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In Print: Jan 5, 2010


Microarray Papers of Note Published in December 2009

Journal: Analytical Chemistry. 2009 Dec 10. [Epub ahead of print]

Title: Effect of physicochemical anomalies of soda-lime silicate slides on biomolecule immobilization.

Authors: North S, et al.

Glass microscope slides are considered by many as the substrate of choice for microarray manufacturing due to their amenability to various surface chemistry modifications, according to the authors of this study. The use of silanes to attach various functional groups onto glass slides has provided a versatile tool for the covalent immobilization of many diverse biomolecules of interest. Still, the authors noted a dramatic reduction in biomolecule immobilization efficiency on standard microscope slides prepared using a well-characterized silanization method. A survey conducted by the authors of commercial soda-lime slides found that slides purchased prior to 2008 had superior immobilization efficiencies when compared to those purchased after 2008. Characterization of the slides by X-ray photoelectron spectroscopy, contact angle measurements, and atomic force microscopy revealed a significant correlation between magnesium content, surface roughness, and bioimmobilization efficiency. High-performance slides had higher magnesium content and higher root-mean-square roughness than slides with lower bioimmobilization efficiencies. Although the exact mechanism of how magnesium content and surface roughness affect silane deposition has not yet been defined, the authors showed in this paper that recent changes in the chemical and physical properties of commercial soda-lime slides affect the ability of these slides to be covalently modified.

Journal: Biometrics. 2009 Dec;65(4):1087-95.

Title: A Bayesian hidden Markov model for motif discovery through joint modeling of genomic sequence and ChIP-chip data.

Authors: Gelfond J, et al.

The authors of this study propose a unified framework for the analysis of chromatin immunoprecipitation microarray data for detecting transcription factor binding sites or motifs. ChIP-chip assays are used to focus the genome-wide search for TFBSs by isolating a sample of DNA fragments with TFBSs and applying this sample to a microarray with probes corresponding to tiled segments across the genome. Current methods use a two-step approach of analyzing array data to estimate IP-enrichment peaks, and then analyzing the corresponding sequences independently of intensity information. The proposed new model integrates peak finding and motif discovery through a unified Bayesian hidden Markov model framework to accommodate the uncertainty in both measurements. A Markov chain Monte Carlo algorithm is then formulated for parameter estimation, adapting recursive techniques used for HMMs. In simulations and applications to a yeast RAP1 dataset, the proposed method has favorable TFBS discovery performance compared to currently available two-stage procedures in terms of both sensitivity and specificity, the authors wrote.

Journal: BMC Bioinformatics. 2009 Dec 22;10(1):440. [Epub ahead of print]

Title: ReseqChip: Automated integration of multiple local context probe data from the MitoChip array in mitochondrial DNA sequence assembly.

Authors: Thieme M, et al.

The authors of this paper describe the Affymetrix MitoChip version 2.0, an oligonucleotide tiling array for resequencing the human mitochondrial genome. For each of 16,569 nucleotide positions of the mitochondrial genome, the array holds two sets of four 25-mer probes each which match the heavy and the light strand of a reference genome and vary only at their central position to interrogate all four possible alleles. In addition, the MitoChip v2.0 carries alternative local context probes to account for known mtDNA variants. These probes have been neglected in most studies due to the lack of software for their automated analysis. The authors also provide ReseqChip, a free software tool that automates the process of resequencing mtDNA using multiple local context probes on the MitoChip v2.0.

Journal: BMC Genomics. 2009 Dec 8;10(1):588.

Title: The pitfalls of platform comparison: DNA copy number array technologies assessed.

Authors: Curtis C, et al.

