Evolutionarily assembled cis-regulatory module at a human ciliopathy locus

  • Science. 2012 Feb 24;335(6071):966-9. doi: 10.1126/science.1213506.
Jeong Ho Lee  1 ,  Jennifer L Silhavy ,  Ji Eun Lee ,  Lihadh Al-Gazali ,  Sophie Thomas ,  Erica E Davis ,  Stephanie L Bielas ,  Kiley J Hill ,  Miriam Iannicelli ,  Francesco Brancati ,  Stacey B Gabriel ,  Carsten Russ ,  Clare V Logan ,  Saghira Malik Sharif ,  Christopher P Bennett ,  Masumi Abe ,  Friedhelm Hildebrandt ,  Bill H Diplas ,  Tania Attié-Bitach ,  Nicholas Katsanis ,  Anna Rajab ,  Roshan Koul ,  Laszlo Sztriha ,  Elizabeth R Waters ,  Susan Ferro-Novick ,  C Geoffrey Woods ,  Colin A Johnson ,  Enza Maria Valente ,  Maha S Zaki ,  Joseph G Gleeson
Affiliations
  • 1. Neurogenetics Laboratory, Howard Hughes Medical Institute (HHMI), Department of Neurosciences, University of California, San Diego, CA, USA.
PMID: 22282472 DOI: 10.1126/science.1213506
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.