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Non-randomness distribution of micro-RNAs on human chromosomes
Egyptian Journal of Medical Human Genetics volume 20, Article number: 33 (2019)
Micro-RNA (miRNA) is one of the non-coding RNAs that exist in human genome. miRNAs play an important role in the expression of target genes. Several studies have indicated that organization of human genome is not random. In order to investigate the distribution of miRNAs on human chromosomes, the present study was carried out.
Using the data from miRBase database, we found 1913 loci coding for miRNAs (MIRs). Human chromosome bands 1p36, 1q22, 1q24, 2q13, 2q35, 3p21, 6p21, 7q22, 8p23, 8q24, 9q22, 9q34, 11q12-q13, 12q13, 14q32, 16p13, 16q24, 17p13, 17q11, 17q21, 17q25, 19p13, 19q13, 20q13, 21p11, 22q13, and Xq26-q28 were significantly bearing higher number of MIRs. The 14q32 and 19q13 with 4.11 and 3.59 MIRs per mega-base pair, respectively, were the most MIR-richest human chromosomal bands. The number of MIRs on chromosomal bands significantly decreased as a function of distance from telomere (r = − 0.949, df = 5, P = 0.001).
Our current data suggest that MIRs are not randomly distributed on human genomes.
Multiple non-coding RNAs such as micro-RNAs (miRNAs), small nucleolar RNAs (snoRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exist in human genome [1, 2]. The size of the mature miRNAs is ~ 22 nucleotides in length that is produced by multiple splicing from a ~ 75 nucleotides primary transcribed precursor . The majority of miRNA (MIR) sequences are found in introns of non-coding or coding transcripts although some MIRs are encoded within exons. The main function of MIRs is post-transcriptional gene regulation. It has been suggested that each MIR is predicted to have multiple potential target mRNAs and a single gene can be modulated by several MIRs .
Control of gene expression by MIRs plays an important role in multiple cellular pathways, such as cell proliferation and differentiation, apoptosis, control of cell cycle, migration, invasion, and many tissue-specific functions [1, 4, 5]. Many studies have demonstrated that MIRs play critical roles in cancers [4, 6]. Over-expression of MIR-197 and MIR-346 repressed the expression of their predicted target genes in vitro and in vivo. The MIR-197 and MIR-346 are contributed to carcinogenesis of follicular thyroid carcinomas . MIR495 is among a group of MIRs which is significantly upregulated in breast cancer cell lines . MIR9, MIR125A, and MIR125B are downregulated in primary neuroblastoma tumors .
Numerous studies indicated that organization of human genome is not random. Mutation rates show significant differences among regions of the mammalian genome [10,11,12]. In recent years, it has been shown that susceptible polymorphic genes involved in complex human diseases such as gastric cancer , breast cancer , schizophrenia , Parkinson’s disease, and multiple sclerosis  are not randomly distributed on the chromosomes. Gene-rich bands and oncogenes are not randomly distributed on human chromosomes [17,18,19,20,21,22,23,24,25].
Calin and his colleagues have reported that human MIRs are commonly located at fragile sites and at genomic regions which are involved in cancers . On the other hand, it has been shown that fragile sites and oncogenes are non-randomly located in light G bands of the human chromosomes ; similarly, human oncogenes show a specific chromosome territory . Oncogenes are mainly located in telomeric regions . Taken together, we suggested that MIR loci may be distributed non-randomly on the human chromosomes. Considering that to date the chromosomal distribution of MIRs in humans has not been investigated, the present study was carried out.
Based on the tools4mir.org, there are numerous databases concerning MIRs. These databases have different citations. Among these databases, TargetScans, MicroCosm Targets, and miRBase have 4440, 1753, and 1664 citations, respectively. Other databases have less than 500 citations. Data from TargetScans database was not available for download. The MicroCosm Target database contains computationally predicted targets of MIRs while the miRBase is a searchable database of published MIR sequences. Therefore, we chose the miRBase database for the present study.
Chromosomal distribution of loci encoding for MIRs was extracted from miRBase database (http://www.mirbase. org/). For evaluation of the non-random chromosomal distribution of MIRs, expected values for numbers of MIRs were estimated using relative lengths of each chromosome and then the differences between observed and expected values were evaluated by chi-square test. Spearman’s correlation coefficient was used to investigate the association between the number of MIRs and distance from the telomere.
In order to investigate the non-random distribution of MIRs on each chromosomal band(s), the statistical method of Tai et al. was used . The relative width of each band was measured using the International System for Chromosome Nomenclature based on 400 bands. The P < 0.001 was considered statistically significant.
Using the miRBase database, there were 1913 loci for MIRs in human genome (Additional file 1: Table S1). There was a significant difference between the number of MIRs which is assigned to each chromosome and expected values based on their relative lengths (χ2 = 501, df = 22, P < 0.001). Chromosomes 14, 16, 17, 19, 22, and X have higher number and chromosomes 3, 4, 5, 6, 13, and 18 have lower number of MIR loci than the expected values.
