International Journal of Computational Bioinformatics and In Silico Modeling Vol. 4, No. 5 (2015): 724-734 Research Article Open Access
ISSN: 2320-0634
In silico analysis of non-synonymous Single nucleotide polymorphisms of BMBR2 (PPH1) gene and demonstration of gene’s network interactions Mohamed A. Taha1*, Sundos Ahmed1, Radowan Elnair1, Enas Basher1, Amro Abdelghani1, Abdel-moneim Mohamed Ali1, Mohamed D. Dafaalla1, Musaab M. alfaki1, Mohamed A. Abdelrahim1, Abdelmohaymin A. Abdalla1, Musab I. Mohammed1, Mohamed Elsheikh1, Abbasher Hussein1,2 and Mohamed Hassan1,3,4 Daoud research group. Faculty of medicine, University of Khartoum. 3 Africa city of technology, applied bioinformatics, Khartoum. 3 University of Tubingen, Division of Molecular Genetics, Institute of Human Genetics, Tubingen. 1 2
*Corresponding author: Mohamed A. Taha; email:
[email protected] Received: 14 August 2015
Accepted: 20 September 2015
Online: 01 October 2015
ABSTRACT Mutations in BMPR2 gene are seen in about 15% of sporadic cases and about 40% of familial cases of PPH. We have studied non-synonymous SNPs in BMPR2-002 (ENST00000374574). Non-synonymous dsSNPs were identified using NCBI-database. Then advanced bioinformatics analysis was used to determine the functionality of each SNP in the coding region. Out of 323 SNPs which were found in the coding region, only 7 were found to be damaging in both SIFT and polyphen. 53 SNPs in 3UTR region were found to disrupt miRNA binding sites, whereas 55 SNPs were found to create new ones. Certain SNPs affect binding sites of certain MicroRNAs that have been linked to hepatic cancer and prostate cancer. BMPR2 gene interactions with other genes were identified and classified according to multiple parameters (physical interaction, co-localization, co-expression, pathway and prediction). BMPR2 is an important regulator in BMP pathway which affects cellular growth. Certain SNPs were found to affect BMPR2 structure hence function for better correlation with clinical cases.
Keywords: Primary pulmonary hypertension gene; PPH1; BMPR2; in silico analysis; computational analysis; SNPs.
1. INTRODUCTION
BMPR2 is a gene with a protein product, located in chromosome 2q33-q34. Bone morphogenetic protein receptor 2 is a serine/threonine kinase that plays a role in cellular growth and differentiation through phosphorylation and recruitment of BMPR1 receptor which phosphorylates SMAD transcription factors leading to gene regulation in nucleus (figure1). Bone morphogenetic proteins are the ligands for BMPR2. BMP are members of transforming growth factor growth factors superfamily. BMPs regulates cellular growth and differentiation of different cell types and http://bioinfo.aizeonpublishers.net/content/2015/5/bioinfo724-734.pdf
plays a regulatory role in osteogenesis as well (Figure2). BMPR2 has, as well, a role in cytokinecytokine interactions. It was found that certain mutations in BMPR2 gene are linked to development of primary pulmonary hypertension. 15% of sporadic and about 40% of familial cases of PPH were found to carry mutations in BMBR2. It was hypothesized that, in addition to the involvement in other complex signaling pathways, loss of function mutations lead to increased apoptosis of Endothelial Cells lining the vasculature of the lung 724
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leading to unregulated smooth muscle cell growth. However, the pathogenesis of PPH remains incompletely understood [1].
penetrance, and/or, involvement of other complex pathways should be present at the same time to have the disease [2].
Although heterozygous germline mutations in BMPR2 are required for the development of PPH, they are not sufficient for the development of the phenotype of the disease. About 90% of carriers of BMPR2 mutations show normal phenotype, hence indicating incomplete
BMPR2 associated mutations linked with PPH were identified to be either frame-shift, missense or nonsense mutations [3], BMPR2 gross gene arrangement constitutes a new cause for primary pulmonary hypertension [4].
