title: Identification of sequences common to more than one therapeutic target to treat complex diseases: simulating the high variance in sequence interactivity evolved to modulate robust phenotypes.
abstract: BACKGROUND
  Genome-wide association studies show that most human traits and diseases are caused by a combination of environmental and genetic causes, with each one of these having a relatively small effect. In contrast, most therapies based on macromolecules like antibodies, antisense oligonucleotides or peptides focus on a single gene product. On the other hand, complex organisms seem to have a plethora of functional molecules able to bind specifically to multiple genes or genes products based on their sequences but the mechanisms that lead organisms to recruit these multispecific regulators remain unclear.
  
  
  RESULTS
  The mutational biases inferred from the genomic sequences of six organisms show an increase in the variance of sequence interactivity in complex organisms. The high variance in the interactivity of sequences presents an ideal evolutionary substrate to recruit sequence-specific regulators able to target multiple gene products. For example, here it is shown how the 3'UTR can fluctuate between sequences likely to be complementary to other sites in the genome in the search for advantageous interactions. A library of nucleotide- and peptide-based tools was built using a script to search for candidates (e.g. peptides, antigens to raise antibodies or antisense oligonucleotides) to target sequences shared by key pathways in human disorders, such as cancer and immune diseases. This resource will be accessible to the community at www.wikisequences.org .
  
  
  CONCLUSIONS
  This study describes and encourages the adoption of the same multitarget strategy (e.g., miRNAs, Hsp90) that has evolved in organisms to modify complex traits to treat diseases with robust pathological phenotypes. The increase in the variance of sequence interactivity detected in the human and mouse genomes when compared with less complex organisms could have expedited the evolution of regulators able to interact to multiple gene products and modulate robust phenotypes. The identification of sequences common to more than one therapeutic target carried out in this study could facilitate the design of new multispecific methods able to modify simultaneously key pathways to treat complex diseases.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. miguel.varela@wikisequences.org.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Varela
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000627:therapeutic use; D017173:Caenorhabditis elegans / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D015723:Gene Library; D059647:Gene-Environment Interaction; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000627:therapeutic use
chemical_list: D020413:3' Untranslated Regions; D000906:Antibodies; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense