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1、Genome-wide identification of orthologs of miR-1302 genes in placental mammals Zhidong Yuan State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China School of Life Science, Hunan University of Science and Technology, Xiao Sun
2、State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China (Corresponding Author) Xiangtan, China AbstractMicroRNAs (miRNAs) are small noncoding RNAs which regulate gene expression. In this research, we used the Multiz alignmen
3、ts data of 44 Vertebrates to retrieve syntenic homolog sequences. And we identified 37 members of miR-1302 family among 71 potential homolog sequences. Then we analyzed the 37 homologs of hsa-mir-1302s by RepeatMasker and found all of these sequences are derived from MER53 elements. Also we show our
4、 method is a good way to acquire the orthologs. Keywords- miRNA; MER53;orthologs; miR-1302 I. INTRODUCTION MicroRNAs (miRNAs) are short (22-nucleotides, nt) small noncoding RNAs 1. Mature miRNAs result from the cleavage of precursors of miRNA (pre-miRNAs). MiRNAs bind partly or completely complement
5、ary sequences in mRNAs, targeting them for degradation and/or inhibiting translation to regulate gene expression. They regulate various developmental and physiological processes 2, 3 and play important roles in many diseases 4, 5. Recently, many miRNAs derived from repetitive elements have been iden
6、tified 6-10. The transposable elements are found not only could evolve new miRNAs8, but also could promote the expansion of miRNA family and miRNA clusters 7, 11. The MER53 elements are a type of DNA transposable elements, which characterized by the presence of terminal inverted repeats and TA targe
7、t site duplications and could form palindromic structure 12. MER53 elements are found in eutheria species (placental mammals) with 193-bp length consensus sequence 12. So if the MER53 elements integrate into genome and transcribe into RNAs, they maybe processed into miRNAs. The miR-1302 family, whic
8、h first be discovered by experiment method in human genome 13. In this research, we acquired 71 homolog sequences from Multiz alignments of 44 Vertebrates. And we identified 37 members of miR-1302 family 13 among the 71 potential homolog sequences. Then we analyzed these homologs of hsa-mir-1302s by
9、 RepeatMasker and found all of these sequences are derived from MER53 elements. Finally, we compared the predicted miRNA sequences with the pre-miR-1302 sequences of chimpanzee and horse that recorded in miRBase 14.0. The compared results show the sequences produced by our method are more accurate t
10、han the sequences acquired only by BLAST search. II. MATERIALS AND METHODS A. Genome wide prediction of MER53-derived miRNAs in 44 species The sequences of the homologs of the eight members of hsa-mir-1302 family in different organisms have been retrieved from the Multiz alignments of 44 vertebrate
11、species 14 after Blat with each human pre-miR-1302 through the University of California Santa Cruz (UCSC) Genome Browser 15. To determine these sequences whether they are miRNAs, we used microPred 16 and MiPred 17 program to compute. We took one sequence as a miRNA precursor only if it has been both
12、 predicted as a miRNA precursor by the two programs. Then these homologs of hsa-mir-1302 were computed by RepeatMasker 18 to further confirm whether these sequences are derived from MER53 elements. Only one pre-miRNA sequence has been covered at least 50% repetitive element and/or mature miRNA seque
13、nce has been covered 100% repetitive element, the miRNA will be considered as repeat-derived miRNA 10. B. Check known miR-1302 members in miRBase 14.0 We compared our results with the miR-1302 members in horse 19 and chimpanzee 20 genome that recorded in miRBase 14.0. We used ClustalX 21 to find the
