圖1. 美國冷泉港實驗室(CSHL：Cold Spring Harbor Laboratory)助理教授 Andrea Schorn研究，在控制下，小RNA片段如何使轉位子(TEs)留置於咱們基因體中。其研究以在CSHL數十年的TE研究為基礎。已故CSHL植物生物學家Barbara McClintock，因發現此些“跳躍基因”，獲得諾貝爾獎。
CSHL Assistant Professor Andrea Schorn studies how small RNA fragments keep transposable elements (TEs) in our genome under control. Her work builds on decades of TE research at CSHL. The late CSHL plant biologist Barbara McClintock won the Nobel Prize for her discovery of these “jumping genes.”
About half of the human genome isn’t quite human. It’s made up of transposable elements (TEs)—descendants of ancient viruses.
大約一半的人類基因體並非完全是人類的。它由古代之病毒後代(衍生物)的轉位子(Tes，是DNA中能改變其在基因體中的位置，有時會產生或逆轉突變，並改變細胞之遺傳本質及基因體大小的核酸序列)所組成。
As a Ph.D. student at the Max-Delbrück Center for Molecular Medicine, Andrea Schorn studied an ancient TE that was resurrected from fish and is active in pretty much all vertebrates—except fish. Today, Schorn is an assistant professor at Cold Spring Harbor Laboratory (CSHL).
當是德國馬克斯-德爾布呂克分子醫學中心的博士生時，Andrea Schorn研究了一種，從魚類中被復活且除了魚類之外，也在幾乎所有脊椎動物中，是活躍的古老轉位子。目前，Schorn是冷泉港實驗室(CSHL)的助理教授。
We visited her lab for an inside look at the ancient, non-human origins of DNA. It turns out Schorn’s work could lead to new strategies for improving pregnancy outcomes and fending off viruses like HIV.
為了深入檢視該古老、非人類起源的DNA，我們造訪了她的實驗室。事實證明，Schorn的研究可能引領出，改善妊娠結果及抵擋病毒(如HIV(Human Immunodeficiency Virus，人類免疫缺陷病毒)的新策略。
We work on transposable elements, or transposons. Specifically, we work with old retroviruses—viruses that infected genomes millions of years ago or sometimes only recently.
我們針對轉位子(也就是transposons)進行研究。具體來說，我們以古老的逆轉錄病毒(數百萬年前或有時最近才感染基因體的病毒)進行研究。
We’re interested in how the host can recognize and silence them when they become active. Usually, they’re only active in early development—but also sometimes in disease. When transposons are active, they can move or jump around cells and turn genes on and off.
我們感興趣於，當它們變得活躍時，宿主如何識別及使其靜默下來。通常，它們於初期發育中才活躍。不過，有時在疾病中也活躍。當轉位子活躍時，它們能在細胞周圍移動或跳躍，及打開與關閉基因。
圖2. Schorn及其團隊是創造轉置測定的專家，如圖所示。這是用肉眼觀察及量化轉位子活動狀態的唯一方法。每一藍點皆是一簇，具有從一處跳到另一處之轉位子的細胞。
Schorn and her team are experts in creating transposition assays, seen here. This is the only way to observe and quantify transposon activity with the naked eye. Each blue dot is a cluster of cells containing a transposon that jumped from one place to another.
I was always interested in RNA and host-pathogen interactions. I became very interested in transposons because it appeared they have a lot to do with how the cell combats invaders. Cells have a defense mechanism built on RNA and a memory of which viruses and transposons they’ve been exposed to.
我始終感興趣於，RNA及宿主與病原體的相互作用。我變得非常感興趣於轉位子，因為顯然它們與細胞如何對抗入侵者，有諸多關係。細胞具有一種以RNA，及一種其曾被曝露於病毒及轉位子之記憶為基礎的防禦機制。
We want to know how RNA can tell whether a retrovirus or transposon is good or bad. Half our DNA is made up of these TEs and old retroviruses. They can be bad if they’re active and move around, but they can also be very good.
