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In Print: Last Month's Microarray Papers of Note: Feb 7, 2012


In Print: Last Month's Microarray Papers of Note

Journal: Analytical Biochemistry. 2012 Jan 15;420(2):127-38.

Title: A secreted protein microarray platform for extracellular protein interaction discovery.

Authors: Gonzalez L, et al.

In this paper, the authors demonstrate that functional protein microarrays are "well-suited" for high-throughput screening of extracellular protein interactions. To evaluate the performance of the platform, they screened a set of 89 immunoglobulin (Ig)-type receptors against an extracellular protein microarray with 686 genes represented. To enhance detection of low-affinity interactions, the authors developed a method to assemble bait Fc fusion proteins into multivalent complexes using protein A microbeads. Based on these screens, they developed a statistical methodology for hit calling and identification of nonspecific interactions on protein microarrays.

Journal: Blood. 2012 Jan 12;119(2):469-75.

Title: A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32.

Authors: Cozen W, et al.

The authors undertook a genome-wide meta-analysis of 393 European-origin adolescent and young adult nodular sclerosing Hodgkin lymphoma patients and 3,315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. They identified 3 SNPs on chromosome 6p21.32 that were significantly associated with NSHL risk. In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio.

Journal: BMC Medical Genomics. 2012 Jan 30;5(1):6.

Title: Routine use of microarray-based gene expression profiling to identify patients with low cytogenetic risk acute myeloid leukemia: accurate results can be obtained even with suboptimal samples.

Authors: Raingeard de la Bletiere D, et al.

The aim of this array-based gene-expression profiling study was to evaluate to what extent suboptimal samples with low leukemic blast load and poor quality control criteria could also be correctly identified. With 10-marker classifiers, all training set samples as well as 97 of the 101 test samples with a low blast load, and all 10 samples with poor quality control criteria were correctly classified. The authors concluded that gene expression profiling and a supervised method requiring 10-marker classifiers enables the identification of favorable cytogenetic risk acute myeloid leukemia even when samples contain low leukemic blast loads or display poor quality control criterion.

Journal: Clinical Genetics. 2012 Jan 27. [Epub ahead of print]

Title: Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Authors: Shoukier M, et al.

This study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants as well as delineating clinical criteria that may help separate patients with pathogenic CNVs from those without them. To do this, the authors performed a retrospective review of clinical and array CGH data of 342 children with unexplained developmental delay or intellectual disability. The phenotypic features of patients with clinically significant CNVs were compared with those of patients without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2 percent of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature, and failure to thrive were clearly more frequent in children with pathogenic CNVs compared to children with normal array CGH results. They determined that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Journal: European Journal of Human Genetics. 2012 Jan 11. [Epub ahead of print]

Title: Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies.

Authors: Delahaye A, et al.

The authors performed oligonucleotide comparative genome hybridization-based microarray analysis in 65 patients who had unexplained ocular developmental anomalies with at least one other birth defect and intellectual disability using Agilent Technologies-manufactured chips. In four patients, array CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development. In four other patients, they found three pathogenic deletions not classically associated with abnormal ocular morphogenesis. The authors said that the results show that array CGH provides a high diagnostic yield in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions.

Journal: European Urology. 2012 Jan 18. [Epub ahead of print]

Title: Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers.

Authors: Kandimalla R, et al.

Genome-wide methylation analysis was performed on 44 bladder tumors using the Agilent 244K Human CpG Island Microarray and validation was done using a custom Illumina 384-plex assay in a retrospective group of 77 independent tumors. The percentage of methylation in tumor and urine samples was then used to identify markers for detection and related to the end point of progression to muscle-invasive disease with Kaplan-Meier models and multivariate analysis. The authors identified four methylation markers that they claim can be used to predict progression in pTa tumors, allowing stratification of patients for personalized follow-up. In addition, the authors identified CpG Islands that will enable detection of bladder tumors in voided urine.

Journal: Genome Biology. 2012 Jan 25;13(1):R2.

Title: Implications for health and disease in the genetic signature of the Ashkenazi Jewish population.

Authors: Guha S, et al.

The authors genotyped more than 1,300 Ashkenazi Jewish healthy volunteers from the Hebrew University Genetic Resource with the Illumina HumanOmni1-Quad platform. Comparison of the genotyping data with that of neighboring European and Asian populations enabled the Ashkenazi Jewish-specific component of the variance to be characterized with respect to disease-relevant alleles and pathways. They identified an Ashkenazi Jewish-specific genetic signature that differentiated these subjects from both European and Middle Eastern samples. Gene ontology analysis of the Ashkenazi Jewish genetic signature revealed an enrichment of genes functioning in transepithelial chloride transport, such as CFTR, and in equilibrioception, potentially shedding light on cystic fibrosis, Usher syndrome, and other diseases over-represented in the Ashkenazi Jewish population, according to the authors.

