什麼造成了黑猩猩和人類的不同？

When the protein-encoding genes of the human are compared with the protein-encoding genes of the chimpanzee, they are about 99 percent the same. Moreover, the one percent that are distinctive aren"t obviously interesting, being involved with such traits as sperm surface proteins and immune responses.

當將編碼人類蛋白的基因與編碼黑猩猩蛋白基因進行比較時，他們之間有99%的相似度。而且，涉及到諸如精子表面蛋白和免疫反應特徵的1%的基因也沒有引起明顯的興趣。

因此，考慮到這個，對於許多方面尤其是意識方面，人類和黑猩猩彼此不同的基因基礎是什麼呢？

A most ingenious approach to this question is being developed in the lab of Katherine Pollard at the University of California in San Francisco. To understand their experiments, we first need a crash course in genes and embryos. I"ll try to make it quick.

在舊金山加利福尼亞大學Katherine Pollard 實驗室設計了一個非常有創意的方法。為了理解他們的試驗，我們首先需要一堂在基因和胚胎方面的速成課，我將試著很快對此作一闡述。

Our single-celled ancestors who lived more than 1.5 billion years ago were already impressively gene-rich and sophisticated, as per last week"s blog. Notably, their genomes encoded a rich toolkit of regulatory molecules that turn on or off the expression of genes as appropriate to the occasion. For example, in the presence of bacterial food, the ancient ancestors turned on the expression of genes that allowed them to crawl around and engulf their prey. When things got lean, they instead turned on genes that allowed them to swim off to find new food sources.

生活在15億年前的單細胞生物祖先就已經擁有豐富而複雜的基因，根據上周的博客。值得注意的是，他們的基因組編碼了一個豐富的工具箱，這個工具箱由可控分子構成，這些分子可以根據合適的情況打開或關閉基因的表達。例如，有細菌性食物時，古代的祖先會打開基因的表達，這些基因允許他們爬過去並且吞噬他們的捕食。相反，當食物貧乏時，他們會打開讓他們游過去找到新的食物來源的基因。

The way these switches work is pretty straightforward to explain, albeit exquisitely intricate in detail. Basically, proteins are encoded by sectors of DNA called genes. Contiguous to each gene is DNA that doesn"t code for protein; instead, it functions as the gene"s on-off switch. When regulatory molecules bind to this switch DNA, the contiguous gene is either expressed or prevented from being expressed. So, very crudely, the thing on the wall is the switch DNA, your finger is the regulator, and gene expression is the light turning on or turning off.

這些開關的工作方式能夠被非常直接明了地解釋，細節上雖然精巧複雜。基本上，蛋白質被稱之為基因的DNA編碼。每個相鄰基因之間是不能編碼蛋白質的DNA；相反，它起著基因啟動－關閉開關的功能。當調控分子與這個開關DNA結合時，相鄰的基因便開始表達或終止表達。因此，大體上可以這麼形容，在牆上的東西就是開關DNA，手指是調控器，基因表達就是打開燈或關閉燈。

The common-ancestral selves were unicellular, whereas the animal lineage has elected to construct multicellular selves. In making this transition, animals hung on to the same switch arrangement and the same sets of regulators used by the ancestors, but they added a splendid additional idea. In addition to being responsive to signals from the environment, they also became responsive to signals coming from their very own cells. So, to highly oversimplify the situation, after a fertilized egg has divided into two and then four, then eight, then 16 cells (where the human has, gulp, ten trillion cells), cell #16 makes a regulator that acts to switch on a set of unique genes in cell #10, the outcome being that cell #10 and its progeny eventually give rise to nervous tissue. Meanwhile, cell #11 expresses a different suite of genes, poising its progeny to influence yet other cells to differentiate into muscle.

