title: The evolution of gene expression and binding specificity of the largest transcription factor family in primates.
abstract: The KRAB-containing zinc finger (KRAB-ZF) proteins represent the largest family of transcription factors (TFs) in humans, yet for the great majority, their function and specific genomic target remain unknown. However, it has been shown that a large fraction of these genes arose from segmental duplications, and that they have expanded in gene and zinc finger number throughout vertebrate evolution. To determine whether this expansion is linked to selective pressures acting on different domains, we have manually curated all KRAB-ZF genes present in the human genome together with their orthologous genes in three closely related species and assessed the evolutionary forces acting at the sequence level as well as on their expression profiles. We provide evidence that KRAB-ZFs can be separated into two categories according to the polymorphism present in their DNA-contacting residues. Those carrying a nonsynonymous single nucleotide polymorphism (SNP) in their DNA-contacting amino acids exhibit significantly reduced expression in all tissues, have emerged in a recent lineage, and seem to be less strongly constrained evolutionarily than those without such a polymorphism. This work provides evidence for a link between age of the TF, as well as polymorphism in their DNA-contacting residues and expression levels-both of which may be jointly affected by selection.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland, 1015.
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland, 1015.
authors.forename: Lisha
authors.initials: L
authors.lastname: Mathew
authors.affiliation: Department of Biology, Carleton University, Ottawa, Canada, K15 5B6.
authors.forename: Alex
authors.initials: A
authors.lastname: Wong
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. jeffrey.jensen@epfl.ch.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland, 1015. jeffrey.jensen@epfl.ch.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Jensen
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D015870:Gene Expression; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors
keywords: DNA-contacting residues; KRAB-containing zinc finger genes; endogenous retroelements; population genetics; regulatory evolution; transcription factors