大西洋月刊：雌性的卵子可能会主动选择某些精子 [美国媒体]

New evidence challenges the oldest law of genetics.

新的证据挑战了最古老的遗传学定律。



In the winner-takes-all game of fertilization, millions of sperm race toward the egg that’s waiting at the finish line. Plenty of sperm don’t even make it off the starting line, thanks to missing or deformed tails and other defects. Still others lack the energy to finish the long journey through the female reproductive tract, or they get snared in sticky fluid meant to impede all but the strongest swimmers. For the subset of a subset of spermatozoa that reach their trophy, the final winner would be determined by one last sprint to the end. The exact identity of the sperm was random, and the egg waited passively until the Michael Phelps of gametes finally arrived. Or so scientists have thought.

在赢者通吃的受精游戏中，数百万的精子冲向了等待在终点线上的卵子。由于尾巴的缺失或畸形，以及其他的缺陷，很多精子甚至都没能跑出起跑线。还有其他一些精子缺乏足够的能量来完成穿越女性生殖道的漫长旅程，或者是陷入粘滞的液体当中，这意味着除了最强壮的游泳健将之外，其他所有的精子都会受到阻碍。对于能够到达它们的奖杯附近的精子小集团来说，最终的获胜者将由最后一段旅程的最后冲刺来决定。精子的确切身份是随机的，卵子一直在被动地等待，直到配子中的迈克尔·菲尔普斯最终到达终点。科学家们过去就是这么认为的。

Joe Nadeau, principal scientist at the Pacific Northwest Research Institute, is challenging this dogma. Random fertilization should lead to specific ratios of gene combinations in offspring, but Nadeau has found two examples just from his own lab that indicate fertilization can be far from random: Certain pairings of gamete genes are much more likely than others. After ruling out obvious alternative explanations, he could only conclude that fertilization wasn’t random at all.

西北太平洋研究所的首席科学家Joe Nadeau正在挑战这一观念。随机的受精应该会导致后代基因组合呈现出特定的比例，但他在自己的实验室中发现了两个例证表明受精过程可能远非随机进行的：某些配对的基因比其他的更有可能出现。在排除了其他显而易见的解释之后，他只能得出这样的结论：受精并不是随机进行的。

“It’s the gamete equivalent of choosing a partner,” Nadeau said.

Nadeau说:“这是一种会选择伴侣的配子。”

His hypothesis—that the egg could woo sperm with specific genes and vice versa—is part of a growing realization in biology that the egg is not the submissive, docile cell that scientists long thought it was. Instead, researchers now see the egg as an equal and active player in reproduction, adding layers of evolutionary control and selection to one of the most important processes in life.

他的假设是：卵子可以用特定的基因来吸引精子，而在生物学上，这是生物学日益认识到的一部分事实，即卵子不是一个科学家们长期以来所认为的顺从的、驯服的细胞。相反，研究人员现在把卵子看作是繁殖的平等和活跃的参与者，在生命最重要的过程中增加了进化控制和选择的层次。

“Female reproductive anatomy is more cryptic and difficult to study, but there’s a growing recognition of the female role in fertilization,” said Mollie Manier, an evolutionary biologist at George Washington University.

乔治华盛顿大学的进化生物学家Mollie Manier说：“雌性生殖解剖学更神秘，更难进行研究，但人们对雌性在受精过程中所扮演角色的认识正变得越来越多。”

The idea of sexual selection is as old as Charles Darwin himself. In On the Origin of Species, he wrote of the peacock’s showy tail and the elk’s giant antlers as examples of traits that evolved to help males show off their appeal as mates to females. For the next century, biologists focused on all the aspects of sexual selection that operated in the events leading up to copulation. After mating, the female had made her choice, and the only competition was among the sperm swimming to the egg.

性选择的概念和查尔斯·达尔文本人一样古老。在物种起源方面，他将孔雀的艳丽尾巴和大角鹿的巨大鹿角作为了这些特征的例子，这些特征有助于雄性向雌性展示自己的吸引力。在接下来的一个世纪里，生物学家将注意力集中在性选择的各个方面，它们都是在交配前的活动中进行的。交配后，雌性已经做出了自己的选择，唯一的竞争便出现在精子游到卵子的过程中。

This male-oriented view of female reproductive biology as largely acquiescent was pervasive, argued Emily Martin, an anthropologist at New York University, in a 1991 paper. “The egg is seen as large and passive. It does not move or journey but passively ‘is transported’ ... along the fallopian tube. In utter contrast, sperm are small, ‘streamlined,’ and invariably active,” she wrote.

纽约大学的人类学家艾米丽·马丁在1991年的一篇论文中指出：这种在很大程度上表现为一方顺从的、以雄性为主导的雌性生殖生物学观点曾经非常流行。她写道：“卵子被认为是大而被动的。它不会移动或展开旅行，而是被动地“被运输”……沿着输卵管行进。与之形成鲜明对比的是：精子体积小，形状呈“流线型”，而且总是很活跃。” 

“There are incredible things that eggs and seminal fluid can do.”

“卵子和精液可以做出一些令人难以置信的事情。”

Beginning in the 1970s, however, the science began to undermine that stereotype. William Eberhard, now a behavioral ecologist at the Smithsonian Tropical Research Institute, documented all the ways that females can affect which males fertilize their eggs even after mating. It’s a long list, and scientists still can’t say for sure whether they’ve documented everything. The belatedness of these discoveries wasn’t all due to sexism. Two walruses dueling with their tusks is easy to observe; games of hide-and-seek with sperm inside the female reproductive tract are much less so.