Journal: Genome Biology. 2012 Jan 20;13(1):R1.

Title: Genetic adaptation to high altitude in the Ethiopian highlands.

Authors:Scheinfeldt L, et al.

Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. In this study, the authors extended this work to high- and low-altitude populations living in Ethiopia for which they measured hemoglobin levels. They genotyped these populations using the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.

Journal: Genomics. 2012 Jan;99(1):25-35.

Title: Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression.

Authors: Smith A, et al.

A high-resolution Roche NimbleGen custom microarray was designed representing all non-repetitive sequences in the telomeric 33 megabases of the short arm of human chromosome 11 to study epigenetic alterations in Beckwith-Wiedemann syndrome. Analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth-suppressing imprinted gene CDKN1C. The authors concluded that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5 alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in chromatin context.

Journal: Hepatology. 2012 Jan 11. [Epub ahead of print]

Title: Genome-wide DNA methylation profiles in hepatocellular carcinoma.

Authors: Shen J, et al.

To identify with a genome-wide approach additional genes hypermethylated in hepatocellular cancer that could be used for more accurate analysis of plasma DNA for early diagnosis, the authors of this study analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of five of these genes; correlation coefficients ranged from 0.92 to 0.97. At least one of these genes was hypermethylated in 87 percent of cases, leading the authors to suggest that measurement of DNA methylation in plasma samples is feasible.

Journal: Human Molecular Genetics. 2012 Jan 19. [Epub ahead of print]

Title: Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas.

Authors: Fejerman L, et al.

Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer, according to the authors. They combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer and Latina controls were genotyped using Affymetrix and Illumina arrays. They identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25. A second region on 11p15 showed a trend toward association. In both regions, breast cancer risk decreased with higher indigenous American ancestry in concordance with observations made on global ancestry. The authors concluded that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and indigenous American origin.

Journal: International Journal of Legal Medicine. 2012 Jan 27. [Epub ahead of print]

Title: Vaginal microbial flora analysis by next generation sequencing and microarrays; can microbes indicate vaginal origin in a forensic context?

Authors: Benschop C, et al.

The authors of this study set out to explore the use of microbial flora to indicate vaginal origin of a sample. First, they surveyed the vaginal microbiome for a set of 240 clinical vaginal samples by next-generation sequencing and found 1,619 different sequences. Next, they selected 389 candidate probes targeting genera or species and designed a microarray, with which they analyzed 43 DNA extracts from vaginal samples and 25 DNA extracts from samples from other body sites, including sites in close proximity of or in contact with the vagina. As no candidate genera or species were found to positively identify all vaginal DNA extracts on their own, the authors suggested using arrays to identify vaginal origin by detecting patterns of multiple species within various genera.

Journal: Molecular Cytogenetics. 2012 Jan 19;5(1):5.

Title: Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene.

Authors: Colovati M, et al.

The authors used the Affymetrix SNP 6.0 array to genotype a female patient with clinical symptoms of Marfan syndrome plus craniostenosis, hypothyroidism, and intellectual deficiency. The individual presented a 1.9 megabase deletion, including the previously associated FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12, and 15. According to the authors, this is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes.

Journal: Nature Genetics. 12 Jan 29. [Epub ahead of print]

Title: Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event.

Authors: Golubchik T, et al.

The authors used array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination, showing the simultaneous transfer of multiple and often large DNA fragments. They showed that new strains quickly became established, spreading from east to west across the United States. The authors claimed that their observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the value of combining genomic and epidemiological information in the surveillance and understanding of infectious diseases.

Journal: Nature Genetics. 2012 Jan 22. [Epub ahead of print]

Title: Discovery of common variants associated with low TSH levels and thyroid cancer risk.

Authors: Gudmundsson J, et al.

Using Illumina microarrays, the researchers genotyped 27,758 individuals from Iceland with known blood thyroid stimulating hormone levels. Along with the sites interrogated directly by the chip itself, they also used genomic data for 457 Icelanders whose genomes were sequenced to 10 times coverage to impute SNP genotypes at millions more sites. The GWAS led to 22 SNPs that were significantly associated with TSH levels, including one on chromosome 9 that was already implicated in thyroid cancer risk. Researchers genotyped the remaining 21 SNPs in 561 individuals with thyroid cancer and nearly 3,200 unaffected individuals. They also included genotyping information for almost 40,000 controls already tested using Illumina arrays. Following analysis, the team was left with three thyroid cancer-associated variants on chromosomes 2, 8, and 14.

