Marcinkowska et al. BMC Genomics 2011, 12:183 http://www.biomedcentral.com/1471-2164/12/183 R E S E A R C H A R T I C L E Open Access Copy number variation of microRNA genes in the human genome Malgorzata Marcinkowska1, Maciej Szymanski2, Wlodzimierz J Krzyzosiak1 and Piotr Kozlowski1* Abstract Background: MicroRNAs (miRNAs) are important genetic elements that regulate the expression of thousands of human genes. Polymorphisms affecting miRNA biogenesis, dosage and target recognition may represent potentially functional variants. The functional consequences of single nucleotide polymorphisms (SNPs) within critical miRNA sequences and outside of miRNA genes were previously demonstrated using both experimental and computational methods. However, little is known about how copy number variations (CNVs) affect miRNA genes. Results: In this study, we analyzed the co-localization of all miRNA loci with known CNV regions. Using bioinformatic tools we identified and validated 209 copy number variable miRNA genes (CNV-miRNAs) in CNV regions deposited in Database of Genomic Variations (DGV) and 11 CNV-miRNAs in two sets of CNVs defined as highly polymorphic. We propose potential mechanisms of CNV-mediated variation of functional copies of miRNAs (dosage) for different types of CNVs overlapping miRNA genes. We also showed that, consistent with their essential biological functions, miRNA loci are underrepresented in highly polymorphic and well-validated CNV regions. Conclusion: We postulate that CNV-miRNAs are potential functional variants and should be considered high priority candidate variants in genotype-phenotype association studies. Background MicroRNAs (miRNAs) are a family of short (~20 nt), single-stranded, noncoding RNAs that are primarily involved in post-transcriptional down-regulation of gene expression in most eukaryotes [1]. Specific miRNAs are engaged in a variety of processes, including develop- ment, cell proliferation, differentiation and apoptosis [2]. Numerous studies have demonstrated that aberrant over-expression or down-regulation of certain miRNAs contribute to carcinogenesis and that these miRNAs can therefore be classified as either oncogenes (oncomirs) or tumor suppressors, respectively [3]. Mature, functional miRNAs are generated from pri- mary precursors (pri-miRNA) encoded either by inde- pendent transcriptional units or within protein- or RNA-coding genes. In mammals, maturation of miRNAs involves two subsequent RNA cleavage steps. The first step takes place in the nucleus and is carried out by the Drosha nuclease to produce the secondary precursor * Correspondence: kozlowp@yahoo.com 1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland Full list of author information is available at the end of the article (pre-miRNA) [4]. The pre-miRNAs (~60 nt) possess a hairpin structure, with the double-stranded portion interrupted by one or more mismatched nucleotides. Upon export to the cytoplasm, the pre-miRNA is further processed into an miRNA duplex by the RNAse III Dicer; [5] one of the duplex strands (passenger) is released, and the other serves as the mature miRNA [6]. The miRNA-induced silencing complex (miRISC) inter- acts with complementary target sequences, which are usually located within the 3’ untranslated regions (3’UTRs) of mRNAs, causing mRNA degradation or inhibition of translation [7-9]. It is estimated that, in humans and other mammals, the expression of at least one-third of protein-coding genes is fine-tuned by approximately 1,000 miRNAs [10,11]. Currently, over 700 human miRNAs have been identified, and their sequences are deposited in miRBase (the microRNA database; http://www.mirbase.org). Polymorphisms in miRNA genes can affect the expres- sion of many downstream-regulated genes [12,13]. The most common form of polymorphism that affects the function of an miRNA (e.g., the structure of miRNA precursors, the efficiency of miRNA biogenesis and © 2011 Marcinkowska et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.