Missing Sequences Research Articles

Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes

DNA double-strand breaks (DSBs) leading to loss of nucleotides in the transcribed region can be lethal. Classical non-homologous end-joining (C-NHEJ) is the dominant pathway for DSB repair (DSBR) in adult mammalian cells. Here we report that during such DSBR, mammalian C-NHEJ proteins form a multiprotein complex with RNA polymerase II and preferentially associate with the transcribed genes after DSB induction. Depletion of C-NHEJ factors significantly abrogates DSBR in transcribed but not in non-transcribed genes. We hypothesized that nascent RNA can serve as a template for restoring the missing sequences, thus allowing error-free DSBR. We indeed found pre-mRNA in the C-NHEJ complex. Finally, when a DSB-containing plasmid with several nucleotides deleted within the E. coli lacZ gene was allowed time to repair in lacZ-expressing mammalian cells, a functional lacZ plasmid could be recovered from control but not C-NHEJ factor-depleted cells, providing important mechanistic insights into C-NHEJ-mediated error-free DSBR of the transcribed genome.

SeqDev: An Algorithm for Constructing Genetic Elements Using Comparative Assembly

With the availability of recent next generation sequencing technologies and their low cost, genomes of different organisms are being sequenced frequently. Therefore, quick assembly of genome, transcriptome, and target contigs from the raw data generated through the sequencing technologies has become necessary for better understanding of different biological systems. This article proposes an algorithm, namely SeqDev (Sequence Developer) for constructing contigs from raw reads using reference sequences. For this, we considered a weighted frequency?based consensus mechanism named BlastAssemb for primary construction of a sequence with gaps. Then, we adopted suffix array and proposed a gap filling search (GFS) algorithm for searching the missing sequences in the primary construct. For evaluating our algorithm, we have chosen Pokkali (rice) raw genome and Japonica (rice) as our reference data. Experimental results demonstrated that our proposed algorithm accurately constructs promoter sequences of Pokkali from its raw genome data. These constructed promoter sequences were 93 ? 100% identical with the reference and also aligned with 96 ? 100% of corresponding reference sequences with eValue ranging from 0.0 ? 2e-14. All these results indicated that our proposed method could be a potential algorithm to construct target contigs from raw sequences with the help of reference sequences. Further wet lab validation with specific Pokkali promoter sequence will boost this method as a robust algorithm for target contig assembly.Plant Tissue Cult. & Biotech. 26(1): 105-121, 2016 (June)

Prediction of missing sequences and branch lengths in phylogenomic data.

The presence of missing data in large-scale phylogenomic datasets has negative effects on the phylogenetic inference process. One effect that is caused by alignments with missing per-gene or per-partition sequences is that the inferred phylogenies may exhibit extremely long branch lengths. We investigate if statistically predicting missing sequences for organisms by using information from genes/partitions that have data for these organisms alleviates the problem and improves phylogenetic accuracy. We present several algorithms for correcting excessively long branch lengths induced by missing data. We also present methods for predicting/imputing missing sequence data. We evaluate our algorithms by systematically removing sequence data from three empirical and 100 simulated alignments. We then compare the Maximum Likelihood trees inferred from the gappy alignments and on the alignments with predicted sequence data to the trees inferred from the original, complete datasets. The datasets with predicted sequences showed one to two orders of magnitude more accurate branch lengths compared to the branch lengths of the trees inferred from the alignments with missing data. However, prediction did not affect the RF distances between the trees. https://github.com/ddarriba/ForeSeqs : diego.darriba@h-its.org Supplementary data are available at Bioinformatics online.

Avoiding Missing Data Biases in Phylogenomic Inference: An Empirical Study in the Landfowl (Aves: Galliformes).