The authors describe a systematic comparison of copy number variation data from four leading microarray technologies, the Affymetrix genome-wide SNP 5.0 array, the Agilent high-density CGH Human 244A array, Illumina HumanCNV370-Duo DNA Analysis BeadChip, and the Roche NimbleGen 385K oligonucleotide array. They compared samples derived from primary breast tumors and their corresponding matched normals, well-established cancer cell lines, and HapMap individuals. By performing a theoretical assessment of the reproducibility, noise, and sensitivity of each platform, notable differences were revealed, according to the authors. They found that NimbleGen exhibited between-replicate array variances an order of magnitude greater than the other three platforms, with Agilent slightly outperforming the others, and a comparison of self-self hybridizations revealed similar patterns. An assessment of the single-probe power revealed that Agilent exhibits the highest sensitivity, according to the authors. They also performed an in-depth visual assessment of the ability of each platform to detect aberrations of varying sizes. As expected, all platforms were able to identify large aberrations in a robust manner. However, some focal amplifications and deletions were only detected in a subset of the platforms. The authors determined that, though there are substantial differences in the design, density, and number of replicate probes, there is a generally high level of concordance between platforms, despite differences in the reproducibility, noise, and sensitivity. In general, they found Agilent to be the best CGH platform and Affymetrix to be the superior SNP-CGH platform.

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Journal: Forensic Science International. 2009 Dec;4(1):43-8.

Title: Evaluation of the 124-plex SNP typing microarray for forensic testing.

Authors: Krjutskov K, et al.

Human identification systems such as criminal databases, forensic DNA testing, and genetic genealogy require genotyping of autosomal, mitochondrial, and Y chromosome markers from different biological materials, including venous blood and saliva. Employing the array primer extension 2 methodology, the authors of this study characterized a 124-plex assay, using specific primer extension, universal primer amplification, and single-base extension on an oligonucleotide array. The assay has been designed for simultaneous genotyping of SNPs from the single copy loci side by side with SNPs from the mitochondrial genome that appears in up to thousands of copies per cell in certain tissue types. All the autosomal SNPs included in the multiplex assay are unlinked and are distributed widely across autosomes, enabling genetic fingerprints to be distinguished. Mitochondrial DNA and Y chromosome polymorphisms that define haplogroups common in European populations are included to allow for maternity and paternity testing and for the analysis of genetic genealogies. After assay optimization, the authors estimated the accuracy and call rate of the protocol on 17 mother-father-child-children families and five internal control DNAs. In addition, 79 unrelated Estonian and Swedish DNA samples were genotyped and the accuracy of mtDNA and Y chromosome haplogroup inference by the multiplex method was assessed using conventional genotyping methods and direct sequencing.

Journal: Genome Research. 2009 Dec;19(12):2271-8.

Title: Industrial fuel ethanol yeasts contain adaptive copy number changes in genes involved in vitamin B1 and B6 biosynthesis.

Authors: Stambuk B, et al.

Using microarray-based comparative genome hybridization, the authors determined gene copy number variations common to five industrially important fuel ethanol Saccharomyces cerevisiae strains responsible for the production of fuel ethanol from sugarcane. The strains have significant amplifications of the telomeric SNO and SNZ genes, which are involved in the biosynthesis of vitamins B6 and B1. The authors showed that increased copy number of these genes confers the ability to grow more efficiently under the repressing effects of thiamin, especially in media lacking pyridoxine and with high sugar concentrations. These genetic changes have likely been adaptive and selected for in the industrial environment, and may be required for the efficient utilization of biomass-derived sugars from other renewable feedstocks, they determined.

Journal: Genome Research. 2009 Dec 22. [Epub ahead of print]

Title: Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.

Authors: Javierre B, et al.

The authors report a high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. They used a cohort of twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Only monozygotic twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. The authors argue that their results support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

Journal: Glycoconjugate Journal. 2009 Dec 2. [Epub ahead of print]

Title: Polysaccharide microarrays for high-throughput screening of transglycosylase activities in plant extracts.

Authors: Kosík O, et al.

The authors of this study describe a polysaccharide microarray in the form of a glycochip that permits high-throughput monitoring of multiple transglycosylase activities in plant extracts. The glycochip, containing donor polysaccharides printed onto nitrocellulose-coated glass slides, was incubated with crude plant extracts, along with a series of fluorophore-labeled acceptor oligosaccharides. After removing unused labeled oligosaccharides by washing, fluorescence retained on the glycochip as a result of transglycosylase reaction was detected with a standard microarray scanner. In this study, the glycochip assay was used to detect transglycosylase activities in crude extracts from nasturtium and mouse-ear cress. A number of previously unknown saccharide donor-acceptor pairs active in transglycosylation reactions that lead to the formation of homo- and hetero-glycosidic conjugates were detected.