我們想知曉，RNA如何能斷定逆轉錄病毒或轉位子的好壞。咱們半數的 DNA是由，此些TE及古老的逆轉錄病毒所組成。
Hosts have adopted genes from retroviruses over the years, and they’ve become essential. It’s a bit like Lego. At first, the pieces are able to move around, but at some point, you have essential infrastructure you can’t take away. So, we are now in this place where we need them but also need to make sure we can sense, control, and manage them.
多年來，宿主已經接受，來自逆轉錄病毒的基因。因此，它們已經變得不可或缺。這有點像樂高(積木玩具)。開始時，此些片段能到處移動，不過在某個時候，就具有無可剝奪之不可或缺的基礎結構。
The retroviruses we study use transfer RNAs (tRNAs)—an essential RNA component in the cell—to replicate. It turns out the cell cleaves tRNAs into many pieces and uses them to find and suppress retroviruses. It’s a very interesting example of small RNAs because we think they’re probably quite ancient, and they’re in all cells.
我們研究的逆轉錄病毒，使用轉移RNA(tRNA，細胞中不可或缺的RNA成分)進行複製。結果證明，細胞將tRNA切割成許多片段，並使用它們來發現及抑制逆轉錄病毒。這是小RNA一個非常令人感興趣的例子，因為我們認為它們可能非常古老，且存在於所有細胞中。
We can only speculate when it comes to evolution, but tRNAs certainly were one of the first molecules to enable life. Then, retroelements brought the machinery to make DNA out of RNA.
談到演化時，我們只能臆測。不過無疑地，tRNA是使生命成為可能的最早分子之一。然後，逆轉錄因子帶來了，從RNA產生DNA的機制。
There’s this “RNA world” hypothesis where there was no DNA as storage for information, but it was all RNA doing everything. RNA can be an enzyme. It can provide code to find transposons. It can be the instructions for making a protein. So, tRNA could be very ancient. It kind of started an evolutionary arms race: the need to suppress transposon mobility, but also using them as building blocks.
有這種，無DNA作為信息儲存所，而一切全由RNA進行的“RNA世界”假說。RNA會是一種酶。它能提供尋找轉位子的標記。它會是製造蛋白質的指令。因此，tRNA可能是非常古老。這有點引發了一場演化武器競賽：需要抑制轉座子的移動性，不過也使用它們作為構材。
We think there are so many in our genome because they’ve become so useful. Originally it was probably like any other infection—kind of obnoxious or a problem. But then, the ones we see today and study as transposons managed to invade the germline of organisms—the cells of the next generation. Whenever that happened, they were able to have a foothold in that organism and be inherited over and over.
我們認為，於咱們基因體中有很多。因為，它們已經變得很有用。最初它可能如同任何其他感染般，有點令人厭惡或有問題。不過後來，這種咱們目前發現及研究作為轉位子的，竟然侵入了生物體的生殖細胞系(種系)。也就是，下一代細胞。
Exactly. There has been a transition in the field. In the past, transposons were often called parasites to emphasize their dangerous behavior. But today, there’s much more appreciation for their benefits and how they’ve supplied building blocks to the cell.
確切地說，該領域已經發生轉變。在過去，轉位子經常被稱為寄生蟲，以強調其危險的作用。不過，就其益處及曾如何為細胞提供構材，目前有更多的評價。
Some of the negative effects are their mobility. They move somewhere and destroy a gene or region. The other effect we’re studying more today is that they drive the expression of neighboring genes. They attract these epigenetic marks to the DNA to affect whether the entire region is active or inactive.
一些負面影響是它們的流動性。它們到處移動且破壞一個基因或區段。目前，我們正更加研究的另一個影響，是它們驅動鄰近基因的表現。它們將這些漸成說(表觀遺傳)的標記吸引到DNA，以影響整個區域是否活躍。
During development, they drive active gene expression, which is desired in this case. But during disease, like in cancer, this is unintended. They drive neighboring genes that become oncogenes and were not supposed to be expressed in the cell. They mess up gene expression.