祖先本身是單細胞的，然而動物進化成多細胞。在這個變化過程中，動物繼續選擇祖先使用開關排列和調控器，但是他們加入了一個非常好的創意。除了對環境的信息作出反應，他們也可以對來自自身的細胞的信號作出反應。因此，為了是這種情況更加簡化，一個受精卵變成2個、4個、8個，16個（人類有10萬億個細胞），#16 細胞變成一個控制器，負責打開#10細胞的獨特基因，結果是#10細胞和它的子代們最終產生了神經組織。同時，#11細胞表達另一套不同的基因，平衡它的子代影響其它細胞分化成肌肉。

As animals, and hence animal embryos, complexified over time, these cell-to-cell interactions have become increasingly impressive. In the developing mammalian brain, for example, neurons migrate up into the cranium, using much the same kind of amoeboid movement that our deep ancestor employed to capture bacteria. Neurons that reach a particular destination switch on genes that allow them to secrete a nerve growth hormone. As the next phalanx of neurons migrates into the region, they follow the hormone gradient, akin to male moths moving up pheromone gradients to find females, avidly competing for hormones that will enable their proliferation. The first to arrive at the pulsating source proceed to form synaptic connections with their targets; any laggards, by contrast, fail to proliferate and instead degenerate.

由於動物和動物胚胎隨著時間變得更加複雜了，這些細胞和細胞之間的相互作用也越來越讓人印象深刻。例如，在進化中哺乳動物的大腦，神經遷入到了頭顱，用我們祖先使用過的變形運動來捕捉細菌。達到特殊部位的神經元可以打開讓他們分泌神經生長激素的基因。隨著神經元跟隨著激素的濃度，大量進入這個部位，同雄蛾向著激素的方向移動尋找雌飛蛾一樣，爭奪著能使它們繁殖的激素。首先到達脈衝源的神經元就會和他們的靶點形成突觸結合，相比之下，落後者不是繁殖而是退化。

Granted that this is an absurdly simplified account of brain development, it suffices to make a key point, which is that brains build themselves. Bottom up. When A happens, that allows B and C to happen; B allows D and E to happen; and so on.

假設這是一個荒謬的腦部發展的簡化描述，它可以成為一個關鍵點，也就是說大腦建立自己。自下而上的。當A發生的時候，允許B和C發生；B允許D、E發生，等等。

Because brain development is so contingent on what has gone on before, it"s pretty easy to alter what happens. For example, if the pioneer neurons in our example carried a switch mutation that prevented them from secreting the nerve growth hormone at the appropriate time, the next phalanx of neurons wouldn"t move towards them and might, instead, pick up on a more distant hormonal signal from another brain region and move in that direction, forming synapses with a new set of neurons altogether. A brain is still constructed, but it will have different kinds of neural pathways and connections and hence, perhaps, different ways of doing things.

由於大腦的進化是根據之前所發生決定的，也很容易改變所發生的。例如，假如先前的神經元發生突變阻礙它們在合適的時間分泌神經生長激素，大量的神經元便不會朝著它們移動，相反，有可能從另一個大腦區選擇一個更遠的激素信號，朝著另外一個方向移動，和一組新的神經元形成突觸。大腦仍然被建造，仍然擁有不同的神經路線和連接方式，因此，可能有不同種做事情的方法。

So now we can return to the chimp-human question. If the chimp and human protein-encoding genes are virtually all the same, then are there any interesting differences in their switch regions? Given the bottom-up nature of development, mutant switches could have large-scale consequences.

到現在為止，我們返回到黑猩猩－人類的問題上。假如黑猩猩和人類的編碼蛋白的基因一樣，那麼在開關區間有什麼有趣的不同之處呢？考慮到自上而下的發展本質，突變開關能產生大規模的結果。

開關序列的鑒別要比基因的鑒別計算起來更具有挑戰性，但是Pollard 實驗室對此進行了研究。

開關序列的鑒別要比基因的鑒別計算起來更具有挑戰性，但是Pollard 實驗室對此進行了研究。

Basically, they compare the DNA sequences adjacent to genes that are found not only in humans and chimps but also in mice and rats, where the most recent common ancestor of these four mammals roamed the planet some 60 million years ago.