Production of massive DNA sequence data sets is transforming phylogenetic inference, but best practices for analyzing such data sets are not well established. One uncertainty is robustness to missing data, particularly in coalescent frameworks. To understand the effects of increasing matrix size and loci at the cost of increasing missing data, we produced a 90 taxon, 2.2 megabase, 4,800 locus sequence matrix of landfowl using target capture of ultraconserved elements. We then compared phylogenies estimated with concatenated maximum likelihood, quartet-based methods executed on concatenated matrices and gene tree reconciliation methods, across five thresholds of missing data. Results of maximum likelihood and quartet analyses were similar, well resolved, and demonstrated increasing support with increasing matrix size and sparseness. Conversely, gene tree reconciliation produced unexpected relationships when we included all informative loci, with certain taxa placed toward the root compared with other approaches. Inspection of these taxa identified a prevalence of short average contigs, which potentially biased gene tree inference and caused erroneous results in gene tree reconciliation. This suggests that the more problematic missing data in gene tree-based analyses are partial sequences rather than entire missing sequences from locus alignments. Limiting gene tree reconciliation to the most informative loci solved this problem, producing well-supported topologies congruent with concatenation and quartet methods. Collectively, our analyses provide a well-resolved phylogeny of landfowl, including strong support for previously problematic relationships such as those among junglefowl (Gallus), and clarify the position of two enigmatic galliform genera (Lerwa, Melanoperdix) not sampled in previous molecular phylogenetic studies.

A clone-free, single molecule map of the domestic cow (Bos taurus) genome.

BackgroundThe cattle (Bos taurus) genome was originally selected for sequencing due to its economic importance and unique biology as a model organism for understanding other ruminants, or mammals. Currently, there are two cattle genome sequence assemblies (UMD3.1 and Btau4.6) from groups using dissimilar assembly algorithms, which were complemented by genetic and physical map resources. However, past comparisons between these assemblies revealed substantial differences. Consequently, such discordances have engendered ambiguities when using reference sequence data, impacting genomic studies in cattle and motivating construction of a new optical map resource--BtOM1.0--to guide comparisons and improvements to the current sequence builds. Accordingly, our comprehensive comparisons of BtOM1.0 against the UMD3.1 and Btau4.6 sequence builds tabulate large-to-immediate scale discordances requiring mediation.ResultsThe optical map, BtOM1.0, spanning the B. taurus genome (Hereford breed, L1 Dominette 01449) was assembled from an optical map dataset consisting of 2,973,315 (439 X; raw dataset size before assembly) single molecule optical maps (Rmaps; 1 Rmap = 1 restriction mapped DNA molecule) generated by the Optical Mapping System. The BamHI map spans 2,575.30 Mb and comprises 78 optical contigs assembled by a combination of iterative (using the reference sequence: UMD3.1) and de novo assembly techniques. BtOM1.0 is a high-resolution physical map featuring an average restriction fragment size of 8.91 Kb. Comparisons of BtOM1.0 vs. UMD3.1, or Btau4.6, revealed that Btau4.6 presented far more discordances (7,463) vs. UMD3.1 (4,754). Overall, we found that Btau4.6 presented almost double the number of discordances than UMD3.1 across most of the 6 categories of sequence vs. map discrepancies, which are: COMPLEX (misassembly), DELs (extraneous sequences), INSs (missing sequences), ITs (Inverted/Translocated sequences), ECs (extra restriction cuts) and MCs (missing restriction cuts).ConclusionAlignments of UMD3.1 and Btau4.6 to BtOM1.0 reveal discordances commensurate with previous reports, and affirm the NCBI’s current designation of UMD3.1 sequence assembly as the “reference assembly” and the Btau4.6 as the “alternate assembly.” The cattle genome optical map, BtOM1.0, when used as a comprehensive and largely independent guide, will greatly assist improvements to existing sequence builds, and later serve as an accurate physical scaffold for studies concerning the comparative genomics of cattle breeds.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1823-7) contains supplementary material, which is available to authorized users.

Viral Genetic Linkage Analysis in the Presence of Missing Data.

Analyses of viral genetic linkage can provide insight into HIV transmission dynamics and the impact of prevention interventions. For example, such analyses have the potential to determine whether recently-infected individuals have acquired viruses circulating within or outside a given community. In addition, they have the potential to identify characteristics of chronically infected individuals that make their viruses likely to cluster with others circulating within a community. Such clustering can be related to the potential of such individuals to contribute to the spread of the virus, either directly through transmission to their partners or indirectly through further spread of HIV from those partners. Assessment of the extent to which individual (incident or prevalent) viruses are clustered within a community will be biased if only a subset of subjects are observed, especially if that subset is not representative of the entire HIV infected population. To address this concern, we develop a multiple imputation framework in which missing sequences are imputed based on a model for the diversification of viral genomes. The imputation method decreases the bias in clustering that arises from informative missingness. Data from a household survey conducted in a village in Botswana are used to illustrate these methods. We demonstrate that the multiple imputation approach reduces bias in the overall proportion of clustering due to the presence of missing observations.

