title: Accelerated Evolution of Enhancer Hotspots in the Mammal Ancestor.
abstract: Mammals have evolved remarkably different sensory, reproductive, metabolic, and skeletal systems. To explore the genetic basis for these differences, we developed a comparative genomics approach to scan whole-genome multiple sequence alignments to identify regions that evolved rapidly in an ancestral lineage but are conserved within extant species. This pattern suggests that ancestral changes in function were maintained in descendants. After applying this test to therian mammals, we identified 4,797 accelerated regions, many of which are noncoding and located near developmental transcription factors. We then used mouse transgenic reporter assays to test if noncoding accelerated regions are enhancers and to determine how therian-specific substitutions affect their activity in vivo. We discovered enhancers with expression specific to the therian version in brain regions involved in the hormonal control of milk ejection, uterine contractions, blood pressure, temperature, and visual processing. This work underscores the idea that changes in developmental gene expression are important for mammalian evolution, and it pinpoints candidate genes for unique aspects of mammalian biology.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
authors.forename: Alisha K
authors.initials: AK
authors.lastname: Holloway
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, CA.
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sukonnik
authors.affiliation: Nina Ireland Laboratory of Developmental Neurobiology and Department of Psychiatry, University of California, San Francisco.
authors.forename: John L
authors.initials: JL
authors.lastname: Rubenstein
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA Department of Epidemiology and Biostatistics, University of California, San Francisco, CA Institute for Human Genetics, University of California, San Francisco, CA katie.pollard@gladstone.ucsf.edu.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D018398:Homeodomain Proteins / Q000235:genetics*; D008322:Mammals / Q000235:genetics*; D051379:Mice
chemical_list: D018398:Homeodomain Proteins
keywords: comparative genomics; development; enhancer evolution; mammal-specific traits