title: Identification of the imprinted KLF14 transcription factor undergoing human-specific accelerated evolution.
abstract: Imprinted genes are expressed in a parent-of-origin manner and are located in clusters throughout the genome. Aberrations in the expression of imprinted genes on human Chromosome 7 have been suggested to play a role in the etiologies of Russell-Silver Syndrome and autism. We describe the imprinting of KLF14, an intronless member of the Krüppel-like family of transcription factors located at Chromosome 7q32. We show that it has monoallelic maternal expression in all embryonic and extra-embryonic tissues studied, in both human and mouse. We examine epigenetic modifications in the KLF14 CpG island in both species and find this region to be hypomethylated. In addition, we perform chromatin immunoprecipitation and find that the murine Klf14 CpG island lacks allele-specific histone modifications. Despite the absence of these defining features, our analysis of Klf14 in offspring from DNA methyltransferase 3a conditional knockout mice reveals that the gene's expression is dependent upon a maternally methylated region. Due to the intronless nature of Klf14 and its homology to Klf16, we suggest that the gene is an ancient retrotransposed copy of Klf16. By sequence analysis of numerous species, we place the timing of this event after the divergence of Marsupialia, yet prior to the divergence of the Xenarthra superclade. We identify a large number of sequence variants in KLF14 and, using several measures of diversity, we determine that there is greater variability in the human lineage with a significantly increased number of nonsynonymous changes, suggesting human-specific accelerated evolution. Thus, KLF14 may be the first example of an imprinted transcript undergoing accelerated evolution in the human lineage.
authors.affiliation: Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Layla
authors.initials: L
authors.lastname: Parker-Katiraee
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Carson
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Sayeda N
authors.initials: SN
authors.lastname: Abu-Amero
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneda
authors.forename: George H
authors.initials: GH
authors.lastname: Perry
authors.forename: Anne C
authors.initials: AC
authors.lastname: Stone
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Makiko
authors.initials: M
authors.lastname: Meguro-Horike
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D019143:Evolution, Molecular; D005321:Extraembryonic Membranes / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D051703:Sp Transcription Factors; D013045:Species Specificity; D013577:Syndrome; D026801:Synteny / Q000235:genetics
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D006657:Histones; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D011506:Proteins; D012333:RNA, Messenger; D051703:Sp Transcription Factors; C498818:Sp6 protein, mouse; C103637:mesoderm specific transcript protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A