轉(zhuǎn)載自Science Focus:?

"Viruses: their extraordinary role in shaping human evolution"

引言

Introduction

病毒給我們帶來了從普通感冒到COVID-19和艾滋病的感染。但研究表明，它們在塑造智人的進化過程中可能也發(fā)揮了關(guān)鍵作用。

Viruses give us infections from the common cold to COVID-19 and AIDS. But research shows that they may also have played a key role in shaping the evolution of Homo sapiens.

冠狀病毒、寨卡病毒、埃博拉病毒、流感，甚至無聊的普通感冒--我們都熟悉困擾人類的病毒。但是，盡管我們知道它們使我們生病，但發(fā)現(xiàn)在數(shù)百萬年的時間里，我們已經(jīng)成功地駕馭和馴化了這些狡猾的入侵者，可能會令人驚訝。

Coronavirus, Zika, Ebola, flu, even the boring old common cold – we’re all familiar with the viruses that plague humanity. But while we know they make us sick, it may be surprising to discover that, over millions of years, we’ve managed to harness and domesticate these crafty invaders.

從生命的萌芽階段到我們臉上綻放笑容，病毒對我們?nèi)祟惍a(chǎn)生了巨大影響。

From the earliest stages of life to the smiles on our faces, viruses have had a huge influence on our human species.

1.病毒如何工作

How viruses work

病毒只不過是一串基因（通常以一種叫做RNA的分子形式存在）被包裝在一個蛋白質(zhì)外殼中，它們都以同樣的基本方式工作。

Viruses are little more than a string of genes (usually in the form of a molecule called RNA) packaged in a protein coat, and they all work in the same basic way.

一旦病毒感染了一個細胞，它就會劫持細胞自身的分子機器來復制其基因并產(chǎn)生病毒蛋白。新的病毒由這些新制造的部件組裝而成，最終迸發(fā)出來，尋找新的細胞進行攻擊。

Once a virus has infected a cell, it hijacks the cell’s own molecular machinery to copy its genes and churn out viral proteins. New viruses are assembled from these freshly manufactured parts, which eventually burst out in search of new cells to attack.

對于大多數(shù)病毒，如流感，故事到此結(jié)束。但是少數(shù)逆轉(zhuǎn)錄病毒--包括HIV--更加狡猾，它們偷渡到我們的DNA中。它們隨機地插入一個生物體的基因組中，低調(diào)行事，直到時機成熟再次開始生產(chǎn)病毒。

For most viruses, such as flu, the story ends there. But a handful of retroviruses – including HIV – are even sneakier, smuggling their way into our DNA. They insert themselves randomly into the genome of an organism, lying low until the time is right to start virus production again.

但是，一旦逆轉(zhuǎn)錄病毒進入了一個生物體的DNA，就不能保證它將留在原地。遺傳指令可以從嵌入的病毒中 "讀取"，轉(zhuǎn)化為DNA，然后粘貼到基因組的另一個位置。一次又一次地重復這個循環(huán)，病毒DNA的多個副本很快就會積累起來。

But once a retrovirus has got into an organism’s DNA, there’s no guarantee that it will stay put. The genetic instructions can be ‘read’ from the embedded virus, converted into DNA and then pasted into another location in the genome. Repeat this cycle again and again, and multiple copies of the viral DNA quickly build up.

經(jīng)過數(shù)百萬年，這些病毒DNA序列隨機變異和改變，失去了從宿主細胞中掙脫的能力。被困于基因組內(nèi)，這些 "內(nèi)源性 "逆轉(zhuǎn)錄病毒中的一些仍然可以跳來跳去，而另一些則永遠停留在它們最后落腳的地方。

Over millions of years, these viral DNA sequences randomly mutate and change, losing their ability to break free from their host cells. trapped inside the genome, some of these ‘endogenous’ retroviruses can still jump around while others are stuck forever where they last landed.

