Mutations and binding sites of human transcription factors.

Frederick Kinyua Kamanu,Boris R Jankovic,Yulia A Medvedeva,John A C Archer,Vladimir B Bajic,Ulf Schaefer

doi:10.3389/fgene.2012.00100

Abstract

Mutations in any genome may lead to phenotype characteristics that determine ability of an individual to cope with adaptation to environmental challenges. In studies of human biology, among the most interesting ones are phenotype characteristics that determine responses to drug treatments, response to infections, or predisposition to specific inherited diseases. Most of the research in this field has been focused on the studies of mutation effects on the final gene products, peptides, and their alterations. Considerably less attention was given to the mutations that may affect regulatory mechanism(s) of gene expression, although these may also affect the phenotype characteristics. In this study we make a pilot analysis of mutations observed in the regulatory regions of 24,667 human RefSeq genes. Our study reveals that out of eight studied mutation types, “insertions” are the only one that in a statistically significant manner alters predicted transcription factor binding sites (TFBSs). We also find that 25 families of TFBSs have been altered by mutations in a statistically significant manner in the promoter regions we considered. Moreover, we find that the related transcription factors are, for example, prominent in processes related to intracellular signaling; cell fate; morphogenesis of organs and epithelium; development of urogenital system, epithelium, and tube; neuron fate commitment. Our study highlights the significance of studying mutations within the genes regulatory regions and opens way for further detailed investigations on this topic, particularly on the downstream affected pathways.

Highlights

Mutations in any genome may lead to phenotype characteristics that determine ability of an individual to cope with environmental challenges (Kopp and Hermisson, 2009)
We find that 25 families of transcription factor binding sites (TFBSs) have been altered by mutations in a statistically significant manner in the promoter regions we considered
Our study reveals for the first time that out of eight studied mutation types, “insertions” is the only type that alters the predicted transcription factor binding sites (TFBSs) in a statistically significant manner

Summary

Introduction

Mutations in any genome may lead to phenotype characteristics that determine ability of an individual to cope with environmental challenges (Kopp and Hermisson, 2009). It is well known that phenotypic specificities determine how individuals react to drugs (Batist et al, 2011; Callahan and Abercrombie, 2011), to infections (González-Hernández et al, 2010), or how predisposed they are to inherited diseases such as cystic fibrosis (Gu et al, 2009; Antigny et al, 2011), Huntington’s disease (Roze, 2011), galactosemia (Bennett, 2010), et cetera. Several databases have been developed in order to facilitate the study of these genetic variations and their consequences. Resources such as the Human Gene Mutation Database (HGMD; Stenson et al, 2009) and the Online Mendelian Inheritance in Man (OMIM) database (Amberger et al, 2009) collect mutations occurring across the entire human genome, whereas other repositories such as the FLCN Gene Database (Lim et al, 2010) are locus specific

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