转载自Science Focus: 

"Viruses: their extraordinary role in shaping human evolution"

引言

Introduction

病毒给我们带来了从普通感冒到COVID-19和艾滋病的感染。但研究表明，它们在塑造智人的进化过程中可能也发挥了关键作用。

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.

冠状病毒、寨卡病毒、埃博拉病毒、流感，甚至无聊的普通感冒--我们都熟悉困扰人类的病毒。但是，尽管我们知道它们使我们生病，但发现在数百万年的时间里，我们已经成功地驾驭和驯化了这些狡猾的入侵者，可能会令人惊讶。

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.

从生命的萌芽阶段到我们脸上绽放笑容，病毒对我们人类产生了巨大影响。

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

病毒只不过是一串基因（通常以一种叫做RNA的分子形式存在）被包装在一个蛋白质外壳中，它们都以同样的基本方式工作。

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.

一旦病毒感染了一个细胞，它就会劫持细胞自身的分子机器来复制其基因并产生病毒蛋白。新的病毒由这些新制造的部件组装而成，最终迸发出来，寻找新的细胞进行攻击。

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.

对于大多数病毒，如流感，故事到此结束。但是少数逆转录病毒--包括HIV--更加狡猾，它们偷渡到我们的DNA中。它们随机地插入一个生物体的基因组中，低调行事，直到时机成熟再次开始生产病毒。

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，一旦逆转录病毒进入了一个生物体的DNA，就不能保证它将留在原地。遗传指令可以从嵌入的病毒中 "读取"，转化为DNA，然后粘贴到基因组的另一个位置。一次又一次地重复这个循环，病毒DNA的多个副本很快就会积累起来。

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.

经过数百万年，这些病毒DNA序列随机变异和改变，失去了从宿主细胞中挣脱的能力。被困于基因组内，这些 "内源性 "逆转录病毒中的一些仍然可以跳来跳去，而另一些则永远停留在它们最后落脚的地方。

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.

而如果这些事件中的任何一个发生在制造卵子和精子的生殖细胞中，那么它们将被代代相传，最终成为生物体基因组的永久组成部分。

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.

大约一半的人类基因组是由数百万个DNA序列组成的，这些序列可以追溯到早已死亡的病毒或类似的 "跳跃基因"，统称为可转座元素或转座子。

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.

一些研究人员甚至将这一数字提高到80%，因为古老的序列现在已经退化到无法识别病毒的程度，像分子化石一样在基因组中风化。

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.

多年来，人类基因组中的大块重复性病毒衍生的DNA被认为是 "垃圾"。在我们的基因躯干中，一部分重复性的东西无疑只是垃圾，但随着研究人员更仔细地观察单个病毒元素，一个更复杂的画面正在出现。

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.

事实证明，除了是我们的基因敌人之外，一些嵌入我们基因组的病毒已经为我们所用。

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.合胞素的进化

Syncytin evolution

大约15年前，美国研究人员发现了一个只在胎盘中活跃的人类基因。他们称其为syncytin，因为它能制造一种分子，将胎盘细胞融合在一起，形成一个特殊的组织层，称为syncitium。奇怪的是，syncytin看起来很像逆转录病毒的基因。

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.

后来又发现了另一个syncytin基因，它也参与了胎盘的形成，以及防止母亲的免疫系统攻击她腹中的胎儿。同样，该基因看起来也是来自于一种逆转录病毒。

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，虽然人类和其他大型灵长类动物有相同的两个合胞素基因，但在任何其他哺乳动物中，都没有发现类似的胎盘融合细胞层。

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.

小鼠也有两个syncytin基因：它们的工作与人类版本相同，但它们看起来像完全不同的病毒。而在猫和狗身上还有另一个单独的病毒衍生的syncytin基因，这两种动物都是同一食肉动物祖先的后代。

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.

显然，所有这些哺乳动物物种在数百万年前都被特定的病毒所感染。随着时间的推移，这些病毒已经被利用起来，在胎盘生长中发挥了关键作用，使它们成为我们基因组中的一个永久的固定物。

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.