而如果這些事件中的任何一個發(fā)生在制造卵子和精子的生殖細胞中，那么它們將被代代相傳，最終成為生物體基因組的永久組成部分。

And if any of these events happen in the germ cells that make eggs and sperm, then they will be passed down the generations and eventually become a permanent part of an organism’s genome.

大約一半的人類基因組是由數(shù)百萬個DNA序列組成的，這些序列可以追溯到早已死亡的病毒或類似的 "跳躍基因"，統(tǒng)稱為可轉(zhuǎn)座元素或轉(zhuǎn)座子。

Around half of the human genome is made up of millions of DNA sequences that can be traced back to long-dead viruses or similar ‘jumping genes’, known collectively as transposable elements or transposons.

一些研究人員甚至將這一數(shù)字提高到80%，因為古老的序列現(xiàn)在已經(jīng)退化到無法識別病毒的程度，像分子化石一樣在基因組中風化。

Some researchers would even put this figure up at 80 per cent, as ancient sequences are now degraded beyond the point of being recognisably virus-like, weathered within the genome like molecular fossils.

多年來，人類基因組中的大塊重復性病毒衍生的DNA被認為是 "垃圾"。在我們的基因軀干中，一部分重復性的東西無疑只是垃圾，但隨著研究人員更仔細地觀察單個病毒元素，一個更復雜的畫面正在出現(xiàn)。

For many years, the large chunks of repetitive virus-derived DNA littering the human genome were dismissed as ‘junk’. A proportion of this repetitive stuff undoubtedly is little more than junk in our genetic trunk, but as researchers look more closely at individual viral elements, a more sophisticated picture is emerging.

事實證明，除了是我們的基因敵人之外，一些嵌入我們基因組的病毒已經(jīng)為我們所用。

And it turns out that as well as being our genetic enemies, some of the viruses embedded in our genome have become our slaves.

2.合胞素的進化

Syncytin evolution

大約15年前，美國研究人員發(fā)現(xiàn)了一個只在胎盤中活躍的人類基因。他們稱其為syncytin，因為它能制造一種分子，將胎盤細胞融合在一起，形成一個特殊的組織層，稱為syncitium。奇怪的是，syncytin看起來很像逆轉(zhuǎn)錄病毒的基因。

Around 15 years ago, US researchers discovered a human gene that was only active in the placenta. They called it syncytin, because it makes a molecule that fuses placental cells together, creating a special layer of tissue known as a syncitium. Curiously, syncytin looks a lot like a gene from a retrovirus.

后來又發(fā)現(xiàn)了另一個syncytin基因，它也參與了胎盤的形成，以及防止母親的免疫系統(tǒng)攻擊她腹中的胎兒。同樣，該基因看起來也是來自于一種逆轉(zhuǎn)錄病毒。

Another syncytin gene was later discovered, which is also involved in forming the placenta as well as preventing the mother’s immune system from attacking the foetus in her womb. Again, the gene looks like it has come from a retrovirus.

但是，雖然人類和其他大型靈長類動物有相同的兩個合胞素基因，但在任何其他哺乳動物中，都沒有發(fā)現(xiàn)類似的胎盤融合細胞層。

But while humans and other large primates have the same two syncytin genes, they aren’t found in any other mammals with similar fused cell layers in the placenta.

小鼠也有兩個syncytin基因：它們的工作與人類版本相同，但它們看起來像完全不同的病毒。而在貓和狗身上還有另一個單獨的病毒衍生的syncytin基因，這兩種動物都是同一食肉動物祖先的后代。

Mice also have two syncytin genes: they do the same job as the human version, but they look like completely different viruses. And there’s another separate virally-derived syncytin gene in cats and dogs, both of which are descended from the same carnivorous ancestors.

顯然，所有這些哺乳動物物種在數(shù)百萬年前都被特定的病毒所感染。隨著時間的推移，這些病毒已經(jīng)被利用起來，在胎盤生長中發(fā)揮了關(guān)鍵作用，使它們成為我們基因組中的一個永久的固定物。

Clearly, all these mammalian species were infected by particular viruses millions of years ago. Over time, those viruses have been harnessed to play a key role in placental growth, making them a permanent fixture in our genome.

