miRNA
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Scientists studying genetics have long investigated global changes in chromosomal balance. Traditional comparative genomic hybridization (CGH) and other microscopy methods provide opportunities for rough chromosome investigation, but shortcomings in spatial resolution, low-throughput methods, and weak analytical tools pose major challenges to researchers. The use of BAC and cDNA microarrays for CGH research improves resolution and throughput, but these microarrays are still compromised by nonspecific hybridization potential, inconsistent quality, limited commercial availability, and suboptimal resolution. Now, oligonucleotide microarrays can enable you to detect large or focal amplifications and deletions, elucidate copy number boundaries within the genome, and characterize chromosomal variations. Novel developments in gene expression research now suggest that there is a significant correlation between DNA copy number aberrations and variation in mRNA expression. Specific examination of the correlation between miRNA and chromosomal copy number changes has revealed that more than one-half of the miRNAs are aligned to genomic fragile sites or regions associated with cancers, and therefore, genome copy abnormalities could involve miRNA genes. Over the past several years, array comparative genomic hybridization (aCGH) has proven its value for analyzing DNA copy number variations and the integration of this data with the occurrence of miRNAs will provide valuable information regarding the relationship between gene anomalies and regulatory function. Traditionally, miRNA expression has been tested using low-throughput techniques such as Northern-blot analysis and real-time PCR, but new developments in microarray technology now enable global profiling of all miRNA genes and their precursors in any sample type.
P. Lamy and fellow researchers in Denmark (2006) examined the localization of microRNAs in genomic regions associated with cancer and reported on 283 miRNAs in the human genome in relation to copy number changes in prostate, bladder, and colon tumors. The group used SNP arrays to identify genomic regions with abnormal copy numbers. In prostate and colon tumors, the group found miRNAs over-represented in regions with copy number gain and under-represented in regions with copy number loss, whereas this pattern appears to be reversed in bladder cancer. Following comparisons to published miRNA expression data, the group did not find a statistically significant relationship between miRNA copy number and expression level. This suggests that miRNA expression is regulated through different mechanisms than mRNA expression and requires additional methods for accurate characterization.
Title: Are microRNAs located in genomic regions associated with cancer?
Authors: Lamy P, Andersen CL, Dyrskjot L, Torring N, Orntoft T, Wiuf C
Journal: Br J Cancer, Vol 95, Issue 10: 1415-8
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An international collaboration between researchers in the United States, Italy, and Greece (2006) provide experimental genomewide documentation of DNA copy alterations involving miRNA genes in epithelial cancers. The research use several different microarray applications (gene expression, CGH, and miRNA arrays) to demonstrate a high frequency of copy number abnormalities in regions containing miRNA and their associated genes in breast cancer, ovarian cancer, and melanoma. Given that miRNA genes may target genes critical for oncogenesis, the data suggest that high-frequency copy number abnormalities occur in miRNA-containing regions throughout the genome in a range of human epithelial cancers. The group identified shared abnormalities in miRNA-containing genomic loci among ovarian cancer, breast cancer, and melanoma. Further, they also identified distinct differences in genomic alterations in miRNA-containing genomic loci between epithelial cancers and previously described hematologic malignancies. DNA copy alterations of loci containing miRNA genes that were unique to specific epithelial cancers were also identified. The importance of this research is the indication that, for many miRNAs, DNA copy changes correlated with miRNA transcript expression.
Title: microRNAs exhibit high frequency genomic alterations in human cancer.
Authors: Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G
Journal: Proc Natl Acad Sci U S A, Vol 103, Issue 24: 9136-41
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Kendy Wong et al (2007) performed a comprehensive analysis of common copy-number variations (CNVs) in the human genome, to measure large scale (>40 kb) segmental gains and losses in >100 individuals to expand knowledge about CNVs and to estimate the extent of this form of variation in the human population, creating a baseline of human genomic variation. The group used a whole-genome array comparative genomic hybridization assay and identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3% (77% of frequent CNVs were novel). Intriguingly, 14 polymorphic regions harbored 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity and disease susceptibility in humans.
Title: A comprehensive analysis of common copy-number variations in the human genome.
Authors: Wong KK, deLeeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, MacAulay C, Ng RT, Brown CJ, Eichler EE, Lam WL
Journal: Am J Hum Genet, Vol 80, Issue 1: 91-104
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Title: Differences in vertebrate microRNA expression.
Authors: Ason B, Darnell DK, Wittbrodt B, Berezikov E, Kloosterman WP, Wittbrodt J, Antin PB, Plasterk RH
Journal: Proc Natl Acad Sci U S A, Vol 103, Issue 39: 14385-9
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Title: The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism.
Authors: Xu P, Vernooy SY, Guo M, Hay BA
Journal: Curr Biol, Vol 13, Issue 9: 790-5
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