耐人寻味的是，猪和马的胎盘中没有一层融合的细胞，而且它们也没有任何看起来像病毒衍生的合胞素的基因。因此，也许它们从未感染过这种融合病毒。

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. 跳跃的基因

Jumping genes

虽然syncytin的案例揭示了全盘采用病毒基因来为我们服务，但还有更多的例子说明古代病毒序列如何影响当今人类的基因活动。

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世纪50年代，长期被忽视的美国遗传学家芭芭拉-麦克林托克艰苦细致的工作揭示了 "跳跃基因 "可以影响玉米植物的基因组。

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.

就像麦克林托克在玉米中发现的 "跳跃基因 "一样，潜伏在我们人类基因组中的内源性逆转录病毒在数百万年中一直在移动，随意跳跃并改变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.

我们的细胞投入了大量的能量，试图阻止这些病毒元素的跳动。它们被贴上了化学标签并被锁定，被称为表观遗传标记。但是，随着病毒元素的移动，这些分子沉默器也随之移动，因此病毒序列的影响可以传播到它们所处的邻近基因。

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，病毒也充满了吸引分子的DNA序列，这些分子可以开启基因。在一个功能性的逆转录病毒中，这些 "开关 "激活了病毒基因，因此它可以再次变得具有传染性。但是，当一个类似病毒的序列被拼接到基因组的另一个区域时，这种作为基因开关的能力最终可能会变得无序。

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，犹他大学的科学家们发现，人类基因组中的一种内源性逆转录病毒--它最初来自于大约4500万到6000万年前感染我们祖先的一种病毒--当它检测到一种叫做干扰素的分子时，会开启一种叫做AIM2的基因，干扰素是警告身体正在遭受病毒感染的 "危险信号"。AIM2然后迫使受感染的细胞自我毁灭，以防止感染进一步扩散。

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.

这些古老的病毒已经成为 "双重代理"，帮助我们的细胞对付试图攻击我们的其他病毒。

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

另一个可能塑造了我们物种的病毒的例子是在一个叫做PRODH的基因附近发现的。PRODH存在于我们的脑细胞中，特别是在海马体。

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.

在人类中，该基因是由一个早已死亡的逆转录病毒制成的控制开关激活的。黑猩猩也有一个版本的PRODH基因，但它在它们的大脑中几乎没有那么活跃。

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.

一种可能的解释是，在数百万年前，一种古老的病毒在我们某个早已死去的祖先的PRODH旁边跳跃了一个自己的副本，但这并没有发生在继续进化成今天的黑猩猩的祖先灵长类身上。

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的故障被认为与某些大脑疾病有关，因此它极有可能至少对人类大脑的布线产生了某种影响。

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.

同样，基因开关的变化也是造成我们在子宫内成长时构建人类面部的细胞与黑猩猩的细胞之间差异的原因。尽管我们的基因与黑猩猩的基因几乎完全相同，但我们看起来肯定不一样。所以区别一定在于控制开关。

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.

从它们的DNA序列来看，许多在生长我们脸部的细胞中活跃的开关似乎最初来自病毒，它们一定是在我们成为今天的平脸物种的进化过程中的某个时候跳到了适当的位置。

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.病毒驯服者

The virus tamers

除了寻找早已死亡的病毒改变我们的生物学的例子之外，科学家们还在寻找支撑其效果的控制机制。关键的罪魁祸首是被称为KRAB锌指蛋白（KRAB ZFPs）的特殊沉默分子，它们抓住基因组中的病毒序列并将其固定在原位。

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.

瑞士洛桑大学的Didier Trono教授和他的团队在人类基因组中发现了300多种不同的KRAB ZFPs，其中每一种似乎都喜欢一个不同的病毒衍生的DNA目标。一旦到了那里，它们就会帮助招募开启或关闭基因的分子机器。

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解释说："这些KRAB ZFPs一直被视为这些内源性逆转录病毒的'杀手'。"但它们实际上是这些元素的利用者，使生物体能够利用驻留在这些病毒序列中的丰富可能性"。

“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.”

