最新有一项研究发现，在人类中一个“时钟”基因的突变可以让人“早睡早起”——家族性睡眠时相提前综合症（*），这为我们得以窥探人类睡眠基因的秘密提供了很好的机会。这篇研究成果发表在2007年1月12日的《Cell》杂志上，解释了在这些人的体内生物钟是如何提早“完工”的。
小鼠的研究表明，如果Period 2 (Per2)时钟基因（**）发生突变，原本可以通过化学修饰调控该蛋白的酶则不再起作用。这种调控功能的丧失导致Per2蛋白表达下降，睡眠模式也发生了特征性地变化。
“对于这些可以影响我们生物钟的因子有助于我们探索一些治疗的方法，用于治疗飞行时差（参见备注1）、轮班睡眠疾患（参见备注2）等症状。”研究者称。
UCSF研究小组发现一种人类Per2基因的突变可以引起FASPS症状。这是S662G突变，即662位点处丝氨酸被甘氨酸取代，从而阻止了该位点的磷酸化修饰。
同时，研究者发现在正常小鼠中插入人类的突变基因会让这些小鼠也起早，印证了人类的FASPS症状。形成对比的是，如果在662位点处发生的突变可以引起磷酸化能力增强的话，PER2的转录水平会上升，小鼠睡眠的时间也会推迟。
结合其他的实验，研究者发现S662G突变的人或者小鼠体内，PER2表达水平都会下降，但是该蛋白的降解过程丝毫未受影响。从而，PER2的表达水平在任何时候都会比正常水平少。在整个日周期的后半段，PER2更早地降到了阈值以下，引起后续生理效应。
对PER2作用的理解增强了我们治疗人类相关疾病的信心，“总有一天，一些不适应飞行时差、轮班睡眠疾患的人只需要服用一片药就可以恢复正常。”作者Fu说道。
英文词汇：
*familial advanced sleep phase syndrome；FASPS
**clock gene。光刺激会调整机体的中心时钟(central clock)，Per2在此过程中起着非常关键的作用。
备注1：
生理时钟与日节律
在一天24小时内，个体在生活上呈现周期性的活动；何时睡眠，何时进食，何时工作，几乎都有一定的顺序，而此等顺序几乎是由个体生理上的运作所决定。像此种决定个体周期性生活活动的生理作用，称为生理时钟（biological Clock）。生理时钟之所以形成，除个体生活习惯因素（如经常上夜班者的生理时钟即与一般人不同）之外，主要受一天24小时变化所决定。例如：一天之内的温度有显著的变化，人类身体的体温，在一天内也有显著的变化，在环境温度降低而人的体温也降低的情况之下，个体就会产生睡眠的需求。每天气温的变化规律，大致是午夜至凌晨五时左右的一段时间最低，人类的体温，也正好是在此一时段，降至最低。因此，对绝大多数的人来说，晚上十一点钟至翌晨六点钟，是睡眠时间。故而生理时钟也称为日节律（circadian rhythm）。
对动物的生活而言，日节律具有极大的支配力。因此，候鸟或鱼类的迁徙，多在地球上的南北向同经度内移动，藉以维持其周期性的生理时钟。人类祖先的活动，本来也像其他动物一样，日出而作，日入而息。惟以现代交通工具快捷，喷射机的飞行，使地球两对面的距离，变为朝发夕至；从台北飞到纽约，正好形成晨昏颠倒，使人遇到了睡眠适应困难的问题。这现象称为飞行时差（jet lag）。飞行时差的一般征候是：身心疲倦，食欲不振，睡眠暂时失常。飞行时差的困扰程度，因飞行方向而异；顺太阳方向（西行去欧洲）飞行时，飞行时差的困扰较少；逆太阳方向（东行去美洲）飞行时，飞行时差的困扰较大。飞行时差形成的睡眠困扰，一般在三天至一周内即可自行消失，而在新环境内重新建立起个人的生理时钟。
备注2：
shift work sleep disorder；医学工作者研究发现，轮班(shift work)可导致人体生物节律紊乱，使人们产生轮班睡眠疾患(shift work sleep disorder)。这种疾病主要发生在轮班制的工作人员，特别是在一定时间内连续进行同样的夜班工作的人更容易发生。
英文原文：
Gene That Makes People 'Early To Bed And Early To Rise' Demystified
The recent discovery that a mutant 'clock' gene made some people 'early to bed and early to rise,' a condition known as familial advanced sleep phase syndrome (FASPS), offered one of the first glimpses into the genetic basis of sleep in humans. Now, researchers report in the Jan. 12, 2007 issue of the journal Cell, published by Cell Press, new evidence that helps to explain just how their bodies' natural alarm clocks get set to such an early wake-up time.
