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Mehdi Tafti, Professor

Mehdi Tafti received his PhD from the University of Montpellier (France) in 1991 after completing his doctoral thesis on sleep regulation in human narcolepsy. He performed a postdoctoral fellowship with Dr. Mignot and Dr. Dement and was a Research Associate at the Department of Psychiatry and Biological Sciences at Stanford University. In 1995 he moved to the Department of Psychiatry in Geneva where he established the first laboratory dedicated to the molecular genetics of sleep and sleep disorders. He joined the Center for Integrative Genomics in September 2004.

Sleep, circadian rhythms, mouse genomics, QTL, sleep disorders

 

 

Research Summary

Genetics of sleep and the sleep EEG

Based on available literature there is no doubt that many aspects of sleep are under a genetic control in both humans and animal models. These include not only the amount and the distribution of sleep but also very specific electroencephalographic (EEG) features of sleep and wakefulness. By using the inbred mouse as a genetic tool, we have been able to demonstrate that sleep as a quantitative trait is amenable to quantitative trait loci analysis (QTL). Although many genes with small effects might affect the amount and the distribution of sleep, some aspects such as the daily amount of paradoxical sleep may be under a major gene control. We have localized such a gene on the mouse chromosome 1 and are currently fine mapping the region to ultimately identify the responsible gene. We have been the first to report that a single gene may dramatically affect the quantitative sleep EEG. An EEG variant specific to paradoxical sleep (slow theta frequency) has been identified as the most heritable phenotype in inbred mice and subsequent mapping and functional studies identified Acads (acyl Coenzyme A dehydrogenase for short chain fatty acids) as the underlying gene. More recently, we have shown that the slow wave activity during sleep is also affected by a single gene (Rarb) involved in the vitamin A signaling pathway. We are now concentrating our research efforts on the genetic dissection of sleep need. Sleep need is homeostatically regulated (loss of sleep leads to compensatory processes, which are responsible for deeper recovery sleep). A gene for sleep need has been mapped on the mouse chromosome 13. Gene expression profiling after sleep deprivation to investigate the molecular correlates of prolonged wakefulness, identified Homer1a on chromosome 13 as the best molecular marker of sleep need. Finally, we are interested in sleep and circadian rhythms and their molecular basis in social species such as ants.

Genetics of sleep disorders
Many sleep disorders run in families but their genetic bases are poorly understood. Our laboratory is specialized in the genetics of narcolepsy and sleepwalking. We perform family – and population – based studies using linkage, candidate gene, and genome-wide associations. We have also initiated a new Center for Investigation and Research in Sleep (CIRS) in collaboration with the Department of Medicine of the University Hospital (CHUV), Lausanne, where we plan to conduct sleep research in normal subjects and patients with sleep disorders. We have localized the first familial susceptibility gene for narcolepsy and have reported the first genetic evidence in sleepwalking. Future plans include genetics of normal sleep in twins, families, and the general population.

 

Representative publications

Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE, Iranzo A, Santamaria J, Peraita Adrados R, Vicario JL, Overeem S, Arnulf I, Theodorou I, Jennum P, Knudsen S, Bassetti C, Mathis J, Lecendreux M, Mayer G, Geisler P, Beneto A, Petit B, Pfister C, Burki JV, Didelot G, Billiard M, Ercilla G, Verduijn W, Claas FH, Vollenweider P, Waeber G, Waterworth DM, Mooser V, Heinzer R, Beckmann JS, Bergmann S, Tafti M. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet. 2010, 42:786-9.

Cvetkovic-Lopes V, Bayer L, Dorsaz S, Maret S, Pradervand S, Dauvilliers Y, Lecendreux M, Lammers GJ, Donjacour CE, Du Pasquier RA, Pfister C, Petit B, Hor H, Muhlethaler M, Tafti M. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest. 2010, 120:713-719.

Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C, Hagenbuchle O, O'Hara BF, Franken P, Tafti M. Homer1a is a core brain molecular correlate of sleep loss. Proc Natl Acad Sci U S A. 2007, 104:20090-20095.

Maret S, Franken P, Dauvilliers Y, Ghyselinck NB, Chambon P, Tafti M. Retinoic acid signaling affects cortical synchrony during sleep. Science. 2005, 310:111-113.

Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, and Franken P. Deficiency in short-chain fatty acid b-oxidation affects theta oscillations during sleep. Nat. Genet., 2003, 34: 320-325.
 


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