Figure 1. BMP signaling and its regulation. Made by : Radowan Elnair. Type I and II BMP receptors mediate BMP signals by their downstream mlecules Smad1,5 and 8. When phosphorylated, Smad1, 5 and 8 proteins form a complex with Smad4 and are then translocated into the nucleus where they interact with other transcription factors. BMP signaling is regulated at different molecular levels: Noggin and other cystine knot-containing BMP antagonists bind with BMP-2, 4 and 7 and block BMP signaling 2) Smad6 binds type I BMP receptor and prevents Smad1, 5 and 8 to be activated 3) Tob interacts specifically with BMP activated Smad proteins and inhibits BMP signaling 4) Smurf1 is a Hect domain E3 ubiquitin ligase 5) Smurf1 also recognizes bone-specific transcription factor Runx2 and mediates Runx2 degradation 6) Smurf1 also forms a complex with Smad6, is exported from the nucleus and targeted to the type I BMP receptors for their degradation (Di Chen et al, 2004).
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Figure 2: TGF-Beta signaling Pathway. Taken from polyphen-2 webpage.
2. MATERIALS AND METHODS
Many SNPs were identified to be related to either sporadic or familial PPH. Our objectives are to identify deleterious SNPs in coding region and their structural and functional effects on BMPR2 protein and then to identify 3UTR SNPs in BMPR2 gene, and finally to describe gene interactions with BMPR2 and related genes in BMP pathway. 2.1 NCBI Database: SNPs of the BMPR2 gene were collected from the NCBI dbSNP database. Firstly, we selected SNPs that were non-synonymous in the coding region of BMPR2 gene model (NM_001204.6). Also, we selected SNPs in 3UTR region to determine changes in binding sites for MiRNAs associated with BMPR2 mRNA. We used The National Center for Biotechnology Information database for selection. http://www.ncbi.nlm.nih.gov/snp/?term=BMPR2 2.2 SIFT: SIFT-software was used to check for the effect of each of the mutations (SNP) on the protein (damaging or not). SIFT assigns scores (SIFT score) to each residue ranging from zero to one. Scores close to zero indicate intolerance to substitution, while scores close to one indicate tolerance to substitution only. Damaging http://bioinfo.aizeonpublishers.net/content/2015/5/bioinfo724-734.pdf
mutations were then submitted via Polyphen-2 program to confirm the damaging nature and to predict the structural and functional consequences of each mutation. http://siftdna.org/www/SIFT_dbSNP.html 2.3 PolyPhen-2: This program was used to predict the structural and functional impact an amino acid change would have on the protein by searching in several protein structure databases for 3D protein structures, multiple alignments of homologous sequences and amino acid contact information. The program also calculates position-specific independent count scores (PSIC) for each of two variants, and then calculates the PSIC scores difference between two variants (ranging between 0-1). The higher a PSIC score difference, the higher the functional impact a particular amino acid substitution is likely to have, with values closer to zero considered benign and those closer to one considered probably damaging. Each SNP was entered manually using Transcript ID (ENST00000374574), amino acid position then amino acid change. http://genetics.bwh.harvard.edu/pph2/
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2.4 POLYMIRTS: All SNPs located within the 3′-UTRs of database were selected separately and submitted to this program, which was designed specifically for the analysis of the 3’UTR region, this allowed for determination of SNPs that may alter miRNA target sites. 2.5 Project hope: An online web-server that searches protein 3D structures by collecting structural information from a series of sources. The sequence and mutation only for those mutations predicted to be damaging by both SIFT and Polyphen (Double Positive) servers was submitted through Project hope in order to analyze the structural and conformational variations that have resulted from single amino acid substitution corresponding to single nucleotide substitution. Three dimensional proteins’
structures were successfully designed by project hope server. http://www.cmbi.ru.nl/hope/input 2.6 GeneMANIA: GeneMANIA finds other genes that are related to a set of input genes submitted through this web interface. It works by generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Using available genomics and proteomics data, GeneMANIA extends the list with functionally similar genes that it identifies using a very large set of functional association data, including protein and genetic interactions, pathways, coexpression, co-localization and protein domain similarity. http://www.genemania.org/
Table 1: Prediction of nsSNPs by SIFT and Polyphen-2. SNP ID
