三支研究小组各自独立在小鼠中发现一个生理节奏基因。诱变筛选（Mutagenesis screens）结果显示，编码FBXL3蛋白的基因发生突变，小鼠的生物钟会延长几个小时；生化分析结果显示FBXL3是生物钟关键蛋白的降解所必需的。文章刊登于两篇Science文章和一篇Cell文章。
“我觉得这是一个非常令人振奋的发现，” Scripps 研究所Steve Kay说（未参与研究），“说明早期遗传学仍旧是鉴别新的钟基因（clock genes）的有利工具。”
哺乳动物的生理节奏是由基因转录和翻译的反馈环产生的。转录因子CLOCK和BMAL1驱动钟基因Period (Per)和Cryptochrome (Cry)表达，这两种基因表达的蛋白与CLOCL和BMAL1相互作用，抑制它们的转录。PER和CRY蛋白降解，抑制作用下降，转录重新开始。回路中有延滞（Delays），以致整个周期约为24小时。一个重要的延滞含有PER和CRY蛋白的翻译后修饰，决定了这些蛋白降解的时长。
第一篇Science文章讲述，英国Harwell医学研究理事会（MRC）Sofia Godinho和剑桥MRC的Elizabeth Maywood率领的研究小组，诱导小鼠发生突变以寻找新的生物钟基因，结果发现一个名为Fbxl3的F-box基因发生突变会导致小鼠的生理周期延长到27个小时（他们称之为“after hours”）。“他们在那些突变动物中发现了一个显著现象，”马萨诸塞大学医学院David Weaver说（未参与实验），“这说明（FBXL3）是一个非常重要的调解者。”
英文原文：
--------------------------------------------------------------------------------
Published Online April 26, 2007
Science DOI: 10.1126/science.1141138
Submitted on February 12, 2007
Accepted on April 18, 2007
The After-Hours Mutant Mouse Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period
Sofia I. H. Godinho 1, Elizabeth S. Maywood 2, Linda Shaw 1, Valter Tucci 1, Alun R. Barnard 1, Luca Busino 3, Michele Pagano 3, Rachel Kendall 1, Mohamed M. Quwailid 1, M. Rosario Romero 1, John O'Neill 2, Johanna E. Chesham 2, Debra Brooker 1, Zuzanna Lalanne 1, Michael H. Hastings 2, Patrick M. Nolan 1*
1 Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
2 MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road, Cambridge CB2 2QH, UK.
3 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
* To whom correspondence should be addressed.
Patrick M. Nolan , E-mail: p.nolan@har.mrc.ac.uk
By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys358Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected PER2 expression and delayed the rate of CRY protein degradation in PER2::LUCIFERASE tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.
