A map of human microRNA variation uncovers unexpectedly high levels of variability

BackgroundMicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in a healthy population seems an obvious requirement for future research on miRNA-related pathologies.MethodsData on 14 populations from the 1000 Genomes Project were analyzed, along with new data extracted from 60 exomes of healthy individuals from a population from southern Spain, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability.ResultsDespite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28.ConclusionsDespite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.

[1]  Y. Nakagawa,et al.  Association Study of Common Genetic Variants in Pre-microRNAs in Patients with Ulcerative Colitis , 2011, Journal of Clinical Immunology.

[2]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[3]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[4]  F. Westermann,et al.  New miRNAs cloned from neuroblastoma , 2008, BMC Genomics.

[5]  P. Visscher,et al.  Divergence between human populations estimated from linkage disequilibrium. , 2008, American journal of human genetics.

[6]  S. Volinia,et al.  Non-coding RNAs: a key to future personalized molecular therapy? , 2010, Genome Medicine.

[7]  Nada Jabado,et al.  What can exome sequencing do for you? , 2011, Journal of Medical Genetics.

[8]  N. Rajewsky,et al.  Widespread changes in protein synthesis induced by microRNAs , 2008, Nature.

[9]  Hyeyoung Min,et al.  Got target?: computational methods for microRNA target prediction and their extension , 2010, Experimental & Molecular Medicine.

[10]  Florian Buettner,et al.  The sufficient minimal set of miRNA seed types , 2011, Bioinform..

[11]  John Novembre,et al.  Spatial patterns of variation due to natural selection in humans , 2009, Nature Reviews Genetics.

[12]  Life Technologies,et al.  A map of human genome variation from population-scale sequencing , 2011 .

[13]  Greg Gibson,et al.  Rare and common variants: twenty arguments , 2012, Nature Reviews Genetics.

[14]  N. Rajewsky,et al.  Natural selection on human microRNA binding sites inferred from SNP data , 2006, Nature Genetics.

[15]  John J Rossi,et al.  SNPs in human miRNA genes affect biogenesis and function. , 2009, RNA.

[16]  C. Pipper,et al.  [''R"--project for statistical computing]. , 2008, Ugeskrift for laeger.

[17]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[18]  L. Lim,et al.  Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression , 2007, Molecular and Cellular Biology.

[19]  Ewa Deelman,et al.  New tools and methods for direct programmatic access to the dbSNP relational database , 2010, Nucleic Acids Res..

[20]  P. Visscher,et al.  Human population dispersal "Out of Africa" estimated from linkage disequilibrium and allele frequencies of SNPs. , 2011, Genome research.

[21]  Sarah A Tishkoff,et al.  Patterns of human genetic diversity: implications for human evolutionary history and disease. , 2003, Annual review of genomics and human genetics.

[22]  S. Nelson,et al.  BFAST: An Alignment Tool for Large Scale Genome Resequencing , 2009, PloS one.

[23]  C. Croce.  Causes and consequences of microRNA dysregulation in cancer , 2009, Nature Reviews Genetics.

[24]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[25]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[26]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[27]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[28]  D. MacArthur,et al.  Loss-of-function variants in the genomes of healthy humans. , 2010, Human molecular genetics.

[29]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[30]  Wen-Hsiung Li,et al.  Human polymorphism at microRNAs and microRNA target sites , 2007, Proceedings of the National Academy of Sciences.

[31]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[32]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[33]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[34]  J. Stephenson.  1000 Genomes Project , 2008 .

[35]  B. Mittal,et al.  Common genetic variants in pre-microRNAs and risk of gallbladder cancer in North Indian population , 2010, Journal of Human Genetics.

[36]  Q. Cui,et al.  An Analysis of Human MicroRNA and Disease Associations , 2008, PloS one.

[37]  Andreas Kowarsch,et al.  PhenomiR: microRNAs in human diseases and biological processes. , 2012, Methods in molecular biology.

[38]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[39]  V. Kim.  MicroRNA biogenesis: coordinated cropping and dicing , 2005, Nature Reviews Molecular Cell Biology.

[40]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[41]  J. Shendure,et al.  Exome sequencing as a tool for Mendelian disease gene discovery , 2011, Nature Reviews Genetics.

[42]  Kaleb M. Pauley,et al.  MicroRNA in autoimmunity and autoimmune diseases. , 2009, Journal of autoimmunity.

[43]  M. Korpal,et al.  The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2* , 2008, Journal of Biological Chemistry.

[44]  Hongbing Shen,et al.  Common genetic variants in pre‐microRNAs were associated with increased risk of breast cancer in Chinese women , 2009, Human mutation.

[45]  H. Horvitz,et al.  The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. , 2005, Developmental cell.

[46]  S. Hébert,et al.  Alterations of the microRNA network cause neurodegenerative disease , 2009, Trends in Neurosciences.

[47]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[48]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..