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Journal: IEEE Transactions on Systems, Man, and Cybernetics. 2009 Dec;39(6):1606-16.

Team: EvoOligo: oligonucleotide probe design with multiobjective evolutionary algorithms.

Authors: Shin S, et al.

The authors of this study propose a multiobjective evolutionary optimization method for oligonucleotide probe design based on the multiobjective nature of the probe design problem. The proposed approach has several distinguishing features, compared with previous methods, according to the authors. First, the evolutionary approach can find better probe sets than existing simple filtering methods with fixed threshold values. Second, the multiobjective approach can incorporate the user's custom criteria or change the existing criteria. Third, the approach tries to optimize the combination of probes for the given set of genes, in contrast to other tools that independently search each gene for qualifying probes. Finally, the multiobjective optimization method provides various sets of probe combinations, among which the user can choose, depending on the target application. The proposed method is implemented as a platform called EvoOligo. In this paper, the authors tested the performance of EvoOligo by designing probe sets for 19 types of human papillomavirus and 52 genes in the Arabidopsis calmodulin multigene family.

Journal: Investigative Ophthalmology & Visual Science. 2009 Dec;50(12):5919-26.

Title: Genotyping microarray for CSNB-associated genes.

Authors: Zeitz C, et al.

Congenital stationary night blindness is a clinically and genetically heterogeneous retinal disease. Although electroretinographic measurements can discriminate clinical subgroups, the identification of the underlying genetic defects has been complicated for CSNB because of genetic heterogeneity, the uncertainty about the mode of inheritance, and time-consuming and costly mutation scanning and direct sequencing approaches, the authors of this paper state. To overcome these challenges, they developed a CSNB genotyping microarray with arrayed primer extension technology. To cover as many mutations as possible, a comprehensive literature search was performed, and DNA samples from a cohort of patients with CSNB were first sequenced directly in known CSNB genes. Subsequently, oligonucleotides were designed representing 126 sequence variations in RHO, CABP4, CACNA1F, CACNA2D4, GNAT1, GRM6, NYX, PDE6B, and SAG and spotted on the chip. Direct sequencing of genes known to be associated with CSNB in the study cohort revealed 21 mutations. The resultant microarray containing oligonucleotides detects 126 known and novel mutations, and was effective in determining the expected sequence changes in all known samples assessed. In addition, investigation of 34 patients with CSNB who were previously not genotyped revealed sequence variants in 18 percent, of which 15 percent are thought to be disease-causing mutations, the authors found.

Journal: Journal of Microbiology Methods. 2009 Dec;79(3):279-88.

Title: Design and development of the AnaeroChip microarray for investigation of methanogenic communities.

Authors: Franke-Whittle I, et al.

The aim of this study was to design a microarray targeting methanogens found in anaerobic digesters, and to apply this chip together with a cloning approach to investigate the methanogenic community present in an anaerobic digester. Oligonucleotide probes were designed based on sequence differences in the 16S rRNA genes in order to target microorganisms in situ. For microarray hybridizations, DNA was subjected to PCR amplification of the 16S rRNA gene and Cy5-labeled. The microarray was tested with pure cultures, and of the 1,854 individual probe-target hybridization reactions performed, there were 28 false positive and 16 false negative signals. The resulting AnaeroChip was hybridized with DNA from an anaerobic sludge. Strong hybridization signals were obtained for Methanoculleus, and weaker signals, in decreasing order, were obtained for Methanosarcina, Methanobacterium, Methanobrevibacter, and Methanosphaera. In order to check the results obtained with the microarray, the archaeal community structure of the same digester was analyzed by 16S rRNA gene cloning and sequencing. Community structure was determined by restriction digestion of almost 200 clones and by sequencing of the 15 different resulting patterns. Methanoculleus was the dominant microorganism in the anaerobic sludge, and Methanobrevibacter, Methanobacterium, Methanosarcina, Methanosphaera, an uncultured archaeon, and Methanothermobacter were also detected. The authors said the results showed the microarray to be a suitable tool for studying methanogenic communities in sludge.