Illumina Synthetic Long Read Sequencing Allows Recovery of Missing Sequences even in the "Finished" C. elegans Genome.

Most next-generation sequencing platforms permit acquisition of high-throughput DNA sequences, but the relatively short read length limits their use in genome assembly or finishing. Illumina has recently released a technology called Synthetic Long-Read Sequencing that can produce reads of unusual length, i.e., predominately around 10 Kb. However, a systematic assessment of their use in genome finishing and assembly is still lacking. We evaluate the promise and deficiency of the long reads in these aspects using isogenic C. elegans genome with no gap. First, the reads are highly accurate and capable of recovering most types of repetitive sequences. However, the presence of tandem repetitive sequences prevents pre-assembly of long reads in the relevant genomic region. Second, the reads are able to reliably detect missing but not extra sequences in the C. elegans genome. Third, the reads of smaller size are more capable of recovering repetitive sequences than those of bigger size. Fourth, at least 40 Kbp missing genomic sequences are recovered in the C. elegans genome using the long reads. Finally, an N50 contig size of at least 86 Kbp can be achieved with 24×reads but with substantial mis-assembly errors, highlighting a need for novel assembly algorithm for the long reads.

Positive selection improves the efficiency of DNA assembly

With the advent of synthetic biology and cell engineering, the demand for large synthetic DNA fragments has been steadily increasing. Consequently, a number of multi-fragment cloning technologies optimized for the assembly of sizable DNA constructs have been developed. Still, screening for the right clone can be tedious because the high incidence of illegitimate assembly results in a relatively large proportion of missing or shuffled DNA elements. To mitigate this risk, we have developed a strategy that reduces the rate of fragment mis-assembly and is compatible with a variety of cloning methodologies. The approach is based on the positive selection of truncated plasmid markers, which are rendered active by providing their missing sequences during the assembly process. The method has been successfully validated in the context of complex in vivo and in vitro homologous recombination workflows, but it could be readily adapted to other cloning strategies, including those based on restriction endonucleases.

Cross-stratigraphies from a seismically active mud lens off Peru indicate horizontal extensions of laminae, missing sequences, and a need for multiple cores for high resolution records

Abstract Marine laminated sediments in dysoxic areas of the ocean floor are an excellent archive for high-resolution climate reconstructions. While the existence of discontinuities produced by natural events, such as underwater landslides (slumps), strong bottom currents, and/or bioturbation is usually acknowledged for long records, the extent of their influence on high-resolution sequences is usually not considered. In the present work we show strong evidence for multiple stratigraphic discontinuities in different gravity and box-cores retrieved off Pisco (Peru) covering the last 600 years. Chronostratigraphies are largely based on cross-correlation of distinct sedimentary structures (determined by X-ray image analysis) and validated using 210Pb, 241Am, and 14C profiles, as well as proxy records. The cross-correlation of distinct stratigraphic layers allows for chronostratigraphic tie points and clearly shows that some sedimentary sequences are continuous across scales of tens of kilometers, indicating that regional processes often determine laminae formation. Some differences in laminae thickness were found among cores, which could be explained by different sedimentation rates, spatially variable deposition of diatom blooms, changes in silica dissolution and partial deposition/erosion caused by bottom currents. Using multiple stratigraphic tie points provides clear evidence for laminated sequences present in some cores to be missing in other cores. Moreover, instantaneous depositions from upslope were identified in all the cores disrupting the continuity of the sediment records. These discontinuities (instantaneous deposits and missing sequences) may be due to slumps, possibly triggered by earthquakes and/or erosion by strong bottom currents. In spite of the missing sequences in some cores, a continuous composite record of the last six centuries was reconstructed from spliced sequences of the different cores, which provides a well-constrained temporal framework to develop further high-resolution proxies in this region. The present work shows that paleoreconstructions developed from single cores, particularly in areas with strong seismic activity and/or strong bottom currents, are subject to both temporal gaps and instantaneous depositions from upslope, both of which could be misinterpreted as abrupt climate changes or anomalous climate events. We stress the need for multiple cores to determine the stratigraphic continuity and chronologies for high-resolution records.

