title: The frequent evolutionary birth and death of functional promoters in mouse and human.
abstract: Promoters are central to the regulation of gene expression. Changes in gene regulation are thought to underlie much of the adaptive diversification between species and phenotypic variation within populations. In contrast to earlier work emphasizing the importance of enhancer evolution and subtle sequence changes at promoters, we show that dramatic changes such as the complete gain and loss (collectively, turnover) of functional promoters are common. Using quantitative measures of transcription initiation in both humans and mice across 52 matched tissues, we discriminate promoter sequence gains from losses and resolve the lineage of changes. We also identify expression divergence and functional turnover between orthologous promoters, finding only the latter is associated with local sequence changes. Promoter turnover has occurred at the majority (>56%) of protein-coding genes since humans and mice diverged. Tissue-restricted promoters are the most evolutionarily volatile where retrotransposition is an important, but not the sole, source of innovation. There is considerable heterogeneity of turnover rates between promoters in different tissues, but the consistency of these in both lineages suggests that the same biological systems are similarly inclined to transcriptional rewiring. The genes affected by promoter turnover show evidence of adaptive evolution. In mice, promoters are primarily lost through deletion of the promoter containing sequence, whereas in humans, many promoters appear to be gradually decaying with weak transcriptional output and relaxed selective constraint. Our results suggest that promoter gain and loss is an important process in the evolutionary rewiring of gene regulation and may be a significant source of phenotypic diversification.
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Young
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, 351-0198, Japan;
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: Department of Biology and Biotech Research and Innovation Centre, Copenhagen University, 2200 Copenhagen N, Denmark;
authors.forename: Robin
authors.initials: R
authors.lastname: Andersson
authors.affiliation: Department of Biology and Biotech Research and Innovation Centre, Copenhagen University, 2200 Copenhagen N, Denmark;
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, 351-0198, Japan; RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Tsurumi-ku, Yokohama, 230-0045, Japan;
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, 351-0198, Japan; RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Tsurumi-ku, Yokohama, 230-0045, Japan;
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Tsurumi-ku, Yokohama, 230-0045, Japan;
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Tsurumi-ku, Yokohama, 230-0045, Japan;
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Bickmore
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Tsurumi-ku, Yokohama, 230-0045, Japan; Systems Biology and Genomics, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
authors.forename: Alistair R
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA; D004251:DNA Transposable Elements; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D016254:Mutagenesis, Insertional; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D013045:Species Specificity
chemical_list: D004251:DNA Transposable Elements; D004247:DNA