耐人尋味的是，豬和馬的胎盤中沒有一層融合的細胞，而且它們也沒有任何看起來像病毒衍生的合胞素的基因。因此，也許它們從未感染過這種融合病毒。

Intriguingly, pigs and horses don’t have a layer of fused cells in their placenta, and they also don’t have any genes that look like virally-derived syncytins. So maybe they never caught one of these fusing viruses.

3.?跳躍的基因

Jumping genes

雖然syncytin的案例揭示了全盤采用病毒基因來為我們服務(wù)，但還有更多的例子說明古代病毒序列如何影響當今人類的基因活動。

While the case of syncytin reveals the wholesale adoption of a virus gene to do our bidding, there are many more examples of how ancient viral sequences can influence gene activity in today’s humans.

早在20世紀50年代，長期被忽視的美國遺傳學家芭芭拉-麥克林托克艱苦細致的工作揭示了 "跳躍基因 "可以影響玉米植物的基因組。

Back in the 1950s, painstakingly detailed work by the long-overlooked American geneticist Barbara McClintock revealed that ‘jumping genes’ could affect the genome of maize plants.

就像麥克林托克在玉米中發(fā)現(xiàn)的 "跳躍基因 "一樣，潛伏在我們?nèi)祟惢蚪M中的內(nèi)源性逆轉(zhuǎn)錄病毒在數(shù)百萬年中一直在移動，隨意跳躍并改變其附近的基因的活性。

And just like the ‘jumping genes’ McClintock identified in maize, the endogenous retroviruses that lurk in our own human genome have been on the move over millions of years, jumping around at random and altering the activity of genes in their immediate vicinity.

我們的細胞投入了大量的能量，試圖阻止這些病毒元素的跳動。它們被貼上了化學標簽并被鎖定，被稱為表觀遺傳標記。但是，隨著病毒元素的移動，這些分子沉默器也隨之移動，因此病毒序列的影響可以傳播到它們所處的鄰近基因。

Our cells invest a lot of energy in attempting to stop these viral elements from going on the hop. They’re labelled and locked down with chemical tags, known as epigenetic marks. But, as the viral elements move, these molecular silencers move with them, so the viral sequences’ effects can spread to neighbouring genes wherever they land.

相反，病毒也充滿了吸引分子的DNA序列，這些分子可以開啟基因。在一個功能性的逆轉(zhuǎn)錄病毒中，這些 "開關(guān) "激活了病毒基因，因此它可以再次變得具有傳染性。但是，當一個類似病毒的序列被拼接到基因組的另一個區(qū)域時，這種作為基因開關(guān)的能力最終可能會變得無序。

Conversely, viruses are also full of DNA sequences that attract molecules which switch genes on. In a functional retrovirus, these ‘switches’ activate the viral genes so it can become infectious again. But when a virus-like sequence gets spliced into another region in the genome, this ability to act as a genetic switch can end up going rogue.

2016年，猶他大學的科學家們發(fā)現(xiàn)，人類基因組中的一種內(nèi)源性逆轉(zhuǎn)錄病毒--它最初來自于大約4500萬到6000萬年前感染我們祖先的一種病毒--當它檢測到一種叫做干擾素的分子時，會開啟一種叫做AIM2的基因，干擾素是警告身體正在遭受病毒感染的 "危險信號"。AIM2然后迫使受感染的細胞自我毀滅，以防止感染進一步擴散。

In 2016, scientists at the University of Utah found that an endogenous retrovirus in the human genome – which originally came from a virus that infected our ancestors roughly 45 million to 60 million years ago – switches on a gene called AIM2 when it detects a molecule called interferon, which is the ‘danger signal’ that warns the body that it’s suffering a viral infection. AIM2 then forces the infected cells to self-destruct, to prevent the infection from spreading any further.