Strong nucleosomes of mouse genome including recovered centromeric sequences

Recently discovered strong nucleosomes (SNs) characterized by visibly periodical DNA sequences have been found to concentrate in centromeres of Arabidopsis thaliana and in transient meiotic centromeres of Caenorhabditis elegans. To find out whether such affiliation of SNs to centromeres is a more general phenomenon, we studied SNs of the Mus musculus. The publicly available genome sequences of mouse, as well as of practically all other eukaryotes do not include the centromere regions which are difficult to assemble because of a large amount of repeat sequences in the centromeres and pericentromeric regions. We recovered those missing sequences using the data from MNase-seq experiments in mouse embryonic stem cells, where the sequence of DNA inside nucleosomes, including missing regions, was determined by 100-bp paired-end sequencing. Those nucleosome sequences, which are not matching to the published genome sequence, would largely belong to the centromeres. By evaluating SN densities in centromeres and in non-centromeric regions, we conclude that mouse SNs concentrate in the centromeres of telocentric mouse chromosomes, with ~3.9 times excess compared to their density in the rest of the genome. The remaining non-centromeric SNs are harbored mainly by introns and intergenic regions, by retro-transposons, in particular. The centromeric involvement of the SNs opens new horizons for the chromosome and centromere structure studies.

Genome-defence small RNAs exapted for epigenetic mating-type inheritance.

In the ciliate Paramecium, transposable elements and their single-copy remnants are deleted during the development of somatic macronuclei from germline micronuclei, at each sexual generation. Deletions are targeted by scnRNAs, small RNAs produced from the germ line during meiosis that first scan the maternal macronuclear genome to identify missing sequences, and then allow the zygotic macronucleus to reproduce the same deletions. Here we show that this process accounts for the maternal inheritance of mating types in Paramecium tetraurelia, a long-standing problem in epigenetics. Mating type E depends on expression of the transmembrane protein mtA, and the default type O is determined during development by scnRNA-dependent excision of the mtA promoter. In the sibling species Paramecium septaurelia, mating type O is determined by coding-sequence deletions in a different gene, mtB, which is specifically required for mtA expression. These independently evolved mechanisms suggest frequent exaptation of the scnRNA pathway to regulate cellular genes and mediate transgenerational epigenetic inheritance of essential phenotypic polymorphisms.

Discovery of common sequences absent in the human reference genome using pooled samples from next generation sequencing.

BackgroundSequences up to several megabases in length have been found to be present in individual genomes but absent in the human reference genome. These sequences may be common in populations, and their absence in the reference genome may indicate rare variants in the genomes of individuals who served as donors for the human genome project. As the reference genome is used in probe design for microarray technology and mapping short reads in next generation sequencing (NGS), this missing sequence could be a source of bias in functional genomic studies and variant analysis. One End Anchor (OEA) and/or orphan reads from paired-end sequencing have been used to identify novel sequences that are absent in reference genome. However, there is no study to investigate the distribution, evolution and functionality of those sequences in human populations.ResultsTo systematically identify and study the missing common sequences (micSeqs), we extended the previous method by pooling OEA reads from large number of individuals and applying strict filtering methods to remove false sequences. The pipeline was applied to data from phase 1 of the 1000 Genomes Project. We identified 309 micSeqs that are present in at least 1% of the human population, but absent in the reference genome. We confirmed 76% of these 309 micSeqs by comparison to other primate genomes, individual human genomes, and gene expression data. Furthermore, we randomly selected fifteen micSeqs and confirmed their presence using PCR validation in 38 additional individuals. Functional analysis using published RNA-seq and ChIP-seq data showed that eleven micSeqs are highly expressed in human brain and three micSeqs contain transcription factor (TF) binding regions, suggesting they are functional elements. In addition, the identified micSeqs are absent in non-primates and show dynamic acquisition during primate evolution culminating with most micSeqs being present in Africans, suggesting some micSeqs may be important sources of human diversity.Conclusions76% of micSeqs were confirmed by a comparative genomics approach. Fourteen micSeqs are expressed in human brain or contain TF binding regions. Some micSeqs are primate-specific, conserved and may play a role in the evolution of primates.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-685) contains supplementary material, which is available to authorized users.

