Spliceman

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Spliceman is an online genomic identification tool used to predict the likelihood that a mutation within a DNA sequence is linked with genetic disease. It was created in 2011 by a Brown University lab, and has been used in several studies to identify disease-causing mutant alleles.

## Context

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Numerous sources cite that approximately one-third of disease-causing mutations affect RNA splicing.[1][2][3] Such mutations frequently affect Exonic splicing enhancers, regions of pre-mRNA that recruit the spliceosome to remove intron sequences and aid in the formation mature mRNA. Spliceman Co-Authors Kian Huat Lim and William Fairbrother write that "Spliceman takes a set of DNA sequences with point mutations and computes how likely these single nucleotide variants alter splicing phenotypes."[4]

The tool takes advantage of findings in 2011 on positional distribution analysis within DNA sequences. Each hexamer of DNA base pairs has a positional distribution near splice sites where it is most likely to occur. Point mutations that change one hexamer to another with large changes in positional distributions were shown to be more likely to cause splicing mutations than mutations with small changes to positional distributions.[5]

Spliceman was created to apply those findings by predicting the likelihood of splicing mutations based on the distances in positional distributions between RNA sequences. Users enter a DNA sequence as input to the program with an indicated mutation. Spliceman isolates the changed hexamers and computes the L1-distance between the frequencies of each hexamer appearing at each location near the splice site to measure the differences in their positional distributions. They distances are then assigned percentile ranks to estimate the likelihood of a splicing mutation.[6]

## Applications

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The Spliceman tool has applications in personalized genomic medicine. It has been used in several studies to identify disease-causing mutant alleles. Its applications so far include aid in the location of mutations related to neural tube defects,[7] pustular psoriasis,[8] chronic ear infection,[9] hypercholesterolemia,[10] and several other genetic illnesses.[11][12][13]

The Spliceman tool is available for free online on the website for the Fairbrother Lab.

A second version of the tool, Spliceman 2.0, has been developed to accept inputs in a wider array of file formats. This makes the tool more compatible with other tools that handle variants. It can handle many more variations than its precursor due to its ability to accept files of larger sizes. Spliceman 2.0 outputs a report that includes more data and visualization of those data.