14、 sequence differences and used MEGA 22-24 program to classify these homologs. III. RESULTS A. The orthologs of hsa-miR-1302 in placental mammals The Multiz alignments data have used synteny filters to ensure that only orthologous conserved elements were considered in whole-genome alignment 25. So we
15、 could use these data to find homologs of miR-1302 gene beside human This work is supported by the National Natural ScienceFoundation of China (Project No. 60671018). 978-1-4244-4713-8/10/$25.00 2010 IEEEgenome. Fortunately, among the 71 potential homologs of hsa-mir-1302 in the 44 species, we have
16、identified the 37 sequences are real orthologs of miR-1302 genes that from 15 placental mammals. The 15 placental mammals include chimpanzee (panTro2, ptr), gorilla (ggo), orangutan (ponAbe2, ppy), rhesus (rheMac2, mml), marmoset (calJac1,cja), tarsier (tsy), mouse lemur (mmr), bushbaby (oga), tree
17、shrew (tbe), guinea pig (cavPor3, cpo), cow (bosTau4, bta), horse (equCab2, eca), elephant (laf), rock hyrax (pca) and sloth (cho). The genome locations (the genomes have been completely sequenced) are: bta-mir-1302-1 (chr17_64804303-64804446_+), bta-mir-1302-2 (chr5_113887806-113887958_+), bta-mir-
18、1302-6 (chr4_27889431-27889502_-), cja-mir-1302-1 (contig471_681564-681705_+), cja-mir-1302-2 (contig11097_45387-45524_+), cja-mir-1302-4 (contig194_788058-788207_-), cja-mir-1302-6 (contig379_58810-58899_+), cja-mir-1302-7 (contig7680_7431-7500_-), cja-mir-1302-8 (contig67_732720-732850_-), cpo-mir
19、-1302-1 (scaffold_115_3780013-3780155_-), eca-mir-1302-1 (chr8_19720304-19720445_+), eca-mir-1302-2 (chr6_30590496-30590646_-), ptr-mir-1302-1 (chr12_114060674-114060816_-), ptr-mir-1302-2 (chrUn_1512127-1512264_-), ptr-mir-1302-4 (chr2b_212856670-212856818_-), ptr-mir-1302-6 (chr7_18299715-18299804
20、_-), ptr-mir-1302-7 (chr8_141630266-141630337_-), ptr-mir-1302-8 (chr9_96558860-96558987_-), ppy-mir-1302-2 (chr2b_21154807-21154944_+), ppy-mir-1302-4 (chr2b_98768701-98768850_-), ppy-mir-1302-6 (chr7_66504483-66504572_+), ppy-mir-1302-7 (chr8_150103359-150103431_-), ppy-mir-1302-8 (chr9_93124282-9
21、3124409_-), mml-mir-1302-2 (chr11_10197-10333_+), mml-mir-1302-4 (chr12_71164776-71164925_-), mml-mir-1302-7 (chr8_144301426-144301496_-). And the other 11 miRNA gene sequences which have not been showed here are their genomes havent been completely sequenced and these data are available upon reques
22、t. B. The members of miR-1302 family are derived from MER53 elements All these sequences are MER53-derived miRNAs that validated by RepeatMasker 18. Many of them completely locate in MER53 elements, such as has-mir-1302s, there are 7 has-mir-1302s completely locate in MER53 elements. As we already k
23、now that MER53 elements exist in eutheria species 26, while marsupials and monotremes diverged from Figure 1. Analysis of sequence differences and classifications of homologs of hsa-mir-1302 in chimpanzee . All that begin with abbreviated 3 words -“ptr”, like “ptr-mir-1302-1” are from miRBase 14.0,
24、others that begin with “panTro2” are from our results. A C panTro2-mir-1302-7 ptr-mir-1302-7 hsa-mir-1302-7 panTro2-mir-1302-4 hsa-mir-1302-4 hsa-mir-1302-5 panTro2-mir-1302-1 ptr-mir-1302-1 hsa-mir-1302-1 hsa-mir-1302-8 panTro2-mir-1302-8 ptr-mir-1302-8 ptr-mir-1302-5 ptr-mir-1302-3 ptr-mir-1302-2
25、panTro2-mir-1302-2 hsa-mir-1302-3 ptr-mir-1302-4 hsa-mir-1302-2 ptr-mir-1302-6 panTro2-mir-1302-6 hsa-mir-1302-635100359913651365997499936361324834100 Beutherian mammals 180 and 210 million years ago, respectively 27. So MER53 elements and MER53-derived miRNA genes emerged after marsupials and monot
26、remes. C. Check and correction to members of miR-1302 family identified by in silico method Apart from the human miR-1302 13, their homologs of miR-1302 members were also found in horse and chimpanzee based homology searching method 19, 20. So we compared our results with the records of the known me