Dynamic genetic features of chromosomes revealed by comparison of soybean genetic and sequence-based physical maps

Despite the intensive soybean [Glycine max (L.) Merrill] genome studies, the high chromosome number (20) of the soybean plant relative to many other major crops has hindered the development of a high-resolution genomewide genetic map derived from a single population. Here, we report such a map, which was constructed in an F15 population derived from a cross between G. max and G. soja lines using indel polymorphisms detected via a G. soja genome resequencing. By targeting novel indel markers to marker-poor regions, all marker intervals were reduced to under 6 cM on a genome scale. Comparison of the Williams 82 soybean reference genome sequence and our genetic map indicated that marker orders of 26 regions were discrepant with each other. In addition, our comparison showed seven misplaced and two absent markers in the current Williams 82 assembly and six markers placed on the scaffolds that were not incorporated into the pseudomolecules. Then, we showed that, by determining the missing sequences located at the presumed beginning points of the five major discordant segments, these observed discordant regions are mostly errors in the Williams 82 assembly. Distributions of the recombination rates along the chromosomes were similar to those of other organisms. Genotyping of indel markers and genome resequencing of the two parental lines suggested that some marker-poor chromosomal regions may represent introgression regions, which appear to be prevalent in soybean. Given the even and dense distribution of markers, our genetic map can serve as a bridge between genomics research and breeding programs.

Complete cpDNA genome sequence of Smilax china and phylogenetic placement of Liliales – Influences of gene partitions and taxon sampling

The complete nucleotide sequence of the chloroplast genome (cpDNA) of Smilax china L. (Smilacaceae) is reported. It is the first complete cp genome sequence in Liliales. Genomic analyses were conducted to examine the rate and pattern of cpDNA genome evolution in Smilax relative to other major lineages of monocots. The cpDNA genomic sequences were combined with those available for Lilium to evaluate the phylogenetic position of Liliales and to investigate the influence of taxon sampling, gene sampling, gene function, natural selection, and substitution rate on phylogenetic inference in monocots. Phylogenetic analyses using sequence data of gene groups partitioned according to gene function, selection force, and total substitution rate demonstrated evident impacts of these factors on phylogenetic inference of monocots and the placement of Liliales, suggesting potential evolutionary convergence or adaptation of some cpDNA genes in monocots. Our study also demonstrated that reduced taxon sampling reduced the bootstrap support for the placement of Liliales in the cpDNA phylogenomic analysis. Analyses of sequences of 77 protein genes with some missing data and sequences of 81 genes (all protein genes plus the rRNA genes) support a sister relationship of Liliales to the commelinids–Asparagales clade, consistent with the APG III system. Analyses of 63 cpDNA protein genes for 32 taxa with few missing data, however, support a sister relationship of Liliales (represented by Smilax and Lilium) to Dioscoreales–Pandanales. Topology tests indicated that these two alignments do not significantly differ given any of these three cpDNA genomic sequence data sets. Furthermore, we found no saturation effect of the data, suggesting that the cpDNA genomic sequence data used in the study are appropriate for monocot phylogenetic study and long-branch attraction is unlikely to be the cause to explain the result of two well-supported, conflict placements of Liliales. Further analyses using sufficient nuclear data remain necessary to evaluate these two phylogenetic hypotheses regarding the position of Liliales and to address the causes of signal conflict among genes and partitions.