Journal: Physiological Genomics. 2012 Jan 18;44(1):25-34.

Title: Acute milk yield response to frequent milking during early lactation is mediated by genes transiently regulated by milk removal.

Authors: Wall E, et al.

Milking dairy cows four times daily instead of twice daily during early lactation stimulates an increase in milk yield that partly persists through late lactation, according to the authors of his study. However, the mechanisms behind this response are unknown. Affymetrix GeneChip Bovine Genome Arrays were used to measure gene expression in animals milked four times a day and animals milked two times a day. They found 855 genes were differentially expressed in mammary tissue between the glands of the cows in the experiment. They concluded that there is an acute transcriptional response to milk removal, but milking four times a day did not elicit differential expression of unique genes.

Journal: PLoS One. 2012;7(1):e28213.

Title: Evidence for transcript networks composed of chimeric RNAs in human cells.

Authors: Djebali S, et al.

The authors used tiling microarrays and RNA sequencing to study chimeric RNAs, a class of RNAs that possess sequences from different genes and about which little is known. Based on their findings, the authors argued that these chimeric transcripts are "important," noting phenomena such as the non-random interconnections of genes involved; the greater phylogenetic depth of the genes involved in many chimeric interactions; the coordination of the expression of connected genes; and the close in vivo and three-dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs.
BioArray News spoke with the authors about the study last month ( BAN 1/17/2012).

Journal: PLoS One. 2012;7(1):e30048.

Title: Microarray analysis of HIV resistant female sex workers reveal a gene expression signature pattern reminiscent of a lowered immune activation state.

Authors: Songok E, et al.

To identify biomarkers for HIV-1 resistance, including pathways that may be critical in anti-HIV-1 vaccine design, the authors carried out a gene expression analysis on blood samples obtained from HIV-1 highly exposed seronegatives from a commercial sex worker cohort in Nairobi and compared their profiles to HIV-1 negative controls using the Affymetrix HUG 133 Plus 2.0 arrays. Pathway analysis through the KEGG signaling database revealed a majority of the impacted pathways had genes that were significantly down regulated. The authors determined that the hallmark of HIV-1 resistance is down regulation of genes in pathways that HIV-1 depends on for infection.

Journal: PLoS One. 2012;7(1):e29534.

Title: Shifting from population-wide to personalized cancer prognosis with microarrays.

Authors: Li S, et al.

The authors described a metric called clinical confidence that serves as a measure of prognostic reliability to facilitate the shift from population-wide to personalized cancer prognosis using microarray-based predictive models. The performance of sample-based models predicted with different clinical confidences was evaluated and compared systematically using three large clinical datasets studying the following cancers: breast cancer, multiple myeloma, and neuroblastoma. Survival curves for patients, with different confidences, were also delineated. The results show that the clinical confidence metric separates patients with different prediction accuracies and survival times.

Journal: Proceedings of the National Academy of Sciences. 2012 Jan 10. [Epub ahead of print]

Title: Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection.

Authors: Barreiro L, et al.

Using the Illumina HumanHT-12 version 4 BeadChip, the authors assessed gene expression patterns across the genomes of dendritic cells derived from white blood cell samples collected from 65 healthy individuals of European ancestry. Comparisons of gene expression patterns in the dendritic cells before and after exposure to M. tuberculosis pointed to nearly 3,000 genes that seemed to be more highly expressed in cells infected by the bug — including several known immune response genes. In an attempt to find expression quantitative trait loci related to these expression shifts, the team used Illumina Omni1-Quad BeadChip arrays to genotype samples from each participating individual — a search that identified 756 potential cis-regulatory variants in uninfected dendritic cells and 720 such variants in infected cells. Of these, researchers verified 198 suspected eQTLs in their subsequent statistical analyses, including 102 eQTLs in the uninfected cells and 96 in the cells exposed to TB.

The Scan

Unique Germline Variants Found Among Black Prostate Cancer Patients

Through an exome sequencing study appearing in JCO Precision Oncology, researchers have found unique pathogenic or likely pathogenic variants within a cohort of Black prostate cancer patients.

Analysis of Endogenous Parvoviral Elements Found Within Animal Genomes

Researchers at PLOS Biology have examined the coevolution of endogenous parvoviral elements and animal genomes to gain insight into using the viruses as gene therapy vectors.

Saliva Testing Can Reveal Mosaic CNVs Important in Intellectual Disability

An Australian team has compared the yield of chromosomal microarray testing of both blood and saliva samples for syndromic intellectual disability in the European Journal of Human Genetics.

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.