特罗诺和他的团队认为，KRAB ZFPs是积极有害的病毒序列和那些已经成为驯服的控制开关之间的缺失环节。

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.

他们有证据表明，这些蛋白质在一种 "军备竞赛 "中与病毒元素一起进化，最初抑制它们，但最终压倒了它们。

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

"我们认为它们所做的是驯化这些元素，"特罗诺说。"而通过驯化，我的意思是不只是确保病毒不动，而是把它们变成对宿主有益的东西，这是一种非常精细的调节所有可能的细胞和情况下的基因活动的方式。"

“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.”

支持这一观点的是发现不同的KRAB ZFPs组在不同类型的细胞中都很活跃。它们还在不同的物种中以特定的模式被发现。

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.

如果它们只是抑制病毒，那么，同样的蛋白质阵列应该存在于所有细胞中。更重要的是，为什么它们会被发现与特罗诺和他的团队已经确定的数千个早已死亡的病毒元素结合在一起？

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?

抑制一个死亡的逆转录病毒是没有意义的，所以它们一定在控制基因活动方面发挥着重要作用。

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

尽管他的想法仍有些争议，但特罗诺认为KRAB ZFPs是病毒奴役者的一种力量，利用这些元素为我们服务，将它们变成基因控制开关。

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.

在几百万年里，这可能是创造新物种的强大马达。例如，如果一种病毒随机地在一种祖先生物中跳跃，而不是在另一种祖先生物中跳跃，然后随着时间的推移被KRAB ZFP驯服，它将创造出新的控制开关，可能对动物的外观或行为产生很大影响。

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，这些跳跃的元素在环境变化的时候会变得更加活跃。随着时间的推移，物种需要找到新的方法来适应，否则它们就会灭亡。

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.

激活这些移动元素会重新洗牌基因组，产生新的遗传变异，为自然选择提供丰富的素材。

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、坏的和有益的

Viruses: the good, the bad, and the beneficial

很明显，被困在我们基因组中的病毒在进化的时间尺度上给我们带来了巨大的好处。但它们并不都是那么有用。大约每20个人类婴儿中就有一个出生时在其基因组的某个地方带有一个新的病毒 "跳跃"，这可能会使一个重要的基因失去活性并导致疾病。

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.

越来越多的证据表明，跳跃的转座子导致了癌细胞内的基因混乱。耐人寻味的研究表明，脑细胞是重新激活跳跃基因的特别好的位置，可能会增加神经细胞的多样性，增强我们的脑力，但也可能导致与年龄有关的记忆问题和精神分裂症等疾病。

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，这些在我们DNA中的病毒是我们的朋友还是我们的敌人？在纽约的纽约大学医学院研究转座子的博士后保罗-米塔（Paolo Mita）表示，两者都有一点。

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.

"他解释说："我称它们为我们的'敌人'，因为当你看到它们在人类寿命中的作用时，如果它们被调动起来，很可能会产生负面影响。"在短期内，它们是我们的敌人。另一方面，如果你跨越时间来看，这些元素是进化的强大力量，它们今天仍然活跃在我们的物种中。

“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.

"进化只是生物体对环境变化的反应方式，在这种情况下，它们绝对是我们的朋友，因为它们塑造了我们现在的基因组工作方式。"

“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.”

那么今天感染我们的病毒，如HIV，是否会对我们未来的进化产生影响？

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

"当然了! 答案是为什么不呢？"米塔笑道。"但要等到我们可以回过头来说这种进化已经发生，那将是很多代人的事情。

“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.

"但是你可以在内源性逆转录病毒和宿主细胞之间的基因组中看到以前军备竞赛的残留物。这是一场持续的战斗，我认为它从未停止过。"

“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.”

水木视界丨iss. 1

感谢阅读

Thanks for your time

定期分享结构生物学前沿进展