MiRNA Identification And Its Dysregulation In Complex Diseases

Complicated diseases are caused by genetic,environmental and lifestyle factors,and the complicated pathogenic mechanisms of complex diseases make the prediction of generic risk,diagnosis,treatment and prognosis a tough work.Complex diseases are usually aberrant responses to physiologic and pathophysiologic stresses,thus the biological components which could affect cellular behaviors have a natural relation with the diseases.miRNAs are important regulators which regulate major cellular behaviors,therefore the dysregulation of miRNAs is the invisible hand which cause the occurrence and progression of complex diseases.This dissertation studies the identification of miRNAs from numerous short biological sequences and explores the dysregulation of miRNAs in complex diseases.The main contribution of the dissertation is outlined as below:1.A discovery approach of the sequence patterns of mature miRNAs is proposed and the pattern-extraction criteria is suggested.The sequence patterns of mature miRNAs are difficult to be discovered due to their short sequence and a variety of isoforms,a sequence pattern discovery approach based on sequence alignment is proposed to extract the sequence patterns from short mature miRNAs.The approach extracts the common bases from mature miRNA sequences as sequence patterns,and suggests the criteria of sequence patterns by comparing the classification performance of extracted patterns on true and fake mature miRNAs.The analysis of the distribution and classification performance of extracted sequence patterns on the mature miRNAs of Drosophila melanogaster,Mus musculus and Homo sapiens supports that the extracted sequence patterns imply conservative information of miRNAs.2.A novel miRNA identification approach,mir PD,is proposed,and the approach is efficient and has similar sensitivity and specificity as other popular identification methods.The new generation of sequencing technology produces many reads which share similar biological features with miRNAs,thus high false positive is inevitable if applying only biological features of miRNAs on filtering miRNAs from reads.Moreover,mapping the enormous reads to the genomes is time-consuming.mir PD employs two-stage filtration which includes pattern filtration and biological feature filtration to meet the two main challenges in identifying miRNAs from the reads: high false positive of biological feature filtration and low efficiency of reads-mapping.All the reads which passed both the stages of filtration are identified miRNAs.Compared with the popular miRNA identification method,mi RDeep,mir PD has similar specificity,accuracy,sensitivity and precision,but mir PD beats mi RDeep with less computation burden.3.A method for identifying the causal SNPs from associated miRNA sequences is developed,and it can identify the causal SNPs without case and control samples.A SNP in a miRNA sequence could cause a disease if it inhabits the maturation of the miRNA or disturbs the interaction between the miRNA and its target mRNAs.According to the influence of the secondary structure of a miRNA on its maturity and the effect of the base complementary of a miRNA and its target mRNAs on miRNA regulation,a miRNA sequence could be segmented.Free energy is then employed to evaluate the destructive effect of a SNP on the structure stability of each segment.A SNP,thus,could be putatively causal one if a significant free energy change could be observed by the addition of a SNP.This method is applied on the miRNAs associated with schizophrenia,and identified 6reported SNPs which could cause the disease.4.A method to identify the dysfunctional miRNA mediated regulation modules is developed and it is not only applied to identify dysregulation miRNA modules but also to identify dysregulated mRNAs.Multiple miRNAs could regulate a gene and the expression of the gene could remain unchanged if the regulation of the miRNAs offset.The genes could be neglected in the researches associated because their expression stays the same even if they undergo dramatic miRNA regulation alteration,but the significant alteration of miRNA mediated regulation deserves to be investigated.Moreover,functional changes often appear in complicated diseases,and the study of the association of miRNA dysregulation is a novel direction on the mechanics of complex diseases.In this method,the regulation coefficient of a miRNA and a target gene is first computed based on the miRNA and mRNA expression profiles by linear regression,and the modules whose regulation coefficients are significantly different between case and control samples are then identified as dysfunctional miRNA mediated regulation modules.The method is applied on the miRNA and mRNA expression profiles of Chromophobe renal cell carcinoma and identifies 70 dysfunctional miRNA mediated regulation modules from 11919 ones.In addition,the method also identifies 148 differentially regulated mRNAs by miRNAs.