A 10‐gene phylogeny of Solanum section Herpystichum (Solanaceae) and a comparison of phylogenetic methods

Solanum section Herpystichum is a lineage that comprises both widespread and very narrowly distributed species. This study investigates the phylogenetic relationships of sect. Herpystichum and evaluates several phylogenetic methods for analysis of multiple sequences. Sequence data from seven nuclear (ITS, GBSSI, and five COSII) and three plastid (psbA-trnH, trnT-trnF, and trnS-trnG) regions were concatenated and analyzed under maximum parsimony and Bayesian criteria. In addition, we used two analytical methods that take into account differences in topologies resulting from the analyses of the individual markers: Bayesian Estimation of Species Trees (BEST) and supertree analysis. The monophyletic Solanum sect. Herpystichum was resolved with moderate support in the concatenated maximum parsimony and Bayesian analyses and the supertree analysis, and relationships within the section were well-resolved and strongly supported. The BEST topology, however, was poorly resolved. Also, because of how BEST deals with missing sequences, >25% of our accessions, including two species, had to be excluded from the analyses. Our results indicate a progenitor-descendent relationship with two species nested within the widespread S. evolvulifolium. Analytical methods that consider individual topologies are important for studies based on multiple molecular markers. On the basis of analyses in this study, BEST had the serious shortcoming that taxa with missing sequences must be removed from the analysis or they can produce spurious topologies. Supertree analysis provided a good alternative for our data by allowing the inclusion of all 10 species of sect. Herpystichum.

Seeing the Trees in Your Terrace

Missing data creates “terraces” of phylogenetic trees with identical optimality scores.

Perspectives on 1/f noise in quantum chaos

The power spectrum of the δn statistic of quantum spectra presents 1/fα noise. For chaotic systems α = 1 while for regular systems α = 2. Although the transition from regularity to chaos is non universal, for a wide variety of systems with a mixed phase space the value of α is intermediate between 1 and 2 and can be related to the fraction of regular or chaotic orbits in the total phase space. This statistic can be a very useful tool for the analysis of experimental spectra, specially in the case of missing levels or spectral sequences with mixed symmetries.

Characterization of a virion occlusion-defective Autographa californica multiple nucleopolyhedrovirus mutant lacking the p26, p10 and p74 genes

Nucleopolyhedroviruses (NPVs), family Baculoviridae, are insect-specific viruses with the potential to control insect pests in agriculture and forestry. NPVs are occluded in polyhedral occlusion bodies. Polyhedra protect virions from inactivation in the environment as well as assisting virions in horizontal transmission in the insect population. The process of virion occlusion in the polyhedra is undefined and the genes that regulate the virion occlusion process have not been well investigated yet. An Autographa californica multiple nucleopolyhedrovirus (AcMNPV) mutant (AcDef) that has a 2136 bp DNA deletion, including p26, p10 and p74 genes, has been isolated. No virions were detected in the polyhedra of AcDef. Restoration of all the missing sequences into AcDef led to proper virion occlusion. Individual gene deletion of either p10 or p26 could not abolish virion occlusion in the polyhedra of AcMNPV, but p10 deletion reduced virion occlusion efficiency more than threefold compared with the wild-type AcMNPV. Previous studies by other research groups on deletion of AcMNPV gene p74 suggested that p74 is a per os infectivity factor, and deletion of the p74 gene did not eliminate virion occlusion. Collectively, the three genes (p26, p10 and p74) may act in concert to regulate the virion occlusion process. Therefore, p26, p10 and p74 are all required for proper virion occlusion in the polyhedra of AcMNPV.