In studies of mice carrying the human FASPS gene, the researchers found that the mutant version of the Period 2 (Per2) clock gene--which is crucial for resetting the body's central clock in response to light--cannot be chemically modified by another enzyme that controls it. That failure leads to a reduction in the number of copies of the Per2 "message," and the characteristic shifted sleep pattern.
Eventually, such insight into the factors influencing people's so-called circadian, or daily, rhythm might lead to therapies that could adjust the body's clock in those suffering from conditions including jet lag or shift work sleep disorder, according to the researchers.
"This study highlights the power of natural human mutations to uncover things [about the circadian clock] that we might not otherwise have learned, or that we might have misunderstood before," said Howard Hughes Investigator Louis PtСcek, of the University of California, San Francisco.
"Most of the information we've had about these clock genes has been based on the Drosophila model and Per2 knockout mice," which lack the Per2 clock gene altogether, added study author Ying-Hui Fu, who is also at UCSF.
Based on those studies, "everybody had thought a short or long period depended on a change in protein stability," she said. "That's how we thought the system should work. But this paper shows that is not the case. It comes back instead to the transcription level as the most important step."
FASPS is a relatively rare, inherited condition in which people are "morning larks," with early morning awakening and early sleep times. People with the condition generally show changes in core body temperatures and other characteristics governed by the circadian clock that are shifted up by three to four hours. The syndrome is passed on in a dominant fashion, meaning that it takes just one copy of the abnormal gene to exhibit symptoms.
The UCSF group had earlier discovered a variant of the human Per2 gene that causes FASPS. They also showed that the so-called "S662G" variant, in which the serine building block normally present at position 662 is replaced by glycine, prevented a regulatory enzyme from tacking a phosphate onto the encoded protein.
Now, the researchers report additional evidence that the lost "phosphorylation" prevents a cascade of chemical modifications that are normally primed by the initial event.
Moreover, they show that the human gene inserted into otherwise normal mice causes them to rise early, symptoms that mirror those in people with FASPS. In contrast, a mutation that mimicked an increase in phosphorylation at amino acid 662 increased the transcription of PER2 and pushed the animals' sleep pattern later.
Their studies in mice revealed that the amino acid change associated with FASPS, which alters the charge of the residue, alters the ability of PER2 to regulate its own transcription. PER2 presumably manages such regulation through interaction with other proteins since it doesn't bind DNA itself, they said.
The findings led the researchers to suggest a model of clock function in which cells sense changing PER2 levels over time, beginning a new daily cycle when a certain threshold is crossed.
"In S662G individuals or mice, the alteration in transcription leads to production of less PER2, while the clock protein's degradation remains unaffected," they explained. Thus, the researchers added, "PER2 levels are lower at all time points and, in the latter half of a cycle, fall below the threshold earlier than normal, leading to activation of transcription earlier and resulting in a shorter period."
The advance in understanding of PER2's role may ultimately lead to methods for people, such as nurses who must care for patients in the middle of the night, to synchronize their internal clocks with their regular or changing daily routines, the researchers said.
Someday "people with jet lag or shift work--some of the most common of sleep disorders--might take a pill and be back to normal again," Fu said.
"When we fly to Europe, we set our watch ahead several time zones and our watch is back on track," PtСcek added. "We don't understand the [internal] human clock well enough to advance or delay it that way. But with all that we've learned from the fruit fly, mouse and now human about the gears and how they are working, we're getting closer to a 'button' that might be able to do that."
