title: Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.
abstract: BACKGROUND
  The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases.
  
  
  RESULTS
  We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations.
  
  
  CONCLUSIONS
  Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.|Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Aleksandr B
authors.initials: AB
authors.lastname: Sahakyan
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. sb10031@cam.ac.uk.|Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK. sb10031@cam.ac.uk.|School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. sb10031@cam.ac.uk.
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D017398:Alternative Splicing; D009202:Cardiomyopathies / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D006801:Humans; D007438:Introns; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*
keywords: Cancer; KEGG pathways; Long genes; Multigenic diseases; Mutations; Splice variants; Topoisomerases