title: Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.
abstract: Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
authors.affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute (HHMI), Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bielas
authors.forename: Kiley J
authors.initials: KJ
authors.lastname: Hill
authors.forename: Miriam
authors.initials: M
authors.lastname: Iannicelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.forename: Saghira Malik
authors.initials: SM
authors.lastname: Sharif
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bennett
authors.forename: Masumi
authors.initials: M
authors.lastname: Abe
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Bill H
authors.initials: BH
authors.lastname: Diplas
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Anna
authors.initials: A
authors.lastname: Rajab
authors.forename: Roshan
authors.initials: R
authors.lastname: Koul
authors.forename: Laszlo
authors.initials: L
authors.lastname: Sztriha
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Waters
authors.forename: Susan
authors.initials: S
authors.lastname: Ferro-Novick
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002526:Cerebellar Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure*; D017124:Conserved Sequence; D021901:DNA, Intergenic; D019143:Evolution, Molecular; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D021381:Protein Transport; D012045:Regulatory Sequences, Nucleic Acid; D012160:Retina / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D021901:DNA, Intergenic; D008565:Membrane Proteins; C570597:TMEM138 protein, human; C551542:TMEM216 protein, human