Karolinska Research Lectures: Michael W. Young
Karolinska Research Lectures i Nobel forum: Michael W. Young. President for Academic Affairs, Laboratory of Genetics, Rockefeller University, New York, USA
Titel: “Genetic regulation of sleep and circadian rhythms”.
Värd: Per Svenningsson
Studies of the molecular basis for circadian rhythmicity began in the early 1980s in
our laboratory at Rockefeller, and in the laboratories of Jeffrey Hall and Michael Rosbash at Brandeis University. Over the past 30 years our groups, which initially focused on the fruitfly Drosophila melanogaster, demonstrated that circadian clocks in animal cells rely on an auto-regulatory network composed of a very small number of genes. In Drosophila, two genes, cyc and clk encode transcriptional activators (Cycle and Clock) that promote the expression of hundreds of genes in most cell types. However, among the regulated genes are per and tim, which form inhibitors of Cycle and Clock. Additional genes contribute to delays in this negative feedback loop, establishing patterns of oscillating gene expression with ~24-hour periodicity across much of the genome.
Recently our laboratory has expanded its focus to include genetic and molecular studies of sleep and circadian rhythms in humans. The role of the inhibitory protein TIM is replaced by CRY in mammals, and we have identified a CRY variant associated with a form of DSPD (Delayed Sleep Phase Disorder). DSPD is the most commonly diagnosed type of circadian rhythm sleep disorder and is characterized by a persistent and intractable delay of sleep onset and offset times relative to the societal norm. The CRY variant we discovered is dominant and encodes a transcriptional inhibitor with enhanced affinity for the circadian activator proteins. It causes reduced expression of key transcriptional targets and lengthening of the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele is carried by ~ 1 in 75 individuals of non-Finnish European ancestry and is also prevalent in Latino and South Asian populations. Reverse phenotyping of several unrelated families corroborates late and/or fragmented sleep patterns in carriers, indicating that the CRY variant affects sleep behavior in a sizeable portion of the human population.
Tatiana Goriatcheva, Nobelkansliet, Nobel Forum,
tel. 524 87805, email@example.com