Chromosome Location rs2229778 202552783 rs143740797 202518937 rs148682262 202518874 rs200339485 202518909 rs368027047 202518970 rs369545039 202520117 rs374694591 202518997 *AA1: Wild amino acid. *AA2: Mutant amino acid
allele change C/T T/A G/A C/T T/C A/C G/C
Amino acid position 494 246 225 237 257 295 266
AA1*
AA2**
A I R R I T R
V N H C T P T
3. RESULTS AND DISCUSSION
311 missense, 9 non-sense and 3 frame shift SNPs were found in BMPR2 in NCBI SNP database. 3.1 Predictions by SIFT and Polyphen-2: Out of 323 SNPs, only 7 were found to be damaging by both SIFT and polyphen-2 (double positive). 5 were probably damaging by polyphen-2 prediction. Polyhen2 score for each SNP ranging from 1.0 to 0.94, and from 0.004 to 0.02 in sift score. (Table 1)
Polyphen prediction Probably damaging Probably damaging Possibly damaging Possibly damaging Probably damaging Probably damaging Probably damaging
Polyphen score 1 1 0.945 0.952 0.998 0.969 0.993
SIFT score 0.004 0.005 0.025 0.002 0.004 0.027 0.01
SIFT prediction DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
residue was buried in the core of the protein. The mutant residue is bigger and probably will not fit. The wild-type residue is very conserved, Based on conservation scores this mutation is probably damaging to the protein. (Figure 3)
Figure 4: SNP ID: rs143740797 leads to conversion of Isoleucine into Asparagine at position 246 (I246N).
Figure 3: SNP ID: rs2229778 leads to conversion of Alanine into Valine at position 494(A494V).
3.2 Description of structural and functional Amino acid substitution on BMPR2 protein using project hope: C/T mutation (rs2229778) leads to conversion of Alanine into Valine at position 494(A494V), the mutant residue is bigger than the wild-type; the wild-type http://bioinfo.aizeonpublishers.net/content/2015/5/bioinfo724-734.pdf
T/A mutation (rs143740797) caused conversion of Isoleucine into Asparagine at position 246 (I246N), The mutant residue is bigger and less hydrophobic than the wild-type residue. The wild-type residue was buried in the core of the protein. The mutant residue is bigger and probably will not fit. The mutation will cause loss of hydrophobic interactions in the core of the protein. The wild-type residue is very conserved, but a few other residue types have been observed at this position too. Neither your mutant residue nor another residue type with similar properties was observed at this 727
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position in other homologous sequences. Based on conservation scores this mutation is probably damaging to the protein. (Figure 4)
Figure 5: SNP ID: rs148682262) leads to conversion of Alanine into a Histidine at position 225 (A225H).
G/A mutation (rs148682262) caused conversion of Alanine into a Histidine at position 225 (A225H),The mutant residue is smaller and neutral while the wildtype residue was positively charged; This can cause loss of interactions with other molecules and a possible loss of external interactions. The wild-type residue is not conserved at this position. (Figure 5)
Figure 6: SNP ID: rs200339485 leads to conversion of Arginine into a Cysteine at position 237 (R237C).
C/T mutation (rs200339485) caused conversion of Arginine into a Cysteine at position 237 (R237C), the mutant residue is smaller and neutral while the wildtype residue was positively charged. The mutant residue is more hydrophobic than the wild-type residue; this can cause loss of interactions with other molecules and a possible loss of external interactions. The wild-type residue is not conserved at this position. (Figure 6)
T/C mutation (rs368027047) caused conversion of Isoleucine into a Threonine at position 257 (I257T), the mutant residue is smaller than the wild-type residue. The wild-type residue is more hydrophobic than the mutant residue; the mutation will cause an empty space in the core of the protein with loss of hydrophobic interactions there. Mutant residue is located near a highly conserved position. (Figure 7) A/C mutation (rs369545039) caused conversion of Threonine into a proline at position 295 (T295P), the mutant residue is more hydrophobic than the wild-type residue; the proline that is introduced by this mutation is a very rigid residue. The mutation might abolish the required flexibility of the protein at this position. The wild-type residue occurs often at this position in the sequence, but other residues have also been observed here. Your mutant residue is among the other residue types that have been observed at this position in homologous sequences. This means that this mutation can occur at this position and is probably not damaging to the protein. The wild-type residue occurs often at this position in the sequence, but other residues have also been observed here. (Figure 8)
Figure 8: SNP ID: rs369545039 leads to conversion of Threonine into a proline at position 295 (T295P).
