The sequence structures of human microRNA molecules and their implications

Abstract

The count of the nucleotides in a cloned, short genomic sequence has become an important criterion to annotate such a sequence as a miRNA molecule. While the majority of human mature miRNA sequences consist of 22 nucleotides, there exists discrepancy in the characteristic lengths of the miRNA sequences. There is also a lack of systematic studies on such length distribution and on the biological factors that are related to or may affect this length. In this paper, we intend to fill this gap by investigating the sequence structure of human miRNA molecules using statistics tools. We demonstrate that the traditional discrete probability distributions do not model the length distribution of the human mature miRNAs well, and we obtain the statistical distribution model with a decent fit. We observe that the four nucleotide bases in a miRNA sequence are not randomly distributed, implying that possible structural patterns such as dinucleotide (trinucleotide or higher order) may exist. Furthermore, we study the relationships of this length distribution to multiple important factors such as evolutionary conservation, tumorigenesis, the length of precursor loop structures, and the number of predicted targets. The association between the miRNA sequence length and the distributions of target site counts in corresponding predicted genes is also presented. This study results in several novel findings worthy of further investigation that include: (1) rapid evolution introduces variation to the miRNA sequence length distribution; (2) miRNAs with extreme sequence lengths are unlikely to be cancer-related; and (3) the miRNA sequence length is positively correlated to the precursor length and the number of predicted target genes.

Figure 1. Biogenesis of mature miRNAs and their functional activity.

Figure 2. Histogram and corresponding Poissonness plot of the sequence lengths (sizes) of human mature miRNA molecules.

Figure 3. Histogram of sequence lengths of human mature miRNA molecules and four fitted models.

Figure 4. The sample proportions of nucleotide bases and GC, AU contents.

Figure 5. Histograms and fitted distributions of the sequence lengths of mature conserved and human – specific miRNAs.

Figure 6. Distributions of the sequence lengths of human pre-miRNAs.

Figure 7. Scatter-plot of the average sequence length of pre-miRNAs versus the sequence length of miRNAs: the red line is the linear regression and the blue curve is the quadratic polynomial regression.

Figure 8. Bar charts of mature miRNAs in the 5′ and 3′ arms of the precursors respectively.

Figure 9. Scatter-plot of the average numbers of predicted target genes versus the mature miRNA sequence length.

Figure 10. Histograms of target site counts of the transcripts predicted by miRNAs with the same sequence lengths.