Journal: Journal of Proteomics. 2009 Dec 1;73(2):252-66.

Title: Validation of serum protein profiles by a dual antibody array approach.

Authors: Rimini R, et al.

In this study, the authors describe a path towards the production of an antibody microarray to allow protein profiling of biotinylated human serum samples with reproducible sensitivity in the picomolar range. Specifically, they describe a cross-platform strategy based on data concordance with a suspension bead array to interrogate the identical set of antibodies with the same cohort of serum samples. Comparative analysis identified high-performing antibodies that displayed consistent results across the two platforms and targeted known serum components, the authors wrote. Additionally, data-processing methods such as sample referencing and normalization were evaluated for their effects on inter-platform agreement. The authors determined that mutual validation of protein-expression profiles using alternative microarray platforms holds great potential for affinity-based high-throughput proteomic screenings.

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Journal: The Lancet. 2009 Dec 10. [Epub ahead of print]

Title: Accurate and rapid identification of bacterial species from positive blood cultures with a DNA-based microarray platform: an observational study.

Authors: Tissari P, et al.

The authors of this study assessed the sensitivity, specificity, and turnaround time of a new molecular sepsis assay. They investigated 2,107 positive blood-culture samples for bacterial species by both conventional culture and Mobidiag's Prove-it sepsis assay in the UK and Finland. The Prove-it assay is a PCR and microarray method that is based on amplification and detection of gyrB, parE, and mecA genes of 50 bacterial species. The authors found that 1,807 of the 2,107 positive blood-culture samples included a pathogen covered by the assay. The assay had a clinical sensitivity of 94.7 percent and a specificity of 98.8 percent, and 100 percent for both measures for methicillin-resistant Staphylococcus aureus bacteremia. The authors also found the assay was a mean 18 hours faster than the conventional culture-based method, which takes an additional one to two working days.

Journal: Molecular Oncology. 2009 Dec;3(5-6):469-82.

Title: Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models.

Authors: Bergamaschi A, et al.

The authors of this paper aim to develop new breast cancer model systems for in vivo studies of hormone-dependent and independent tumor growth, progression, and invasion, and for in vivo experimental therapy studies. They collected primary mammary tumor specimens from patients, and implanted them in immunodeficient mice. Primary tumor tissue from 29 patients with breast cancer was implanted subcutaneously with matrigel in mice. The tumors were transferred into new animals when reaching a diameter of 15 millimeters and engrafted tumors were harvested for morphological and molecular characterization from passage six. Gene-expression profiling was then performed using Agilent Human Whole Genome Oligo Microarrays, as well as DNA copy number analysis using Agilent Human Genome CGH 244K Microarrays. Of the 30 primary tumors implanted into mice, two gave rise to viable tumors beyond passage ten. One showed high expression levels of estrogen receptor-alpha protein while the other was negative. Histopathological evaluation of xenograft tumors was carried out at passage 10-12; both xenografts maintained the morphological characteristics of the original tumors. The genomic profile of the ER-positive xenograft tumor resembled the profile of the primary tumor, while the profile obtained from the ER-negative parental tumor was different from the xenograft. However, the ER-negative parental tumor and xenograft clustered on the same branch using unsupervised hierarchical clustering analysis on RNA microarray expression data of intrinsic genes. A significant variation was observed in the expression of extracellular matrix-related genes, which were found downregulated in the engrafted tumors compared to the primary tumor. By IHC and qRT-PCR, the authors also found that the downregulation of stroma-related genes was compensated by the overexpression of such molecules by the mouse host tissue. The two established breast cancer xenograft models showed different histopathological characteristics and profound diversity in gene-expression patterns that in part can be associated to their ER status and were described as basal-like and luminal-like phenotype, respectively.

Journal: Molecular Plant-Microbe Interactions. 2009 Dec;22(12):1504-13.

Title: Comparative analysis of expression profiles in shoots and roots of tomato systemically infected by tomato spotted wilt virus reveals organ-specific transcriptional responses.

Authors: Catoni M, et al.