G/C mutation (rs374694591) caused conversion of Arginine into a Threonine at position 266 (R266T), the mutant residue is smaller and neutral while the wildtype residue was positively charged. The mutant residue is more hydrophobic than the wild-type residue; this will cause a possible loss of external interactions. The wild-type residue is not conserved at this position. Your mutant residue is among the observed residue types at this position in other, homologous sequences. This sometimes suggests that this variant is not damaging for the protein's structure and function, but in this case you have already established that the mutation is deleterious. (Figure 9)
Figure 7: SNP ID: rs368027047 leads to conversion of Isoleucine into a Threonine at position 257 (I257T). Figure 9: SNP ID: rs374694591 leads to conversion of Arginine into a Threonine at position 266 (R266T). http://bioinfo.aizeonpublishers.net/content/2015/5/bioinfo724-734.pdf
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Table 2: SNPs and INDELs in miRNA target sites. dbSNP ID
miR ID
Conservation
rs45502895
hsa-miR-1233-5p hsa-miR-1273h-5p hsa-miR-149-3p hsa-miR-30b-3p hsa-miR-3689a-3p hsa-miR-3689b-3p hsa-miR-3689c hsa-miR-4728-5p hsa-miR-6732-5p hsa-miR-6752-5p hsa-miR-6778-5p hsa-miR-6779-5p hsa-miR-6780a-5p hsa-miR-6785-5p hsa-miR-6799-5p hsa-miR-6842-5p hsa-miR-6883-5p hsa-miR-7106-5p hsa-miR-7110-5p hsa-miR-3179 hsa-miR-3202 hsa-miR-3936 hsa-miR-4747-5p hsa-miR-5196-5p hsa-miR-6782-5p hsa-miR-1909-3p hsa-miR-4684-3p hsa-miR-6132 hsa-miR-6511b-5p hsa-miR-6722-3p hsa-miR-6811-5p hsa-miR-6836-5p hsa-miR-744-3p hsa-miR-5095 hsa-miR-7151-3p hsa-miR-4422 hsa-miR-6835-3p hsa-miR-9-3p hsa-miR-134-3p hsa-miR-3664-5p hsa-miR-618 hsa-miR-7114-5p hsa-miR-200c-5p hsa-miR-4775 hsa-miR-550a-3p hsa-miR-5696 hsa-miR-579-3p hsa-miR-664b-3p hsa-miR-6740-3p hsa-miR-6506-3p hsa-miR-3914 hsa-miR-3927-5p hsa-miR-198 hsa-miR-338-3p hsa-miR-451b hsa-miR-4530 hsa-miR-663b hsa-miR-7108-5p hsa-miR-1252-5p hsa-miR-4312 hsa-miR-4635 hsa-miR-532-5p hsa-miR-6126 hsa-miR-6864-5p hsa-miR-1254 hsa-miR-3116 hsa-miR-3202 hsa-miR-4533 hsa-miR-661 hsa-miR-4426 hsa-miR-4477a hsa-miR-4647 hsa-miR-4662b hsa-miR-3662
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
rs144391987
rs192184184 rs147815007
rs184723247
rs187966248
rs192634289 rs7572177
rs6435156
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Function Class N N N N N N N N N N N N N N N N N N N C C C C C C N N N N N N N N C C N N N N N N N N N N C C C C N C C C C C C N N C C C C C C N N N N N C C C C N
729
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rs35926349
rs35267647 rs149892154
rs113305949
rs189652117
rs181247917
rs115467510
rs35289309
rs184927111 rs189804689
rs17199249
