title: Alignment-free clustering of transcription factor binding motifs using a genetic-k-medoids approach.
abstract: BACKGROUND
  Familial binding profiles (FBPs) represent the average binding specificity for a group of structurally related DNA-binding proteins. The construction of such profiles allows the classification of novel motifs based on similarity to known families, can help to reduce redundancy in motif databases and de novo prediction algorithms, and can provide valuable insights into the evolution of binding sites. Many current approaches to automated motif clustering rely on progressive tree-based techniques, and can suffer from so-called frozen sub-alignments, where motifs which are clustered early on in the process remain 'locked' in place despite the potential for better placement at a later stage. In order to avoid this scenario, we have developed a genetic-k-medoids approach which allows motifs to move freely between clusters at any point in the clustering process.
  
  
  RESULTS
  We demonstrate the performance of our algorithm, GMACS, on multiple benchmark motif datasets, comparing results obtained with current leading approaches. The first dataset includes 355 position weight matrices from the TRANSFAC database and indicates that the k-mer frequency vector approach used in GMACS outperforms other motif comparison techniques. We then cluster a set of 79 motifs from the JASPAR database previously used in several motif clustering studies and demonstrate that GMACS can produce a higher number of structurally homogeneous clusters than other methods without the need for a large number of singletons. Finally, we show the robustness of our algorithm to noise on multiple synthetic datasets consisting of known motifs convolved with varying degrees of noise.
  
  
  CONCLUSIONS
  Our proposed algorithm is generally applicable to any DNA or protein motifs, can produce highly stable and biologically meaningful clusters, and, by avoiding the problem of frozen sub-alignments, can provide improved results when compared with existing techniques on benchmark datasets.
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, 10461, USA. pilib.obroin@einstein.yu.edu.|National Centre for Biomedical Engineering Science, National University of Ireland, University Road, Galway, Ireland. pilib.obroin@einstein.yu.edu.
authors: Pilib Ó
authors: PÓ
authors: Broin
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, 10461, USA. terry.smith@nuigalway.ie.
authors: Terry J
authors: TJ
authors: Smith
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, 10461, USA. aaron.golden@einstein.yu.edu.|Department of Mathematical Sciences, Yeshiva University, New York, 10033, NY, USA. aaron.golden@einstein.yu.edu.
authors: Aaron Aj
authors: AA
authors: Golden
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D016000:Cluster Analysis; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D030541:Databases, Genetic; D006801:Humans; D059372:Nucleotide Motifs; D011485:Protein Binding; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA
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