在發育過程中，它們驅動活躍的基因表現，這在此種情況下，是被期盼的。不過在疾病期間，如於癌腫中，這是不被預期的。它們驅動鄰近之成為致癌基因，及在細胞中不應該被作出表現的基因。
TEs that get reactivated during development help define which regions are active. They are like the on switch in certain times of development, and then they need to be turned off for proper development to proceed.
在發育期間，重新被激活的轉位子有助於，界定哪些區域是活躍的。
它們像是在發育的某些時期打開開關，然後為了進行適當的發育，需要被關閉。
Today, we know some examples of how they’ve been domesticated and are essential. One famous example is a protein called Syncytin, an old virus envelope protein that can fuse to other cells.
目前，我們知道了一些，它們已經如何被引進且是不可或缺的例子。一個著名的例子是，一種被稱為合胞素(Syncytin)的蛋白質。這是一種，能與其他細胞融合的古老病毒包膜蛋白。
In mammals, it helps the placenta, which is a part of the embryo, to invade the mother’s tissue. This happened multiple independent times in evolution—in rabbits, mice, and humans. But if you take the protein away, the pregnancy will fail.
在哺乳動物中，它有助於胚胎的胎盤部分侵入母體組織。這在兔子、小鼠及人類的演化中，多次獨立發生過。不過，倘若去掉此蛋白質，懷孕會失敗。
圖3. 身為Martiernsen實驗室的博士後研究員，Andrea Schorn發現了轉運核糖核酸(tRNAs：Transfer RNA)，如何在哺乳動物早期發育過程中，保護胚胎幹細胞。在這裡，她與CSHL大學部研究計劃的學生Daisy Rubio討論病毒。
As a postdoctoral fellow in the Martiennsen lab, Andrea Schorn discovered how tRNAs protect embryonic stem cells in mammals during early development. Here, she discusses viruses with Daisy Rubio, a student in CSHL’s Undergraduate Research Program
It’s basically an aberrant gene expression. That could be cancer or neurological defects. We will need more research to see if this is a consequence or causal—that’s not clear. There are examples where transposons jumped into key genes in colorectal tumors, contributing to uncontrolled cancer growth.
基本上，這是一種異常的基因表現。那可能是癌症或神經系統缺陷。我們將需要更多的研究，來瞭解這是一種結果，或是具有因果關係性質。那並不清楚。有些轉位子躍入結腸直腸癌中之關鍵基因，導致癌腫失控生長的例子。
Are there examples where it doesn’t result in cancer or disease? Like how Barbara McClintock’s corn changed color?
有不會導致癌症或疾病的例子？如同二十世紀中葉，Barbara McClintock在美國對玉米進行之實驗，以研究細胞中，染色體的結構及功能時，玉米如何改變顏色般？
There are many examples where we can transposon activity, often in adult cells. The corn you mentioned is a classic example. The change between pinot grigio and pinot noir is basically a transposon inserted into a color gene. There’s a famous fur color pattern variation in mice, associated with obesity.
有諸多往往於成體細胞中，我們能“發現”轉位子活躍的例子。你提到的玉米是一個典型例子。灰皮諾葡萄與黑皮諾葡萄之間的改變，基本上是一個轉位子嵌入一個顏色基因中。於小鼠中，有一種與肥胖有關之著名毛皮顏色樣式的改變。
If the transposon jumped the geneline, like in pinot. However, in Agouti mice, the transposon has been there all along and sporadically escapes the epigenetic on-off switch, which leads to the trait popping up in some offspring.
即使該轉位子，如同於皮諾葡萄中躍過基因系。不過，在Agouti小鼠(刺小鼠)中，轉位子已經一直存在，且偶發性地躲開漸成說之開啟與關閉的開關。這導致了，於某些後代中，發生此種特徵。
We’re studying transposons in stem cells, and how tRNA fragments recognize and regulate retroviruses in mice and humans. They are a relatively novel small RNA class. They clearly overlap with other RNA silencing pathways.