27、mbers of miR-1302 family in miRBase 14.0. Among the 37 real homologs, 6 chimpanzee precursors of miR-1302 have been validated in our work. But there are already have 8 chimpanzee pre-mir-1302s identified by computational method recently and have been recorded in miRBase 14.0 20. We found all ptr-mir
28、-1302 members in miRBase 14.0 have lost one base at the 3 terminal or 5 terminal (Figure 1 A, B). We think these data had been forgotten subtracting one to each start coordinate because the internal database representations of coordinates always have a zero-based start in UCSC Genome Browser. The fo
29、ur copies of hsa-mir-1302-2 and the hsa-mir-1302-3 are duplicates in human genome and only the same homolog locates at chrUn: 1512127-1512264 (strand: -) in current chimpanzee genome sequence. Because we use Multiz alignment data which used synteny filters 25, so we havent found ptr-mir-1302-3 and m
30、ore copies of ptr-mir-1302-2 in chimpanzee genome by this method. We think the ptr-mir-1302-4 in miRBase 14.0 is more similar to hsa-mir-1302-3 than hsa-mir-1302-4, so it should be ptr-mir-1302-3. Moreover the ptr-mir-1302-3 in miRBase 14.0 has lost a base at 5 terminus (Figure 1 A, B, C). And ptr-m
31、ir-1302-5 in miRBase 14.0 is more similar to hsa-mir-1302-2 and hsa-mir-1302-3 but not similar to hsa-mir-1302-5, and it may better change to ptr-mir-1302-2b, while ptr-mir-1302-2 in miRBase 14.0 could be ptr-mir-1302-2a after add one “A” at the 3 terminal (Figure 1 B, C). So our predicted ptr-mir-1
32、302-4 is the true one. The corresponding syntenic region of human chr20:48664206-48664933 (strand: +) which includes hsa-mir-1302-5 is a gap (chr20:48091211-48092424, Strand: +) in the current genome sequence of chimpanzee (Mar.2006/panTro2). So we havent found the ortholog of hsa-mir-1302-5. There
33、are also have 6 horse precursors of miR-1302 in miRBase 14.0 (identified by homologous search recently, based BLAST search) 19 while we have identified 2 homologs of hsa-mir-1302-1 and one homolog of hsa-mir-1302-2 in horse genome, their sequences also different with the correspondences in miRBase 1
34、4.0 (Figure 2 A, B), the other syntenic sequences of has-mir-1302 havent been predicted as miRNA precursors. But we think our sequences are more credible than the correspondences in miRBase 14.0, for our method is based on syntenic homology by use the Multiz alignment data and both predicted as pre-
35、miRNA by microPred 16 and MiPred 17 program. IV. DISCUSSION MiR-1302 family is a newly discovered miRNA family 13 in human genome. So we retrieved syntenic homolog sequences of has-mir-1302 from Multiz data and identified 37 members of miR-1302 family. In recent years, many miRNAs that derived from
36、repetitive elements have been identified 6-10. We also found miR-1302 family originated from MER53 elements. MER53 element is a type non-autonomous DNA transposon and it could form palindromic structure 12. If MER53 elements integrated in active transcription regions of genome and fixed by natural s
37、election, it may be transcribed and processed into miRNAs. Figure 2. Sequence alignments of homologs of hsa-mir-1302 in horse genome. All that begin with abbreviated 3 words -“eca”, like “eca-mir-1302-1” are from miRBase 14.0, others that begin with “equCab2” are from our results. Because MER53 elem
38、ents exist in eutheria species, that are placental mammals, so the 37 orthologs of hsa-mir-1302 were only found in 15 placental mammals from the 44-species Multiz 14 data. As the Multiz alignments data have used synteny filters to ensure that only orthologous conserved elements were considered in wh
39、ole-genome alignment 25, we think our method can be used to search orthologs of miRNAs and the homologs of hsa-mir-1302 in chimpanzee and horse that recorded in miRBase 14.0 are need to revised. And from our view, combining MULTIZ genome alignments with BLAST search is a robust method to find paralo
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