hsa-miR-3606-3p hsa-miR-513a-3p hsa-miR-513c-3p hsa-miR-3153 hsa-miR-4668-5p hsa-miR-5093 hsa-miR-6733-5p hsa-miR-6739-5p hsa-miR-2110 hsa-miR-4271 hsa-miR-4725-3p hsa-miR-6780b-5p hsa-miR-4802-3p hsa-miR-1292-5p hsa-miR-4471 hsa-miR-8059 hsa-miR-587 hsa-miR-3622b-5p hsa-miR-4252 hsa-miR-1256 hsa-miR-4436b-5p hsa-miR-6509-3p hsa-miR-135a-3p hsa-miR-365a-5p hsa-miR-365b-5p hsa-miR-7845-5p hsa-miR-890 hsa-miR-510-3p hsa-miR-3148 hsa-miR-3978 hsa-miR-6124 hsa-miR-4477b hsa-miR-651-3p hsa-miR-3653 hsa-miR-3658 hsa-miR-15a-5p hsa-miR-15b-5p hsa-miR-16-5p hsa-miR-195-5p hsa-miR-424-5p hsa-miR-497-5p hsa-miR-545-3p hsa-miR-6838-5p hsa-miR-4433-3p hsa-miR-4459 hsa-miR-4768-3p hsa-miR-6888-5p hsa-miR-375 hsa-miR-425-3p hsa-miR-6746-5p hsa-miR-6771-5p hsa-miR-3153 hsa-miR-450a-1-3p hsa-miR-4668-5p hsa-miR-6733-5p hsa-miR-6739-5p hsa-miR-2110 hsa-miR-3150a-3p hsa-miR-4271 hsa-miR-450a-2-3p hsa-miR-4725-3p hsa-miR-6763-5p hsa-miR-6780b-5p hsa-miR-6810-5p hsa-miR-6857-5p hsa-miR-4717-3p hsa-miR-5589-3p hsa-miR-589-3p hsa-miR-424-3p hsa-miR-3190-3p hsa-miR-4491 hsa-miR-4657 hsa-miR-4698 hsa-miR-6833-5p hsa-miR-186-5p hsa-miR-3133 hsa-miR-4427 hsa-miR-15b-3p
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0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
C C C O O O O O O O O O O O O O O N N C C C N N N N C N C C C N N C C C C C C C C C C N N N N C C C C O O O O O O O O O O O O O O N N C N C C C C C C C C N
730
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rs144896813
rs149030267
rs186119737 rs77006932 rs67584944 rs190829513
rs13382817
rs56355338 rs143416345 rs181966045 rs185938504
rs112395230
rs141628209
rs146406897
hsa-miR-5187-3p hsa-miR-2355-3p hsa-miR-382-5p hsa-miR-3973 hsa-miR-520g-3p hsa-miR-520h hsa-miR-676-3p hsa-miR-320a hsa-miR-320b hsa-miR-320c hsa-miR-320d hsa-miR-330-3p hsa-miR-4429 hsa-miR-4446-5p hsa-miR-16-2-3p hsa-miR-195-3p hsa-miR-513c-5p hsa-miR-514b-5p hsa-miR-3129-3p hsa-miR-4471 hsa-miR-4475 hsa-miR-5583-5p hsa-miR-6750-5p hsa-miR-6822-5p hsa-miR-6892-5p hsa-miR-8059 hsa-miR-6841-5p hsa-miR-4803 hsa-miR-380-3p hsa-miR-4799-5p hsa-miR-129-5p hsa-miR-192-3p hsa-miR-4776-3p hsa-miR-629-5p hsa-miR-6793-5p hsa-miR-6839-3p hsa-miR-1296-3p hsa-miR-193b-5p hsa-miR-3170 hsa-miR-6742-5p hsa-miR-6855-5p hsa-miR-1271-3p hsa-miR-16-1-3p hsa-miR-455-5p hsa-miR-550a-3-5p hsa-miR-550a-5p hsa-miR-550b-2-5p hsa-miR-590-3p hsa-miR-574-3p hsa-miR-574-3p hsa-miR-125b-1-3p hsa-miR-3615 hsa-miR-6800-3p hsa-miR-23a-5p hsa-miR-23b-5p hsa-miR-3940-5p hsa-miR-4507 hsa-miR-635 hsa-miR-6774-5p hsa-miR-6839-3p hsa-miR-26b-3p hsa-miR-593-3p hsa-miR-642b-5p hsa-miR-1236-3p hsa-miR-6515-3p hsa-miR-6817-3p hsa-miR-6873-3p hsa-miR-6895-3p hsa-miR-7110-3p hsa-miR-2053 hsa-miR-569 hsa-miR-302b-5p hsa-miR-302d-5p hsa-miR-2053 hsa-miR-569 hsa-miR-6844 hsa-miR-302b-5p hsa-miR-302d-5p
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0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
N N N N N N N C C C C C C N C C C C N N N N N N N N C C C C O O O N N N C C C C C N N N N N N O N N N N N C C C C C C C N N N C C C C C C O O O O O O O O O
731