## References

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1. ^ Velasco, Alyssa Bianca (2012-03-16). "'Spliceman' app catches disruptive mutations". Brown Daily Herald. Retrieved 2016-06-22.
2. ^ Lim, Kian Huat; Ferraris, Luciana; Filloux, Madeleine E.; Raphael, Benjamin J.; Fairbrother, William G. (2011-07-05). "Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes". Proceedings of the National Academy of Sciences of the United States of America. 108 (27): 11093–11098\. doi:10.1073/pnas.1101135108. ISSN 1091-6490. PMC 3131313. PMID 21685335.11093-11098&rft.date=2011-07-05&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131313#id-name=PMC&rft.issn=1091-6490&rft_id=info:pmid/21685335&rft_id=info:doi/10.1073/pnas.1101135108&rft.aulast=Lim&rft.aufirst=Kian+Huat&rft.au=Ferraris,+Luciana&rft.au=Filloux,+Madeleine+E.&rft.au=Raphael,+Benjamin+J.&rft.au=Fairbrother,+William+G.&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131313&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
3. ^ Vaz-Drago, Rita; Pinheiro, Marco T.; Martins, Sandra; Enguita, Francisco J.; Carmo-Fonseca, Maria; Custódio, Noélia (2015-05-15). "Transcription-coupled RNA surveillance in human genetic diseases caused by splice site mutations". Human Molecular Genetics. 24 (10): 2784–2795\. doi:10.1093/hmg/ddv039. ISSN 1460-2083. PMID 25652404.2784-2795&rft.date=2015-05-15&rft.issn=1460-2083&rft_id=info:pmid/25652404&rft_id=info:doi/10.1093/hmg/ddv039&rft.aulast=Vaz-Drago&rft.aufirst=Rita&rft.au=Pinheiro,+Marco+T.&rft.au=Martins,+Sandra&rft.au=Enguita,+Francisco+J.&rft.au=Carmo-Fonseca,+Maria&rft.au=Custódio,+Noélia&rft_id=https://doi.org/10.1093%2Fhmg%2Fddv039&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
4. ^ "Will a genetic mutation cause trouble? Ask Spliceman". www.sciencedaily.com. March 5, 2012. Retrieved 2016-06-22.
5. ^ Lim, Kian Huat; Ferraris, Luciana; Filloux, Madeleine E.; Raphael, Benjamin J.; Fairbrother, William G. (5 July 2011). "Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes". Proceedings of the National Academy of Sciences of the United States of America. 108 (27): 11093–11098\. doi:10.1073/pnas.1101135108. PMC 3131313. PMID 21685335.11093-11098&rft.date=2011-07-05&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131313#id-name=PMC&rft_id=info:pmid/21685335&rft_id=info:doi/10.1073/pnas.1101135108&rft.aulast=Lim&rft.aufirst=Kian+Huat&rft.au=Ferraris,+Luciana&rft.au=Filloux,+Madeleine+E.&rft.au=Raphael,+Benjamin+J.&rft.au=Fairbrother,+William+G.&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131313&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
6. ^ Lim, Kian Huat; Fairbrother, William G. (10 February 2012). "Spliceman—a computational web server that predicts sequence variations in pre-mRNA splicing" (PDF). Bioinformatics. 28 (7): 1031–1032\. doi:10.1093/bioinformatics/bts074. PMC 3315715. PMID 22328782. Retrieved 13 June 2016.1031-1032&rft.date=2012-02-10&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315715#id-name=PMC&rft_id=info:pmid/22328782&rft_id=info:doi/10.1093/bioinformatics/bts074&rft.aulast=Lim&rft.aufirst=Kian+Huat&rft.au=Fairbrother,+William+G.&rft_id=http://fairbrother.biomed.brown.edu/Publications/Lim_2012.pdf&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
7. ^ Krupp, Deidre R.; Soldano, Karen L.; Garrett, Melanie E.; Cope, Heidi; Ashley-Koch, Allison E.; Gregory, Simon G. (2014-08-01). "Missing Genetic Risk in Neural Tube Defects: Can Exome Sequencing Yield an Insight?". Birth Defects Research. Part A, Clinical and Molecular Teratology. 100 (8): 642–646\. doi:10.1002/bdra.23276. ISSN 1542-0752. PMC 4169137. PMID 25044326.642-646&rft.date=2014-08-01&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169137#id-name=PMC&rft.issn=1542-0752&rft_id=info:pmid/25044326&rft_id=info:doi/10.1002/bdra.23276&rft.aulast=Krupp&rft.aufirst=Deidre+R.&rft.au=Soldano,+Karen+L.&rft.au=Garrett,+Melanie+E.&rft.au=Cope,+Heidi&rft.au=Ashley-Koch,+Allison+E.&rft.au=Gregory,+Simon+G.&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169137&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
