最新有一項(xiàng)研究發(fā)現(xiàn),，在人類中一個(gè)“時(shí)鐘”基因的突變可以讓人“早睡早起”——家族性睡眠時(shí)相提前綜合癥（*），這為我們得以窺探人類睡眠基因的秘密提供了很好的機(jī)會(huì),。這篇研究成果發(fā)表在2007年1月12日的《Cell》雜志上,，解釋了在這些人的體內(nèi)生物鐘是如何提早“完工”的。
小鼠的研究表明,，如果Period 2 (Per2)時(shí)鐘基因（**）發(fā)生突變,，原本可以通過化學(xué)修飾調(diào)控該蛋白的酶則不再起作用。這種調(diào)控功能的喪失導(dǎo)致Per2蛋白表達(dá)下降,，睡眠模式也發(fā)生了特征性地變化,。
“對于這些可以影響我們生物鐘的因子有助于我們探索一些治療的方法，用于治療飛行時(shí)差（參見備注1）,、輪班睡眠疾患（參見備注2）等癥狀,。”研究者稱,。
UCSF研究小組發(fā)現(xiàn)一種人類Per2基因的突變可以引起FASPS癥狀。這是S662G突變,，即662位點(diǎn)處絲氨酸被甘氨酸取代,，從而阻止了該位點(diǎn)的磷酸化修飾。
同時(shí),，研究者發(fā)現(xiàn)在正常小鼠中插入人類的突變基因會(huì)讓這些小鼠也起早,，印證了人類的FASPS癥狀。形成對比的是,，如果在662位點(diǎn)處發(fā)生的突變可以引起磷酸化能力增強(qiáng)的話,，PER2的轉(zhuǎn)錄水平會(huì)上升，小鼠睡眠的時(shí)間也會(huì)推遲,。
結(jié)合其他的實(shí)驗(yàn),，研究者發(fā)現(xiàn)S662G突變的人或者小鼠體內(nèi)，PER2表達(dá)水平都會(huì)下降,，但是該蛋白的降解過程絲毫未受影響,。從而，PER2的表達(dá)水平在任何時(shí)候都會(huì)比正常水平少,。在整個(gè)日周期的后半段,，PER2更早地降到了閾值以下，引起后續(xù)生理效應(yīng),。
對PER2作用的理解增強(qiáng)了我們治療人類相關(guān)疾病的信心,，“總有一天，一些不適應(yīng)飛行時(shí)差,、輪班睡眠疾患的人只需要服用一片藥就可以恢復(fù)正常,。”作者Fu說道。
英文詞匯：
*familial advanced sleep phase syndrome,；FASPS
**clock gene,。光刺激會(huì)調(diào)整機(jī)體的中心時(shí)鐘(central clock)，Per2在此過程中起著非常關(guān)鍵的作用,。
備注1：
生理時(shí)鐘與日節(jié)律
在一天24小時(shí)內(nèi),，個(gè)體在生活上呈現(xiàn)周期性的活動(dòng)；何時(shí)睡眠,，何時(shí)進(jìn)食,，何時(shí)工作，幾乎都有一定的順序,，而此等順序幾乎是由個(gè)體生理上的運(yùn)作所決定,。像此種決定個(gè)體周期性生活活動(dòng)的生理作用，稱為生理時(shí)鐘（biological Clock）,。生理時(shí)鐘之所以形成,，除個(gè)體生活習(xí)慣因素（如經(jīng)常上夜班者的生理時(shí)鐘即與一般人不同）之外，主要受一天24小時(shí)變化所決定,。例如：一天之內(nèi)的溫度有顯著的變化,，人類身體的體溫，在一天內(nèi)也有顯著的變化,，在環(huán)境溫度降低而人的體溫也降低的情況之下,，個(gè)體就會(huì)產(chǎn)生睡眠的需求。每天氣溫的變化規(guī)律,，大致是午夜至凌晨五時(shí)左右的一段時(shí)間最低,，人類的體溫，也正好是在此一時(shí)段,，降至最低,。因此，對絕大多數(shù)的人來說,，晚上十一點(diǎn)鐘至翌晨六點(diǎn)鐘,，是睡眠時(shí)間。故而生理時(shí)鐘也稱為日節(jié)律（circadian rhythm）,。
對動(dòng)物的生活而言,，日節(jié)律具有極大的支配力。因此,，候鳥或魚類的遷徙,，多在地球上的南北向同經(jīng)度內(nèi)移動(dòng)，藉以維持其周期性的生理時(shí)鐘,。人類祖先的活動(dòng),，本來也像其他動(dòng)物一樣，日出而作,，日入而息,。惟以現(xiàn)代交通工具快捷，噴射機(jī)的飛行,，使地球兩對面的距離,，變?yōu)槌l(fā)夕至；從臺(tái)北飛到紐約,，正好形成晨昏顛倒,，使人遇到了睡眠適應(yīng)困難的問題。這現(xiàn)象稱為飛行時(shí)差（jet lag）,。飛行時(shí)差的一般征候是：身心疲倦,，食欲不振，睡眠暫時(shí)失常,。飛行時(shí)差的困擾程度,，因飛行方向而異,；順太陽方向（西行去歐洲）飛行時(shí)，飛行時(shí)差的困擾較少,；逆太陽方向（東行去美洲）飛行時(shí),，飛行時(shí)差的困擾較大。飛行時(shí)差形成的睡眠困擾,，一般在三天至一周內(nèi)即可自行消失,，而在新環(huán)境內(nèi)重新建立起個(gè)人的生理時(shí)鐘。
備注2：
shift work sleep disorder,；醫(yī)學(xué)工作者研究發(fā)現(xiàn),，輪班(shift work)可導(dǎo)致人體生物節(jié)律紊亂，使人們產(chǎn)生輪班睡眠疾患(shift work sleep disorder),。這種疾病主要發(fā)生在輪班制的工作人員,，特別是在一定時(shí)間內(nèi)連續(xù)進(jìn)行同樣的夜班工作的人更容易發(fā)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."