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rs191179468
rs111387927
rs35842894 rs182801062
rs188264164 rs201880241
rs151319724 rs190515827
rs35217987 rs114155347
rs140700152 rs111259092
rs182989560
rs187619865
rs77637390
hsa-miR-148b-5p hsa-miR-3168 hsa-miR-5584-3p hsa-miR-6874-3p hsa-miR-568 hsa-miR-3148 hsa-miR-4796-3p hsa-miR-548az-5p hsa-miR-548t-5p hsa-miR-6124 hsa-miR-875-3p hsa-miR-4433-3p hsa-miR-4459 hsa-miR-4768-3p hsa-miR-4266 hsa-miR-4695-5p hsa-miR-4779 hsa-miR-651-5p hsa-miR-4803 hsa-miR-3180-5p hsa-miR-520a-5p hsa-miR-525-5p hsa-miR-1180-3p hsa-miR-4664-3p hsa-miR-494-3p hsa-miR-5192 hsa-miR-548av-3p hsa-miR-548g-3p hsa-miR-185-5p hsa-miR-4306 hsa-miR-4644 hsa-miR-548a-3p hsa-miR-548ar-3p hsa-miR-548az-3p hsa-miR-548e-3p hsa-miR-548f-3p hsa-miR-1294 hsa-miR-4316 hsa-miR-4677-3p hsa-miR-4731-5p hsa-miR-5089-5p hsa-miR-5589-5p hsa-miR-619-5p hsa-miR-6506-5p hsa-miR-133a-5p hsa-miR-138-5p hsa-miR-4774-5p hsa-miR-5681b hsa-miR-6131 hsa-miR-6504-3p hsa-miR-640 hsa-miR-4695-3p hsa-miR-7641 hsa-miR-4459 hsa-miR-665 hsa-miR-6894-5p hsa-miR-1281 hsa-miR-6778-3p hsa-miR-1306-5p hsa-miR-1273f hsa-miR-129-5p hsa-miR-143-3p hsa-miR-4708-5p hsa-miR-4770 hsa-miR-6088 hsa-miR-8055 hsa-miR-3198 hsa-miR-4309 hsa-miR-4464 hsa-miR-4748 hsa-miR-555 hsa-miR-1229-5p hsa-miR-197-5p hsa-miR-3132 hsa-miR-4650-3p hsa-miR-5197-3p hsa-miR-1272 hsa-miR-4450
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0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
N N N N C C C C C C C N N N C C C C O N N N C C N N N N C C C C C C C C C C C N N N N N C C C C C C O N N C C C N N C O O O O O O O N N N N N C C C C C N N
732
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rs1048829 rs192515585
rs184222221
rs145822696 rs187466173 rs192721303
rs111343977
rs138378218
rs142864631
rs150216929
rs1046590
rs184637642
rs188609750 rs138750669 rs3731696
rs191822894
hsa-miR-5187-5p hsa-miR-6857-5p hsa-miR-3144-5p hsa-miR-3191-3p hsa-miR-4652-5p hsa-miR-6810-5p hsa-miR-577 hsa-miR-181a-3p hsa-miR-548ao-5p hsa-miR-548ax hsa-miR-5585-5p hsa-miR-4766-5p hsa-miR-10a-3p hsa-miR-3182 hsa-miR-4659a-3p hsa-miR-4659b-3p hsa-miR-3682-5p hsa-miR-338-5p hsa-miR-4666a-3p hsa-miR-548m hsa-miR-1295b-5p hsa-miR-1912 hsa-miR-3130-5p hsa-miR-4482-5p hsa-miR-5591-3p hsa-miR-580-5p hsa-miR-1245a hsa-miR-8062 hsa-miR-8079 hsa-miR-548a-3p hsa-miR-548ar-3p hsa-miR-548az-3p hsa-miR-548e-3p hsa-miR-548f-3p hsa-miR-5582-3p hsa-miR-510-3p hsa-miR-570-3p hsa-miR-30a-3p hsa-miR-30d-3p hsa-miR-30e-3p hsa-miR-3177-5p hsa-miR-4276 hsa-miR-4302 hsa-miR-6733-3p hsa-let-7a-2-3p hsa-let-7c-3p hsa-let-7g-3p hsa-miR-335-3p hsa-miR-4289 hsa-miR-493-5p hsa-miR-2681-3p hsa-miR-6516-3p hsa-miR-96-3p hsa-miR-154-3p hsa-miR-487a-3p hsa-miR-8076 hsa-miR-3927-5p hsa-miR-4668-3p hsa-miR-454-5p hsa-miR-548as-3p hsa-miR-652-5p hsa-miR-33a-3p hsa-miR-374a-5p hsa-miR-374b-5p hsa-miR-409-3p hsa-miR-552-3p hsa-miR-154-5p hsa-miR-376c-3p hsa-miR-216a-5p hsa-miR-216b-5p hsa-miR-3675-3p hsa-miR-454-5p hsa-miR-6883-3p hsa-miR-1976 hsa-miR-3912-5p hsa-miR-4279 hsa-miR-4421 hsa-miR-5699-3p