基本上，他們比較了與基因相鄰的DNA序列，這些基因不僅能在人類和黑猩猩身上找到，而且在大鼠和小鼠身上也可以找到，而且60萬年前生活在這個星球的四種哺乳動物最近的共同祖先就擁有這個序列。

The Pollard logic is this:

Pollard 的邏輯是這樣的：

1) If a given set of sequences isn"t doing anything important, which is usually the case, then the rat, mouse, human, and chimp versions are expected to be very different from one another. That"s because they aren"t under selection, so they tend to accumulate mutations. In genomic lingo, the sequences are said to "drift."

假如一系列既定的序列不發揮任何重要作用，通常也是這樣的情況，那麼大鼠、小鼠、人類和黑猩猩彼此就會差別很大。那是由於他們沒有進行選擇，因此他們易於積累突變。用基因組術語，這個序列稱之為「漂移」。

2) By contrast, if the sequences function as switches, then they are expected to be very similar because they are under selection to maintain their gene-regulating function.

相比之下，假如序列執行開關的職能，那麼它們會非常相似，因為它們經過選擇保持他們的基因調控功能。

3) Of particular interest are cases where the mouse, rat, and chimp sequences are all identical, indicating intense selection to maintain them, whereas the human sequence is markedly different from the other three. The Pollard lab has thus far identified 202 such cases, where each is called a human accelerated regions or HAR.

特別有趣的是大鼠、小鼠和黑猩猩的序列是一樣的，表明是經過挑選來維持的，然而人類的序列與這三類有著顯著的差別。Pollard 實驗室到目前為止確定202種這樣的情況，每個被稱為人類加速地區或HAR.

Now the fun begins. A researcher picks out a HAR (e.g. HAR34), figures out what gene it"s contiguous to, and then asks: Where and when is that gene switched on/off during embryological development? And then: Is its expression pattern different in the human than in mouse, rat, or chimp? If it is, then the novel pattern may prove to be relevant to an understanding of how humans are distinctive creatures.

現在興緻來了。一位研究員挑出一個HAR，指出它與什麼基因相連，然後問：在胚胎髮育期基因是何時何地被打開或關閉？然後問：它的表達方式在人類和在大鼠、小鼠或黑猩猩體內有差別嗎？假如有，新的方式可以證明與理解人類是獨特的物種的原因有關。

Thus far there are three preliminary stories relevant to the brain. HAR1 proves to mark a genetic region that is expressed early in the development of the neocortex; HAR152 is near the gene encoding a protein called neurogenin-2 that is expressed in a region of the hippocampus with a central role in learning and memory; and HAR2 is near a gene with strong expression in the hand, perhaps playing some role in human-specific hand coordination.

到現在為止有三個與大腦有關的表述。HAR1證明了標碼在大腦皮質形成過程中早期表達的基因區；HAR152 靠近編碼蛋白基因，稱之為神經元配基－2，神經元配基－2在海馬區表達，在學習和記憶分面扮演著重要的角色；HAR2靠近在手上有強表達的基因，在人類特有的手協調方面發揮著某些功能。

The knee-jerk response to this account is to think "Aha — maybe some of those novel HAR sequences are running some new human-specific brain module or widget! Like my consciousness!"

對於這個數據下意識的反應就是思考「或許一些新的HAR序列正運行著某些人類所特有的新的大腦模式或部件，就像意識一樣！」

But if we circle back to our core notion, that brains build themselves, and think about the HARs in this context, then we realize that we"re not likely to be talking about new modules or widgets. Just as in our hypothetical example, where a group of neurons failed to secrete a hormone and the second phalanx of neurons wandered off to find new targets, a mutant HAR is more likely to result in some human-specific pattern of regional brain differentiation. Indeed, going back to the finch-song domesticated-ape story told here and here, some of the mutant HARs may have the effect of releasing constraints on ape-brain organization, opening things up to greater novelty and plasticity

但是假如我們返回到核心觀念，即大腦可以自我組建，在這個背景下思考HARs，那是我們便會意識到我們不可能談論新的模式或是部件。就像我們假設的例子一樣，神經元沒有分泌激素並且大量神經元沒有找到新的靶點，突變的HAR更可能導致人類特有的大腦區域差別模式。的確，返回到這裡所講的馴養的猩猩，一些突變的HARs可能對猩猩大腦的組織產生抑制，開啟更新具有更大可塑性的東西。

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