals sequenced by the 1000 Genomes Project. Genome-wide association of replication timing with genetic variation identified 16 loci at which inherited alleles associate with replication timing. We call these “replication timing quantitative trait loci” (rtQTLs). rtQTLs involved the differential use of replication origins, exhibited allele-specific effects on replication timing, and associated with gene expression variation at megabase scales. Our results show replication timing to be shaped by genetic polymorphism and identify a means by which inherited polymorphism regulates the mutability of nearby sequences.
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•Replication timing, a driver of locus-specific mutation rates, varies among humans•Whole genome sequence data can be used to study DNA replication activity•Replication timing associates with common polymorphisms near replication origins•Replication timing QTLs have megabase-scale effects on replication and transcription
Replication timing varies among humans, and genetic variants associate with replication timing. These replication timing quantitative trait loci are cis-acting modifiers of replication timing, gene expression levels, and local mutation rates and are an unexpected source of potential wide-reaching variation between individuals.
The variant call format and VCFtools Danecek, Petr; Auton, Adam; Abecasis, Goncalo ...
Bioinformatics,
08/2011, Letnik:
27, Številka:
15
Journal Article
Recenzirano
Odprti dostop
The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored ...in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API.
Availability:
http://vcftools.sourceforge.net
Contact:
rd@sanger.ac.uk
Accurate and complete analysis of genome variation in large populations will be required to understand the role of genome variation in complex disease. We present an analytical framework for ...characterizing genome deletion polymorphism in populations using sequence data that are distributed across hundreds or thousands of genomes. Our approach uses population-level concepts to reinterpret the technical features of sequence data that often reflect structural variation. In the 1000 Genomes Project pilot, this approach identified deletion polymorphism across 168 genomes (sequenced at 4 × average coverage) with sensitivity and specificity unmatched by other algorithms. We also describe a way to determine the allelic state or genotype of each deletion polymorphism in each genome; the 1000 Genomes Project used this approach to type 13,826 deletion polymorphisms (48-995,664 bp) at high accuracy in populations. These methods offer a way to relate genome structural polymorphism to complex disease in populations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In this study, clonal hematopoiesis with somatic mutations was found in 10% of otherwise healthy people older than 65. The risk of hematologic cancer was substantially increased among these persons; ...in two cases, the subsequent cancer was related to the clone that predated the cancer.
The development of disease often involves dynamic processes that begin years or decades before the clinical onset. In many cases, however, the process of pathogenesis goes undetected until after the patient has symptoms and presents with clinically apparent disease.
Cancer arises owing to the combined effects of multiple somatic mutations, which are likely to be acquired at different times.
1
Early mutations may be present many years before disease develops. In some models of cancer development, early mutations lead to clonal expansions by stem cells or other progenitor cells.
2
Such clonal expansions greatly increase the likelihood that later, cooperating mutations would . . .
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including ...single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.
The interpretation of genome-wide association results is confounded by linkage disequilibrium between nearby alleles. We have developed a flexible bioinformatics query tool for single-nucleotide ...polymorphisms (SNPs) to identify and to annotate nearby SNPs in linkage disequilibrium (proxies) based on HapMap. By offering functionality to generate graphical plots for these data, the SNAP server will facilitate interpretation and comparison of genome-wide association study results, and the design of fine-mapping experiments (by delineating genomic regions harboring associated variants and their proxies). Availability: SNAP server is available at http://www.broad.mit.edu/mpg/snap/. Contact: debakker@broad.mit.edu
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