8. ^ Setta-Kaffetzi, Niovi; Simpson, Michael A.; Navarini, Alexander A.; Patel, Varsha M.; Lu, Hui-Chun; Allen, Michael H.; Duckworth, Michael; Bachelez, Hervé; Burden, A. David (2014-05-01). "AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking". American Journal of Human Genetics. 94 (5): 790–797\. doi:10.1016/j.ajhg.2014.04.005. ISSN 0002-9297. PMC 4067562. PMID 24791904.790-797&rft.date=2014-05-01&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067562#id-name=PMC&rft.issn=0002-9297&rft_id=info:pmid/24791904&rft_id=info:doi/10.1016/j.ajhg.2014.04.005&rft.aulast=Setta-Kaffetzi&rft.aufirst=Niovi&rft.au=Simpson,+Michael+A.&rft.au=Navarini,+Alexander+A.&rft.au=Patel,+Varsha+M.&rft.au=Lu,+Hui-Chun&rft.au=Allen,+Michael+H.&rft.au=Duckworth,+Michael&rft.au=Bachelez,+Hervé&rft.au=Burden,+A.+David&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067562&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
9. ^ Allen, E. Kaitlynn; Chen, Wei-Min; Weeks, Daniel E.; Chen, Fang; Hou, Xuanlin; Mattos, José L.; Mychaleckyj, Josyf C.; Segade, Fernando; Casselbrant, Margaretha L. (2013-12-01). "A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2". Journal of the Association for Research in Otolaryngology. 14 (6): 791–800\. doi:10.1007/s10162-013-0411-2. ISSN 1525-3961. PMC 3825021. PMID 23974705.791-800&rft.date=2013-12-01&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825021#id-name=PMC&rft.issn=1525-3961&rft_id=info:pmid/23974705&rft_id=info:doi/10.1007/s10162-013-0411-2&rft.aulast=Allen&rft.aufirst=E.+Kaitlynn&rft.au=Chen,+Wei-Min&rft.au=Weeks,+Daniel+E.&rft.au=Chen,+Fang&rft.au=Hou,+Xuanlin&rft.au=Mattos,+José+L.&rft.au=Mychaleckyj,+Josyf+C.&rft.au=Segade,+Fernando&rft.au=Casselbrant,+Margaretha+L.&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825021&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
10. ^ Sun, Li-Yuan; Zhang, Yong-Biao; Jiang, Long; Wan, Ning; Wu, Wen-Feng; Pan, Xiao-Dong; Yu, Jun; Zhang, Feng; Wang, Lu-Ya (2015-06-16). "Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing". Scientific Reports. 5: 11380. doi:10.1038/srep11380. ISSN 2045-2322. PMC 4468422. PMID 26077743.
11. ^ Sandbacka, Maria; Laivuori, Hannele; Freitas, Érika; Halttunen, Mervi; Jokimaa, Varpu; Morin-Papunen, Laure; Rosenberg, Carla; Aittomäki, Kristiina (2013-08-16). "TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia". Orphanet Journal of Rare Diseases. 8: 125. doi:10.1186/1750-1172-8-125. ISSN 1750-1172. PMC 3847609. PMID 23954021.
12. ^ Soliman, Neveen A.; Elmonem, Mohamed A.; van den Heuvel, Lambertus; Abdel Hamid, Rehab H.; Gamal, Mohamed; Bongaers, Inge; Marie, Sandrine; Levtchenko, Elena (2014-01-25). "Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis". JIMD Reports. 14: 87–97\. doi:10.1007/8904_2013_288. ISBN 978-3-662-43747-6. ISSN 2192-8304. PMC 4213330. PMID 24464559.87-97&rft.date=2014-01-25&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213330#id-name=PMC&rft_id=info:doi/10.1007/8904_2013_288&rft_id=info:pmid/24464559&rft.issn=2192-8304&rft.isbn=978-3-662-43747-6&rft.aulast=Soliman&rft.aufirst=Neveen+A.&rft.au=Elmonem,+Mohamed+A.&rft.au=van+den+Heuvel,+Lambertus&rft.au=Abdel+Hamid,+Rehab+H.&rft.au=Gamal,+Mohamed&rft.au=Bongaers,+Inge&rft.au=Marie,+Sandrine&rft.au=Levtchenko,+Elena&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213330&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">
13. ^ Mattos, Eduardo P.; Sanseverino, Maria Teresa V.; Magalhães, José Antônio A.; Leite, Júlio César L.; Félix, Temis Maria; Todeschini, Luiz Alberto; Cavalcanti, Denise P.; Schüler-Faccini, Lavinia (2015-03-01). "Clinical and molecular characterization of a Brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations". Genetics and Molecular Biology. 38 (1): 14–20\. doi:10.1590/S1415-475738120140147. ISSN 1415-4757. PMC 4415563. PMID 25983619.14-20&rft.date=2015-03-01&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415563#id-name=PMC&rft.issn=1415-4757&rft_id=info:pmid/25983619&rft_id=info:doi/10.1590/S1415-475738120140147&rft.aulast=Mattos&rft.aufirst=Eduardo+P.&rft.au=Sanseverino,+Maria+Teresa+V.&rft.au=Magalhães,+José+Antônio+A.&rft.au=Leite,+Júlio+César+L.&rft.au=Félix,+Temis+Maria&rft.au=Todeschini,+Luiz+Alberto&rft.au=Cavalcanti,+Denise+P.&rft.au=Schüler-Faccini,+Lavinia&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415563&rfr_id=info:sid/en.wikipedia.org:Spliceman" class="Z3988">

## External links

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* Spliceman Home Page