這些古老的病毒已經(jīng)成為 "雙重代理"，幫助我們的細胞對付試圖攻擊我們的其他病毒。

These ancient viruses have become ‘double agents’, helping our cells to tackle other viruses that are trying to attack us.

另一個可能塑造了我們物種的病毒的例子是在一個叫做PRODH的基因附近發(fā)現(xiàn)的。PRODH存在于我們的腦細胞中，特別是在海馬體。

Another example of a virus that may have shaped our species is found near a gene called PRODH. PRODH is found in our brain cells, particularly in the hippocampus.

在人類中，該基因是由一個早已死亡的逆轉(zhuǎn)錄病毒制成的控制開關(guān)激活的。黑猩猩也有一個版本的PRODH基因，但它在它們的大腦中幾乎沒有那么活躍。

In humans, the gene is activated by a control switch made from a long-dead retrovirus. Chimpanzees also have a version of the PRODH gene, but it’s not nearly so active in their brains.

一種可能的解釋是，在數(shù)百萬年前，一種古老的病毒在我們某個早已死去的祖先的PRODH旁邊跳躍了一個自己的副本，但這并沒有發(fā)生在繼續(xù)進化成今天的黑猩猩的祖先靈長類身上。

One possible explanation is that an ancient virus hopped a copy of itself next to PRODH in one of our long-dead ancestors, millions of years ago, but that this didn’t happen in the ancestral primates that went on to evolve into today’s chimps.

今天，PRODH的故障被認為與某些大腦疾病有關(guān)，因此它極有可能至少對人類大腦的布線產(chǎn)生了某種影響。

Today, faults in PRODH are thought to be involved in certain brain disorders, so it’s highly likely to have had at least some kind of influence on the wiring of human brains.

同樣，基因開關(guān)的變化也是造成我們在子宮內(nèi)成長時構(gòu)建人類面部的細胞與黑猩猩的細胞之間差異的原因。盡管我們的基因與黑猩猩的基因幾乎完全相同，但我們看起來肯定不一樣。所以區(qū)別一定在于控制開關(guān)。

Similarly, variations in genetic switches are responsible for the differences between the cells that build our human faces as we grow in the womb and those of chimps. Although our genes are virtually identical to chimpanzee genes, we certainly don’t look the same. So the difference must lie in the control switches.

從它們的DNA序列來看，許多在生長我們臉部的細胞中活躍的開關(guān)似乎最初來自病毒，它們一定是在我們成為今天的平臉物種的進化過程中的某個時候跳到了適當?shù)奈恢谩?/p>

Judging by their DNA sequences, many of the switches that are active in the cells that grow our faces seem to have originally come from viruses, which must have hopped into place sometime in our evolutionary journey towards becoming the flat-faced species we are today.

4.病毒馴服者

The virus tamers

除了尋找早已死亡的病毒改變我們的生物學的例子之外，科學家們還在尋找支撐其效果的控制機制。關(guān)鍵的罪魁禍首是被稱為KRAB鋅指蛋白（KRAB ZFPs）的特殊沉默分子，它們抓住基因組中的病毒序列并將其固定在原位。

As well as searching for examples of long-dead viruses that have altered our biology, scientists are searching for the control mechanisms that underpin their effects. The key culprits are special silencing molecules called KRAB Zinc Finger Proteins (KRAB ZFPs), which grab hold of viral sequences in the genome and pin them in place.

瑞士洛桑大學的Didier Trono教授和他的團隊在人類基因組中發(fā)現(xiàn)了300多種不同的KRAB ZFPs，其中每一種似乎都喜歡一個不同的病毒衍生的DNA目標。一旦到了那里，它們就會幫助招募開啟或關(guān)閉基因的分子機器。

Prof Didier Trono and his team at the University of Lausanne in Switzerland have discovered more than 300 different KRAB ZFPs in the human genome, each of which seems to prefer a different virally-derived DNA target. Once there, they help to recruit the molecular machinery that turns genes on or off.

