Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus

• Published in: Science (American Association for the Advancement of Science) Vol. 335; no. 6071; pp. 966 - 969
• Main Authors: JEONG HO LEE, SILHAVY, Jennifer L, GABRIEL, Stacey B, RUSS, Carsten, LOGAN, Clare V, MALIK SHARIF, Saghira, BENNETT, Christopher P, ABE, Masumi, HILDEBRANDT, Friedhelm, DIPLAS, Bill H, ATTIE-BITACH, Tania, KATSANIS, Nicholas, JI EUN LEE, RAJAB, Anna, KOUL, Roshan, SZTRIHA, Laszlo, WATERS, Elizabeth R, FERRO-NOVICK, Susan, GEOFFREY WOODS, C, JOHNSON, Colin A, MARIA VALENCE, Enza, ZAKI, Maha S, GLEESON, Joseph G, AL-GAZALI, Lihadh, THOMAS, Sophie, DAVIS, Erica E, BIELAS, Stephanie L, HILL, Kiley J, LANNICELLI, Miriam, BRANCATI, Francesco
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 24.02.2012; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Cell Line; Cerebellar Diseases - genetics; Cerebellar Diseases - metabolism; Cerebellar Diseases - pathology; Cilia - metabolism; Cilia - ultrastructure; Classical genetics, quantitative genetics, hybrids; Conserved Sequence; DNA, Intergenic; Evolution, Molecular; Evolutionary biology; Eye Abnormalities - genetics; Eye Abnormalities - metabolism; Eye Abnormalities - pathology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene loci; Genetic disorders; Genetic Heterogeneity; Genetic Loci; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human; Humans; Kidney Diseases, Cystic - genetics; Kidney Diseases, Cystic - metabolism; Kidney Diseases, Cystic - pathology; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Multigene Family; Mutation; Mutation, Missense; Phenotype; Protein Transport; Regulatory Sequences, Nucleic Acid; Retina - abnormalities; Retina - metabolism; Retina - pathology; Transport Vesicles - metabolism; Transport Vesicles - ultrastructure; Human; Nervous system diseases; Malformation; Joubert syndrome; Central nervous system disease; Genetics; Mutation; Genetic disease; Cerebral disorder
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1213506

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.