Tomato, a model species for the family Solanaceae, is severely affected by tomato spotted wilt virus worldwide. The authors of this study measured systemic transcriptional response of plants to TSWV infection using microarrays. They found that parallel analysis of both shoots and roots revealed organ-specific responses, although the virus was present in similar concentration. In the shoots, genes related to defense and to signal transduction were induced, while there was general repression of genes related to primary and secondary metabolism as well as to amino acid metabolism. In roots, expression of genes involved in primary metabolism and signal transduction appear unaffected by TSWV infection, while those related to the response to biotic stimuli were induced and those associated to the response to abiotic stress were generally repressed or unaltered. Additionally, the authors determined that genes related to amino acid metabolism were unaffected, except for those involved in synthesis of secondary compounds, where induction was evident. Differential expression of genes involved in metabolism and response to ethylene and abscisic acid was also observed in the two organs.

Journal: Nucleic Acids Research. 2009 Dec 6. [Epub ahead of print]

Title: Beyond Affymetrix arrays: expanding the set of known hybridization isotherms and observing pre-wash signal intensities.

Authors: Pozhitkov A, et al.

According to the authors of this study, microarray hybridization studies have attributed the nonlinearity of hybridization isotherms to probe saturation and post-hybridization washing. The authors here examined hybridization isotherms generated on different microarray platforms using a ribosomal RNA target and then investigated hybridization signals at equilibrium and after stringent wash. Hybridization signal at equilibrium was achieved by treating the microarray with isopropanol, which prevents nucleic acids from dissolving into solution. Their results suggested that: a) the shape of hybridization isotherms varied by microarray platform with some being hyperbolic or linear, and others following a power-law distribution; b) at equilibrium, fluorescent signal of different probes hybridized to the same target were not similar even with excess of target; and c) the amount of target removed by stringent washing depended upon the hybridization time, the probe sequence, and the presence or absence of nonspecific targets.

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Journal: Physical Biology. 2009 Dec 21;7:16004.

Title: Physico-chemical modeling of target depletion during hybridization on oligonucleotide microarrays.

Authors: Burden C, et al.

In this paper, the effect of target molecule depletion from the supernatant solution was incorporated into a physico-chemical model of hybridization on oligonucleotide microarrays. Two possible regimes were identified: a local depletion, where depletion by a given probe feature only affects that particular probe; and global depletion, where all features responding to a given target species are affected. In the paper, examples are given of two existing spike-in data sets experiencing measurable effects of target depletion. The first, from a custom array experiment with a broad range of probe lengths and mismatch positions, was verified to exhibit local and not global depletion. The second data set, from a well-known Affymetrix HGU133a Latin square experiment, was shown to be very well explained by a global depletion model. The authors concluded that microarray calibrations relying on Langmuir isotherm models, which ignore depletion effects, will significantly underestimate specific target concentrations. They also determined that a combined analysis of perfect match and mismatch probe signals in terms of a simple graphical summary, namely the hook curve method, can discriminate between cases of local and global depletion.

Journal: Poultry Science. 2009 Dec;88(12):2600-9.

Title: Prehatch intestinal maturation of turkey embryos demonstrated through gene expression patterns.

Authors: de Oliveira J, et al.

Some of the challenges faced by neonatal turkeys include weakness, reduced feed intake, impaired growth, susceptibility to disease, and mortality. To better understand enteric development in turkeys just before hatch, the authors of this study developed a method to identify the patterns of intestinal gene expression by using a focused microarray. The duodenums of 24 turkey embryos were sampled on embryonic days 20, 24, 26, and hatch 28. The RNA populations of 96 chosen genes were measured at each time point, from which 81 significantly changed. These genes were clustered by gene expression pattern similarity into four groups. Based on the expression pattern of hormone receptors, the authors determined that intestinal tissues may be less responsive to growth hormone, insulin, glucagon, and triiodothyronine during the last 48 hours before hatch, when developmental emphasis switches from cell proliferation to functional maturation. They concluded that, at hatch, turkeys should have the capacity to digest disaccharides but not oligopeptides, due to increased expression of sucrase-isomaltase but decreased expression of aminopeptidases; and absorb monosaccharides and small peptides due to high expression of sodium-glucose cotransporter-4 and peptide transporter-1.