"Trono解釋說："這些KRAB ZFPs一直被視為這些內(nèi)源性逆轉(zhuǎn)錄病毒的'殺手'。"但它們實際上是這些元素的利用者，使生物體能夠利用駐留在這些病毒序列中的豐富可能性"。

“These KRAB ZFPs have been viewed as ‘killers’ of these endogenous retroviruses,” Trono explains. “But they are actually exploiters of these elements that allow the organism to exploit the wealth of possibility that resides in these viral sequences.”

特羅諾和他的團隊認為，KRAB ZFPs是積極有害的病毒序列和那些已經(jīng)成為馴服的控制開關(guān)之間的缺失環(huán)節(jié)。

Trono and his team believe that KRAB ZFPs are the missing link between viral sequences that are actively harmful and those that have become tamed control switches.

他們有證據(jù)表明，這些蛋白質(zhì)在一種 "軍備競賽 "中與病毒元素一起進化，最初抑制它們，但最終壓倒了它們。

They have evidence that the proteins have evolved alongside the viral elements in a kind of ‘a(chǎn)rms race’, initially suppressing them but eventually overpowering them.

"我們認為它們所做的是馴化這些元素，"特羅諾說。"而通過馴化，我的意思是不只是確保病毒不動，而是把它們變成對宿主有益的東西，這是一種非常精細的調(diào)節(jié)所有可能的細胞和情況下的基因活動的方式。"

“We think that what they do is domesticate these elements,” Trono says. “And by domestication, I mean not just making sure that the viruses stay put, but turning them into something beneficial for the host, which is a very refined way of regulating gene activity in all possible cells and situations.”

支持這一觀點的是發(fā)現(xiàn)不同的KRAB ZFPs組在不同類型的細胞中都很活躍。它們還在不同的物種中以特定的模式被發(fā)現(xiàn)。

Supporting this idea is the finding that distinct groups of KRAB ZFPs are active in different types of cells. They’re also found in specific patterns in different species.

如果它們只是抑制病毒，那么，同樣的蛋白質(zhì)陣列應(yīng)該存在于所有細胞中。更重要的是，為什么它們會被發(fā)現(xiàn)與特羅諾和他的團隊已經(jīng)確定的數(shù)千個早已死亡的病毒元素結(jié)合在一起？

If they were just suppressing viruses, the argument goes, the same array of proteins should be present in all cells. What’s more, why would they be found bound to the many thousands of long-dead viral elements that Trono and his team have identified?

抑制一個死亡的逆轉(zhuǎn)錄病毒是沒有意義的，所以它們一定在控制基因活動方面發(fā)揮著重要作用。

There’s no point suppressing a dead retrovirus, so they must be playing an important role in controlling gene activity.

盡管他的想法仍有些爭議，但特羅諾認為KRAB ZFPs是病毒奴役者的一種力量，利用這些元素為我們服務(wù)，將它們變成基因控制開關(guān)。

Although his idea is still a little controversial, Trono sees the KRAB ZFPs as a force of viral slavedrivers, harnessing these elements to do our bidding and turning them into genetic control switches.

在幾百萬年里，這可能是創(chuàng)造新物種的強大馬達。例如，如果一種病毒隨機地在一種祖先生物中跳躍，而不是在另一種祖先生物中跳躍，然后隨著時間的推移被KRAB ZFP馴服，它將創(chuàng)造出新的控制開關(guān)，可能對動物的外觀或行為產(chǎn)生很大影響。

Over many millions of years, this could have been a powerful motor for creating new species. For example, if a virus randomly goes on the hop in one ancestral creature and not another and is then tamed over time by a KRAB ZFP, it will create new control switches that could have a big impact on an animal’s appearance or behaviour.

更重要的是，這些跳躍的元素在環(huán)境變化的時候會變得更加活躍。隨著時間的推移，物種需要找到新的方法來適應(yīng)，否則它們就會滅亡。

What’s more, these jumping elements become more active during times of environmental change. As times get tough, species need to find new ways to adapt or they will die out.