Disruption of Normal Gene Sequence May Lead to Schizophrenia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessDisruption of Normal Gene Sequence May Lead to SchizophreniaJun YanJun YanSearch for more papers by this authorPublished Online:2 May 2008https://doi.org/10.1176/pn.43.9.0022aChunks of DNA fragments that are scattered throughout chromosomes and sometimes mess up functional gene sequences may in part explain the development of schizophrenia and other neuropsychiatric disorders, according to new research produced independently by two groups of researchers.Two studies in different patient populations were combined into one paper and published online in Science on March 27.A group of National Institute of Mental Health (NIMH) researchers, led by Anjene Addington, Ph.D., and Judith Rapoport, M.D., found that 28 percent of patients with childhood-onset schizophrenia (COS) carried certain rare structural variants that disrupted normal genes. Similarly, researchers from Cold Spring Harbor Laboratory and the University of Washington, led by Jonathan Sebat, Ph.D., and Jon McClellan, M.D., found that 15 percent of patients with the classic type of schizophrenia carried rare structural variants in their genomes. Among patients with classic schizophrenia, 20 percent of those with an onset before age 18 carried rare structural variants. In contrast, only 5 percent of healthy, unrelated controls had these variants.Structural variations or mutations refer to chunks of repeated or missing DNA sequences (that is, microduplications and microdeletions, respectively) throughout a chromosome. Such variations may arise from mistakes during replication or chromosome misalignment during the development of sperm or eggs. Some of these mutations, also known as copy number variations, are common to all or most people. Certain rare variations have been linked to diseases.The researchers systematically scanned and compared the genomes of schizophrenia patients and of healthy controls, and of COS patients and their healthy parents to identify rare structural variations that were more frequent in patients with the disorder.The genes disrupted by rare structural variants associated with schizophrenia were concentrated in brain-development pathways. For example, one of the genes disrupted, SLC1A3, codes for a glutamate transporter protein found in many synapses in the brain. Transcription from these genes may be defective, or the protein produced may be dysfunctional because of the random deletion or duplication of DNA sections.'Smoking Gun' Remains ElusiveTo further complicate the picture, “virtually every rare structural mutation detected in our [study] was different,” the authors wrote. Scientists have been searching for a few common genetic mutations in patients with schizophrenia with a focus on common mutations within the suspect genes themselves, but so far have been unable to find “the smoking gun.” Many genes seem to be involved in the disease but none has a large association.The new findings “suggest a new model for finding new genes and mechanisms,” Rapoport, a senior investigator and child psychiatrist at NIMH, told Psychiatric News. Each specific mutation was rare by itself, and many were confined to one family or a single patient. In other words, patients with the same clinical diagnoses have different mutations that affect different genes on different chromosomes. Collectively, however, they are associated with a substantial proportion of schizophrenia patients.“It means that there are different ways to disrupt the same neurological pathway and that there are different pathways to schizophrenia,” commented Rapoport. She noted that the COS patients studied by her group had a higher likelihood of carrying these rare structural mutations than did the classic schizophrenia cohort, probably because the COS patients are a more homogeneous group. COS is a rare and severe form of the disease with an onset before age 13.Mutations Came From Healthy ParentsMost of the rare mutations identified in the COS patients were inherited from their healthy parents, which adds to the mystery. “[The mutations] are risk factors, but they are neither necessary nor sufficient for developing schizophrenia,” she said. Structural mutations may also occur spontaneously.This type of genetic variations throughout chromosomes may be a lot more important to disease pathology than previously expected. In a study published in the April 20, 2007, Science, Jonathan Sebat and colleagues linked the same type of structural mutations to autism spectrum disorders. The number of genes disrupted by these mutations and the signaling pathways affected by these disrupted genes may be staggering.In the current study, a particular microdeletion and a microduplication identified in several COS patients in the study had previously been linked to autism, mental retardation, and bipolar disorder. All this evidence seems to suggest that one psychiatric disorder in different patients may originate from a variety of genetic mutations in a complex web of pathways during brain development, and different disorders may share some of the same mutations and pathways. “Anyone in the [schizophrenia genetics] research knows that the reality is exponentially more complicated than what we already know,” Rapoport said.An abstract of “Rare Structural Variants Disrupt Multiple Genes in Neuro-developmental Pathways in Schizophrenia” is posted at<www.sciencemag.org/cgi/content/abstract/1155174>.▪ ISSUES NewArchived

Forbidden patterns in financial time series

The existence of forbidden patterns, i.e., certain missing sequences in a given time series, is a recently proposed instrument of potential application in the study of time series. Forbidden patterns are related to the permutation entropy, which has the basic properties of classic chaos indicators, such as Lyapunov exponent or Kolmogorov entropy, thus allowing to separate deterministic (usually chaotic) from random series; however, it requires fewer values of the series to be calculated, and it is suitable for using with small datasets. In this paper, the appearance of forbidden patterns is studied in different economical indicators such as stock indices (Dow Jones Industrial Average and Nasdaq Composite), NYSE stocks (IBM and Boeing), and others (ten year Bond interest rate), to find evidence of deterministic behavior in their evolutions. Moreover, the rate of appearance of the forbidden patterns is calculated, and some considerations about the underlying dynamics are suggested.