Journal: Prenatal Diagnostics. 2009 Dec;29(12):1156-66.

Title: Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray.

Authors: Coppinger J, et al.

The authors of this study set out to determine the detection rates of whole-genome microarray technology compared to targeted microarray analysis for chromosome abnormalities in prenatal samples submitted for testing. For their microarray analyses, the authors used either whole-genome bacterial artificial chromosome-based and oligonucleotide-based arrays or targeted BAC microarrays on 182 and 62 prenatal cases, respectively, from North American healthcare providers without previously known chromosome abnormalities or family history of a parent with a known chromosome rearrangement. They identified clinically significant chromosome alterations in seven out of 182 prenatal specimens, two of which each had two unrelated abnormalities. After excluding two of the cases in which the abnormality would have been identified by routine karyotyping, the diagnostic yield of clinically significant findings was five out of 182, according to the authors. The authors concluded that whole-genome prenatal array comparative genomic hybridization detected clinically significant submicroscopic chromosome abnormalities in addition to chromosome abnormalities that could be identified by concurrent karyotyping without an increase in unclear results or benign copy number variations compared to targeted aCGH.

Journal: Proceedings of the National Academy of Sciences. 2009 Dec 22 [Epub ahead of print]

Title: Genome-wide patterns of population structure and admixture in West Africans and African Americans.

Authors: Bryca K, et al.

To obtain a fine-scale genome-wide perspective of ancestry, the authors of this study analyzed Affymetrix GeneChip 500K genotype data from African Americans and individuals with ancestry from West Africa and Europe. They found that population structure within the West African sample reflects primarily language and secondarily geographical distance, echoing the Bantu expansion. Among African Americans, analysis of genomic admixture by a principal component-based approach indicates that the median proportion of European ancestry is 18.5 percent, with very large variation among individuals. In the African-American sample as a whole, few autosomal regions showed exceptionally high or low mean African ancestry, but the X chromosome showed elevated levels of African ancestry, consistent with a sex-biased pattern of gene flow with an excess of European male and African female ancestry. The authors also found that genomic profiles of individual African Americans afford personalized ancestry reconstructions differentiating ancient versus recent European and African ancestry. Finally, patterns of genetic similarity among inferred African segments of African-American genomes and genomes of contemporary African populations included in this study suggest African ancestry is most similar to non-Bantu, Niger-Kordofanian-speaking populations, consistent with historical documents of the African diaspora and trans-Atlantic slave trade.

Journal: Proteomics. 2009 Dec;9(24):5562-6.

Title: Improved reproducibility of reverse-phase protein microarrays using array microenvironment normalization.

Authors: Anderson T, et al.

The authors of this paper discussed an experimental methodology for a reverse-phase protein microarray platform. The methodology, called array microenvironment normalization, increases the statistical power of the platform. For instance, in the experiment, it enabled the detection of a 1.1-fold shift in prostate-specific antigen concentration using approximately six technical replicates rather than the 37 replicates previously required. The improved reproducibility and statistical power should facilitate clinical implementation of the platform, the authors believe.

The Scan

Octopus Brain Complexity Linked to MicroRNA Expansions

Investigators saw microRNA gene expansions coinciding with complex brains when they analyzed certain cephalopod transcriptomes, as they report in Science Advances.

Study Tracks Outcomes in Children Born to Zika Virus-Infected Mothers

By following pregnancy outcomes for women with RT-PCR-confirmed Zika virus infections, researchers saw in Lancet Regional Health congenital abnormalities in roughly one-third of live-born children.

Team Presents Benchmark Study of RNA Classification Tools

With more than 135 transcriptomic datasets, researchers tested two dozen coding and non-coding RNA classification tools, establishing a set of potentially misclassified transcripts, as they report in Nucleic Acids Research.

Breast Cancer Risk Related to Pathogenic BRCA1 Mutation May Be Modified by Repeats

Several variable number tandem repeats appear to impact breast cancer risk and age at diagnosis in almost 350 individuals carrying a risky Ashkenazi Jewish BRCA1 founder mutation.