激活這些移動元素會重新洗牌基因組，產(chǎn)生新的遺傳變異，為自然選擇提供豐富的素材。

Activating these mobile elements reshuffles the genome, throwing up novel genetic variations that provide rich fodder for natural selection to work on.

5. 病毒：好的、壞的和有益的

Viruses: the good, the bad, and the beneficial

很明顯，被困在我們基因組中的病毒在進化的時間尺度上給我們帶來了巨大的好處。但它們并不都是那么有用。大約每20個人類嬰兒中就有一個出生時在其基因組的某個地方帶有一個新的病毒 "跳躍"，這可能會使一個重要的基因失去活性并導致疾病。

It’s clear that the viruses trapped in our genome have brought us enormous benefits on an evolutionary timescale. But they aren’t all so helpful. Around one in 20 human babies is born with a new viral ‘jump’ somewhere in its genome, which could deactivate an important gene and cause disease.

越來越多的證據(jù)表明，跳躍的轉(zhuǎn)座子導致了癌細胞內(nèi)的基因混亂。耐人尋味的研究表明，腦細胞是重新激活跳躍基因的特別好的位置，可能會增加神經(jīng)細胞的多樣性，增強我們的腦力，但也可能導致與年齡有關(guān)的記憶問題和精神分裂癥等疾病。

There’s increasing evidence that jumping transposons contribute to the genetic chaos inside cancer cells. And intriguing research suggests that brain cells are particularly good locations for reactivating jumping genes, possibly increasing the diversity of nerve cells and enhancing our brainpower but also potentially causing ageing-related memory problems and conditions such as schizophrenia.

那么，這些在我們DNA中的病毒是我們的朋友還是我們的敵人？在紐約的紐約大學醫(yī)學院研究轉(zhuǎn)座子的博士后保羅-米塔（Paolo Mita）表示，兩者都有一點。

So are these viruses inside our DNA our friends or our enemies? Paolo Mita, a postdoctoral fellow researching transposons at NYU School of Medicine in New York, suggests that it’s a bit of both.

"他解釋說："我稱它們?yōu)槲覀兊?#39;敵人'，因為當你看到它們在人類壽命中的作用時，如果它們被調(diào)動起來，很可能會產(chǎn)生負面影響。"在短期內(nèi)，它們是我們的敵人。另一方面，如果你跨越時間來看，這些元素是進化的強大力量，它們今天仍然活躍在我們的物種中。

“I call them our ‘frenemies’, because when you look at their role in one human lifespan, most likely if they are mobilised there are going to be negative effects,” he explains. “In the short term, they are our enemies. On the other hand, if you are looking across time, these elements are a powerful force of evolution and they are still active in our species today.

"進化只是生物體對環(huán)境變化的反應(yīng)方式，在這種情況下，它們絕對是我們的朋友，因為它們塑造了我們現(xiàn)在的基因組工作方式。"

“Evolution is just the way that organisms respond to changes in the environment, and in this case they are definitely our friends because they have shaped how our genome works now.”

那么今天感染我們的病毒，如HIV，是否會對我們未來的進化產(chǎn)生影響？

And are the viruses infecting us today, such as HIV, going to have an impact on our evolution in the future?

"當然了! 答案是為什么不呢？"米塔笑道。"但要等到我們可以回過頭來說這種進化已經(jīng)發(fā)生，那將是很多代人的事情。

“Of course! The answer is why not?” laughs Mita. “But it will be many generations until we can look back and say this evolution has happened.

"但是你可以在內(nèi)源性逆轉(zhuǎn)錄病毒和宿主細胞之間的基因組中看到以前軍備競賽的殘留物。這是一場持續(xù)的戰(zhàn)斗，我認為它從未停止過。"

“But you can see the remnants of previous arms races in the genome between the endogenous retroviruses and the host cells. It’s a continuous battle, and I don’t think it has ever stopped.”

水木視界丨iss. 1

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