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0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
N N C C C C N C N N N C N N N N C C C C N N N N N N C C C N N N N N N C C N N N N N N N C C C C C C N N N C C C N N C C C C C C C N C C N N N C C N N N N N
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rs149345058 rs144181329
rs184259311 rs189115616 rs182058086
hsa-miR-6748-3p hsa-miR-1247-5p hsa-miR-4713-5p hsa-miR-629-3p hsa-miR-6867-3p hsa-miR-152-5p hsa-miR-4320 hsa-let-7a-3p hsa-let-7b-3p hsa-let-7f-1-3p hsa-let-7f-2-3p hsa-miR-1185-1-3p hsa-miR-1185-2-3p hsa-miR-21-5p hsa-miR-300 hsa-miR-381-3p hsa-miR-4666a-3p hsa-miR-4789-5p hsa-miR-590-5p hsa-miR-98-3p hsa-let-7a-2-3p hsa-let-7c-3p hsa-let-7g-3p hsa-miR-493-5p hsa-miR-4666a-3p hsa-miR-181c-3p hsa-miR-4668-3p hsa-miR-3662 hsa-miR-139-5p
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3.3 3D Models of nsSNPS by Project hope Seven proteins 3D structures were successfully designed by project hope. The protein is colored grey, the side chain of the wild-type residue is colored green, while that of the mutant residue is colored red. 3.4 Analysis of 3UTR SNPs by Polymirts (v3.0): Many miRNA binding sites have been affected due to SNPs in 3UTR regions in BMPR2. Table (2) shows disruption of sites either by creation or destruction of binding to miRNA. Liver cancer and prostate cancer associated miRNA have been found to be linked to somatic mutations in somamiR Database.
N C C C C N C N N N N N N N N N N N N N C C C C N C N C C
namely liver and prostate cancers. We recommend further clinical correlation.
5. Acknowledgments This research was supported by Africa City of Technology and Daoud research group.
6. REFERENCES
3.5 Demonstration of gene network interactions by geneMANIA: BMPR2 gene in BMP pathway has been highlighted then different types of interactions have been shown with different genes (Please refer to Appendages).
4. CONCLUSION
BMPR2 is an important regulator in BMP pathway which affects cellular growth. Certain SNPs were found to affect BMPR2 structure and hence function. Certain somatic mutations were found to affect miRNA binding sites that are associated with certain neoplasms,
1. 2.
3. 4.
Teichert-Kuliszewska, K. (2006). Bone Morphogenetic Protein Receptor-2 Signaling Promotes. Circulation Research; 98:209-217. Machado, R. D. (2001). BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for primary Pulmonary Hypertension. American Society of Human Genetics; 68:9297. Joshua P. Fessel1, J. E. (2011). The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulmonary Circulation; 1:305-319. Joy D. Cogan, C. L.-J. (2005). Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genetics IN Medicine; 7:169-174.
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