我們正進行研究幹細胞中的轉位子，及tRNA片段如何識別與調節小鼠及人類中的逆轉錄病毒。相對上，它們是一種新穎的小RNA。它們明顯與其他RNA的靜默途徑部分同時發生。
How are they similar and how are they different? How many genes are regulated by this? How pervasive is this type of control? Given that tRNAs are precious, essential molecules, what’s behind the decision to cleave them? How can cells tell a bad retrovirus from a good, domesticated one?
它們有多相似及多不同？有多少基因受此調控？這種控制有多普遍？鑒於tRNA是寶貴、不可或缺的分子，那麼背後是什麼決定切割它們？細胞如何能從引進的好逆轉錄病毒，識別壞的逆轉錄病毒？
RNA silencing is like a primitive immune system. We can think of this very much in evolutionary terms. How did it evolve, and how does it sort out which RNAs are OK and which are not? I think retroviruses are key to this question. How do you tell whether a retrovirus is still dangerous and actively jumping around within the cell or settled down, essential, and on the good side?
RNA靜默如同是個原始免疫系統。我們能從演化角度來深切思考這。它如何演化，及其如何區分哪些RNA是好的，哪些不是？我認為，逆轉錄病毒是此問題的關鍵。你如何斷言，逆轉錄病毒是否仍然危險，且在細胞內到處活躍地跳躍，或穩定下來、不可或缺且朝好的方面？
Yes, the type of transposons we work on are all retroviruses, and they’re directly related to HIV. Generally speaking, viruses come in many different flavors, but they’re infectious. They can spread between cells and individuals. Transposons come in different classes, but they stay within one cell. There’s an overlap because some of the retroviruses that infected us became transposons.
不錯，我們研究的轉位子類型皆是逆轉錄病毒，且它們直接與人類免疫缺乏病毒(HIV：Human Immunodeficiency Virus)有關。一般來說，病毒有諸多不同特色，不過它們皆具有傳染性。它們能在細胞與個體之間傳播。轉位子有諸多不同類別，不過它們逗留於一個細胞內。有一部分同時發生，因為有些感染我們的逆轉錄病毒，變成了轉位子。
Once we understand better how tRNA fragments recognize these types of transposons, we can learn how to prevent or manage retrovirus infection. These small RNAs are also strongly expressed and abundant in early embryo stem cells. So, understanding how tRNA fragments know friend from foe could help improve pregnancy outcomes, because this is a time transposons go rogue.
一旦我們更深入瞭解tRNA片段，如何識別這些轉位子的類型，我們能得悉如何預防或妥善處理逆轉錄病毒感染。這些小RNA在初期胚胎幹細胞中，也強烈地作出表現且豐富。因此，瞭解tRNA片段如何區分敵友，可能有助於改善懷孕結果。因為，這是轉位子失控的時期。
The same process that happens in early embryo stem cells often happens in cancer cells. Many cancer cell types and tumors have very high transposon expression. So, if we could use tRNA fragments to control and inhibit them, we could get a handle on cancer. We could improve patient care and outcomes.
於初期胚胎幹細胞中發生的相同過程，也經常於癌細胞中發生。諸多癌細胞類型及腫瘤，具有非常高的轉座子表現。因此，倘若我們能使用tRNA片段，來控制及抑制它們，我們可能控制癌腫。我們可能改善病患的照護及治療結果。
Ancient viral invaders don’t just sound cool. They’re part of us. Over millions of years, retroviruses and other transposons have become essential to human development. Thanks to the work of Andrea Schorn, they may also provide essential clues for improving pregnancy outcomes and treating diseases like cancer and HIV. Where will these clues emerge, and where will they take us next? We’ll be watching closely.
古老的病毒入侵者不僅聽起來酷。它們是我們的一部分。數百萬年來，逆轉錄病毒及其他轉位子，對人類發展已經成為不可或缺。由於Andrea Schorn 的研究，它們可能也為改善妊娠結果，及治療諸如癌症及人類免疫缺乏病毒等疾病，提供至關重要的線索。這些線索會出現於何處，而接下來它們會帶我們往何處？我們將密切關注。
網址：https://www.cshl.edu/where-did-our-dna-come-from/
翻譯：許東榮
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