title: Negative selection maintains transcription factor binding motifs in human cancer.
abstract: Somatic mutations in cancer cells affect various genomic elements disrupting important cell functions. In particular, mutations in DNA binding sites recognized by transcription factors can alter regulator binding affinities and, consequently, expression of target genes. A number of promoter mutations have been linked with an increased risk of cancer. Cancer somatic mutations in binding sites of selected transcription factors have been found under positive selection. However, action and significance of negative selection in non-coding regions remain controversial.
  
  
  
  Here we present analysis of transcription factor binding motifs co-localized with non-coding variants. To avoid statistical bias we account for mutation signatures of different cancer types. For many transcription factors, including multiple members of FOX, HOX, and NR families, we show that human cancers accumulate fewer mutations than expected by chance that increase or decrease affinity of predicted binding sites. Such stability of binding motifs is even more exhibited in DNase accessible regions.
  
  
  
  Our data demonstrate negative selection against binding sites alterations and suggest that such selection pressure protects cancer cells from rewiring of regulatory circuits. Further analysis of transcription factors with conserved binding motifs can reveal cell regulatory pathways crucial for the survivability of various human cancers.
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, GSP-1, Gubkina 3, Moscow, Russia.
authors.forename: Ilya E
authors.initials: IE
authors.lastname: Vorontsov
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, GSP-1, Gubkina 3, Moscow, Russia.
authors.forename: Grigory
authors.initials: G
authors.lastname: Khimulya
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, GSP-1, Gubkina 3, Moscow, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Lukianova
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, GSP-1, Vorobyevy Gory 1-73, Moscow, Russia.
authors.forename: Daria D
authors.initials: DD
authors.lastname: Nikolaeva
authors.affiliation: Group of Protein Biosynthesis Regulation, Institute of Protein Research, 142290, Institutskaya 4, Pushchino, Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Eliseeva
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, GSP-1, Gubkina 3, Moscow, Russia. ivan.kulakovskiy@gmail.com.|Engelhardt Institute of Molecular Biology, 119991, GSP-1, Vavilova 32, Moscow, Russia. ivan.kulakovskiy@gmail.com.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Kulakovskiy
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, GSP-1, Gubkina 3, Moscow, Russia. vsevolod.makeev@gmail.com.|Moscow Institute of Physics and Technology, 141700, Dolgoprudny, Moscow Region, Russia. vsevolod.makeev@gmail.com.|Engelhardt Institute of Molecular Biology, 119991, GSP-1, Vavilova 32, Moscow, Russia. vsevolod.makeev@gmail.com.
authors.forename: Vsevolod J
authors.initials: VJ
authors.lastname: Makeev
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012641:Selection, Genetic; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D004247:DNA
keywords: Cancer somatic mutations; DNA motifs; Negative selection; Transcription factor binding sites