title: A comprehensive study of small non-frameshift insertions/deletions in proteins and prediction of their phenotypic effects by a machine learning method (KD4i).
abstract: BACKGROUND
  Small insertion and deletion polymorphisms (Indels) are the second most common mutations in the human genome, after Single Nucleotide Polymorphisms (SNPs). Recent studies have shown that they have significant influence on genetic variation by altering human traits and can cause multiple human diseases. In particular, many Indels that occur in protein coding regions are known to impact the structure or function of the protein. A major challenge is to predict the effects of these Indels and to distinguish between deleterious and neutral variants. When an Indel occurs within a coding region, it can be either frameshifting (FS) or non-frameshifting (NFS). FS-Indels either modify the complete C-terminal region of the protein or result in premature termination of translation. NFS-Indels insert/delete multiples of three nucleotides leading to the insertion/deletion of one or more amino acids.
  
  
  RESULTS
  In order to study the relationships between NFS-Indels and Mendelian diseases, we characterized NFS-Indels according to numerous structural, functional and evolutionary parameters. We then used these parameters to identify specific characteristics of disease-causing and neutral NFS-Indels. Finally, we developed a new machine learning approach, KD4i, that can be used to predict the phenotypic effects of NFS-Indels.
  
  
  CONCLUSIONS
  We demonstrate in a large-scale evaluation that the accuracy of KD4i is comparable to existing state-of-the-art methods. However, a major advantage of our approach is that we also provide the reasons for the predictions, in the form of a set of rules. The rules are interpretable by non-expert humans and they thus represent new knowledge about the relationships between the genotype and phenotypes of NFS-Indels and the causative molecular perturbations that result in the disease.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bermejo-Das-Neves
authors.forename: Hoan-Ngoc
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.affiliation: ICube Laboratory and Strasbourg Federation of Translational Medicine (FMTS), University of Strasbourg and CNRS, Strasbourg, France. thompson@unistra.fr.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Thompson
mesh_terms: D001185:Artificial Intelligence; D006801:Humans; D054643:INDEL Mutation; D016547:Kinesins / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; D016547:Kinesins
references.citation: Proteins. 2003 Mar 1;50(4):629-35
references.pmid: 12577269
references.citation: Hum Mol Genet. 2010 Oct 15;19(R2):R131-6
references.pmid: 20858594
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D613-9
references.pmid: 19906737
references.citation: Bioinformatics. 2005 Aug 15;21(16):3433-4
references.pmid: 15955779
references.citation: Genome Res. 2011 Jun;21(6):830-9
references.pmid: 21460062
references.citation: Proc Natl Acad Sci U S A. 1990 Aug;87(16):6388-92
references.pmid: 2385597
references.citation: PLoS Genet. 2008 Aug 15;4(8):e1000160
references.pmid: 18704161
references.citation: PLoS Genet. 2012;8(11):e1003066
references.pmid: 23209432
references.citation: BMC Bioinformatics. 2006 Jun 23;7:318
references.pmid: 16792820
references.citation: Nat Rev Genet. 2011 Aug 18;12(9):628-40
references.pmid: 21850043
references.citation: PLoS One. 2013 Oct 23;8(10):e77940
references.pmid: 24194902
references.citation: Bioinformatics. 2010 Mar 15;26(6):851-2
references.pmid: 20106818
references.citation: Database (Oxford). 2012 Apr 03;2012:bas018
references.pmid: 22491796
references.citation: Nature. 2008 Apr 17;452(7189):872-6
references.pmid: 18421352
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D5-12
references.pmid: 17170002
references.citation: J Theor Biol. 1986 Mar 21;119(2):205-18
references.pmid: 3461222
references.citation: Genome Biol. 2013 Mar 13;14(3):R23
references.pmid: 23497682
references.citation: J Pept Sci. 1995 Sep-Oct;1(5):319-29
references.pmid: 9223011
references.citation: Nucleic Acids Res. 2001 Jan 1;29(1):308-11
references.pmid: 11125122
references.citation: Genome Res. 2013 May;23(5):749-61
references.pmid: 23478400
references.citation: Genome Res. 1998 Dec;8(12):1229-31
references.pmid: 9872978
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Am J Hum Genet. 2002 Nov;71(5):1189-94
references.pmid: 12355402
references.citation: J Biomol Struct Dyn. 2012;29(4):799-813
references.pmid: 22208280
references.citation: Genome Res. 2006 Sep;16(9):1182-90
references.pmid: 16902084
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D344-7
references.pmid: 23161676
references.citation: Nat Rev Genet. 2005 Apr;6(4):287-98
references.pmid: 15803198
references.citation: Nat Biotechnol. 2008 Oct;26(10):1135-45
references.pmid: 18846087
references.citation: J Clin Endocrinol Metab. 1998 Aug;83(8):2960-3
references.pmid: 9709976
references.citation: Curr Protoc Bioinformatics. 2012 Sep;Chapter 1:Unit1.13
references.pmid: 22948725
references.citation: Hum Mutat. 2011 May;32(5):564-7
references.pmid: 21472891
references.citation: Nat Biotechnol. 2008 Mar;26(3):256
references.pmid: 18327223
references.citation: Brief Bioinform. 2014 Mar;15(2):256-78
references.pmid: 23341494
references.citation: Hum Genet. 2011 Jul;130(1):3-14
references.pmid: 21706342
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W71-5
references.pmid: 22641855
references.citation: Hum Mutat. 2010 Feb;31(2):127-35
references.pmid: 19921752
references.citation: PLoS One. 2012;7(10):e46688
references.pmid: 23056405
references.citation: Annu Rev Genomics Hum Genet. 2006;7:61-80
references.pmid: 16824020
references.citation: Annu Rev Med. 2012;63:35-61
references.pmid: 22248320
references.citation: J Mol Biol. 2003 Sep 5;332(1):265-74
references.pmid: 12946363
references.citation: Genome Biol. 2012 Feb 09;13(2):R9
references.pmid: 22322200
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D290-301
references.pmid: 22127870
references.citation: Proteins. 2004 Dec 1;57(4):811-9
references.pmid: 15390262
references.citation: Methods Mol Biol. 2007;406:89-112
references.pmid: 18287689
references.citation: J Mol Recognit. 2004 Jan-Feb;17(1):17-32
references.pmid: 14872534
references.citation: Nat Methods. 2012 Sep;9(9):855-6
references.pmid: 22936163