In the next step, we determine which chromosomal bands bear higher number of MIRs. Figure 1 shows the distribution of these loci on human chromosomes. Table 1 shows the number of MIRs and relative length of selected chromosomal bands, as well as the calculated F statistics and its degrees of freedom (df). All of the comparisons were statistically significant (P < 0.001). The bands 1p36, 1q22, 1q24, 2q13, 2q35, 3p21, 6p21, 7q22, 8p23, 8q24, 9q22, 9q34, 11q12-q13, 12q13, 14q32, 16p13, 16q24, 17p13, 17q11, 17q21, 17q25, 19p13, 19q13, 20q13, 21p11, 22q13, and Xq26-q28 were MIR-rich regions. The 14q32 and 19q13 with 4.11 and 3.59 MIRs per mega-base pair (Mbp), respectively, were the most MIR-richest human chromosomal bands.
There was a significant negative association between the number of MIRs and their distance from telomere (Fig. 2). This means that majority of MIRs are located near the telomeres of the chromosomes. We know that p and q arms of the human chromosomes have different lengths; therefore, the abovementioned association might be a quasi-association. In order to address this point, we analyzed the MIR distribution from telomere to position 21 Mbp. Although these regions account for approximately 30% of the human genome, 45.1% of the MIRs were located within 21 Mbp from telomeres. Number of MIRs located within 0–3, 3–6, 6–9, 9–12, 12–15, 15–18, and 18–21 Mbp regions, were 189, 167, 150, 93, 115, 77, and 72, respectively. Statistical analysis revealed that there was a very strong negative correlation between distance from telomeres and number of MIRs (r = − 0.949, df = 5, P = 0.001).
In the first step of the present study, we found that some human chromosomes (14, 16, 17, 19, 22, and X) are bearing higher and some other chromosomes (3, 4, 5, 6, 13, and 18) are bearing lower numbers of MIRs. Similar findings regarding the number of functional genes in human chromosomes have been reported previously. Chromosomes 1, 11, 12, 16, 17, 19, 20, and 22 have higher number of active genes . Human chromosome 19 has the highest MIR density in comparison with the other human chromosomes. It should be noted that several studies have indicated that human chromosome 19 has some unusual characteristics compared to other human chromosomes including the highest gene density [25, 28, 29], high expression levels , and high density of minisatellites .
Based on human chromosomal distribution of 186 MIRs, it has been reported that the majority of MIRs are located in cancer-associated genomic regions or at fragile sites, indicating the non-random distribution of MIRs . In the present study, we investigated the distribution of large numbers of MIRs (1913 loci) at cytogenetic level and we found that MIRs were distributed in a non-random way on human chromosomes, which is consistent with the results of Calin and his colleagues . In the present study and in the study of Calin and his colleagues, 1913 and 198 MIR loci were studied, respectively. It is self-evident that by increasing the number of MIR loci, the statistical power of the comparison will increase too.
It has been reported that MIR clusters are located on some human chromosomes, such as human chromosomes 14 and 19 . It is well established that physically adjacent MIRs are exclusively or preferentially expressed in a tissue-specific manner [33, 34]. For example, the MIR clusters of chromosomes 14 and 19 are expressed in the human placenta [34,35,36,37]. The chromosome 19 MIR cluster is exclusively found in primates while the MIR located on human chromosome 14 appears to be conserved among eutherian species .
Our study furthermore demonstrated as evidence for non-random distribution of genetic materials across the human chromosomes. It should be noted that chromosome 19q13 is bearing polymorphic genes associated with the risk of breast  and gastric cancers , as well as late-onset Alzheimer’s disease  and multiple sclerosis .
As mentioned in the “Results” section, there is a very strong negative correlation between distance from telomeres and the number of MIRs. This means that the number of MIRs significantly decreased as a function of distance from telomere. This is a novel finding about chromosomal distribution of MIRs in human genomes, which has not been reported previously. However, similar distribution was reported for oncogenes on human chromosomes [18, 19].
Accordingly, our present data suggest that MIRs are not randomly distributed on human genome. Considering that MIRs are involved in the regulation of target genes, and the chromosome segments bearing a greater number of MIRs have been associated with several human complex diseases, further studies are needed to explain the biological significance of the non-random distribution of MIRs on human chromosomes. Attempts to confirm non-random distribution of functional genes on human genome/chromosomes may lead to new direction in etiology of human multifactorial traits and after that may lead to development of a novel tool for mass screening of complex diseases.
In the present study, we investigated the chromosomal distribution of 1913 loci coding for MIRs. Results indicated that some segments of human chromosomes are bearing higher numbers of MIRs. The 14q32 and 19q13 were the MIR-richest human chromosomal bands. The number of MIRs on chromosomal bands significantly decreased as a function of distance from telomere.
Availability of data and materials
The dataset analyzed during the current study is presented as a supplement file.
Degree of freedom
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This study was supported by Shiraz University.
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Boroumand, F., Saadat, I. & Saadat, M. Non-randomness distribution of micro-RNAs on human chromosomes. Egypt J Med Hum Genet 20, 33 (2019). https://doi.org/10.1186/s43042-019-0041-2