然而，从上世纪70年代开始，科学就开始削弱这种刻板印象。William Eberhard现在是史密森尼热带研究所的一名行为生态学家，他记录了雌性动物在交配后会影响到其卵子的所有方式。这是一个很长的列表，科学家们还不能确定他们是否记录了所有的事情。这些发现迟迟才出现并不全是因为性别歧视。两头海象用它们的象牙进行决斗是很容易被观察到的；但要观察到雌性生殖道内与精子进行的捉迷藏的游戏则要难得多。

“As soon as you have eggs and sperm, you have sexual selection. There are incredible things that eggs and seminal fluid can do,” explained Andrea Pilastro, an evolutionary biologist at the University of Padova in Italy.

意大利帕多瓦大学的进化生物学家Andrea Pilastro解释说：“一旦有了卵子和精子，你就有了性选择。卵子和精液可以做出一些令人难以置信的事情。” 

In those species in which fertilization happens outside the body, the females often coat their eggs with a thick, protein-rich ovarian fluid. Experiments in 2013 by Matthew Gage of the University of East Anglia in England showed that this fluid contains chemical signals to help attract the correct species of sperm. When they exposed eggs from salmon and trout to mixtures of sperm from both species, the eggs’ own species successfully fertilized 70 percent of the time, significantly more than to be expected by chance.

对于那些体外受精的物种来说，雌性通常会用厚厚的富含蛋白质的卵巢液来覆盖它们的卵。2013年，英国东安格利亚大学的Matthew Gage进行的实验表明：这种液体中含有能帮助吸引正确的精子的化学信号。当他们把鲑鱼和鳟鱼的卵和这两种鱼的精子放在一起的时候，这些卵与同种精子的结合成功率达到了70%，远远超过了预期的几率。

“The sperm behaved differently in different ovarian fluids. They actually swam straighter in their own fluid,” Gage said.

Gage说：“精子在不同卵巢液中的表现不同。事实上，它们在自己的液体中游得路线更笔直。”

Internal fertilizers have their own methods of what Eberhard dubbed “cryptic female choice.” Some female reproductive tracts are labyrinthine, complete with false starts and dead ends that can stymie all but the strongest sperm. Some females, including many species of reptiles, fish, birds, and amphibians, that copulate with more than one male (which biologists estimate are a vast majority of species) can store sperm for months, even years, altering the storage environment to stack the odds to favor one male over another. Many female birds, including domestic chickens, can eject sperm after mating, which lets them bias fertilization in favor of the best male.

内部受精的物种也有自己的办法，Eberhard称之为“神秘的雌性选择”。一些雌性生殖道就像迷宫一样，有错误的开端和死胡同，这些都可能阻碍除了最强者之外的精子。一些会与不止一个雄性交配的雌性动物——包括许多爬行动物、鱼类、鸟类和两栖动物(生物学家估计包括了绝大多数的物种)——可以将精子储存数个月甚至数年时间，并且可以通过改变储存环境让它有利于一个雄性而不是另一个雄性。许多雌性鸟类——包括家养的鸡——可以在交配后排出精子，这使得它们倾向于选择最佳的雄性个体。

All these strategies, however, provide females with opportunities only to select the sperm of different males. Within an ejaculate, which sperm fertilized the egg still seemed to be left to chance.

然而，所有这些策略都只是为雌性提供了选择不同雄性精子的机会。在同一次射精中，精子使卵子受精的几率仍然存在。

“We’ve been blinded by our preconceptions.”

“我们被自己的偏见蒙蔽了。”

In fact, the randomness of fertilization is implicit in the principle of segregation—the first law of genetics going back to Gregor Mendel. Parents carry two copies of each gene, which are divided randomly into gametes that carry only one copy. It’s what gives rise to many of the probabilities students learn in high-school biology. If both parents are heterozygotes—meaning they carry two alternate versions of the same gene—then half their offspring would also be heterozygotes. A quarter of the offspring would be homozygotes carrying two copies of one version, and the remaining quarter would be homozygotes with the other version.

事实上，受精的随机性隐藏在了隔离的原则中——也就是要追溯至孟德尔的遗传学第一定律。父母各自携带了一套基因的两份副本，这些基因被随机分为只携带一份副本的配子。这就导致了学生在高中生物学中学习到的诸多概率。如果双亲都是杂合子——意思就是他们携带了相同基因的两个不同版本，那么其一半的后代也会是杂合子。四分之一的后代是携带了同一个版本的两份副本的纯合子，剩下的四分之一是另一个版本的纯合子。

“It’s one of the most broadly applicable rules in biology,” Nadeau said.

Nadeau说:“这是生物学中最广泛适用的规则之一。”

Yet these probabilities work out only if fertilization is random. If the egg or the sperm can somehow influence the identity of the other gamete involved in fertilization, then those ratios could be very different. This striking difference was what caught Nadeau’s attention back in 2005. When he started looking at the inheritance of two particular genes in mice, the probabilities were all off. In his Seattle lab, he began to wonder: Could Mendel have been wrong?

然而，这些概率只有在受精是随机进行的情况下才会发生。如果卵子或精子能在某种程度上影响受精过程中其他配子的身份，那么这些概率就会大不相同。这一惊人的差异在2005年引起了Nadeau的关注。当他开始研究小鼠身上的两种特殊基因的遗传时，这些概率就全部消失了。在他位于西雅图的实验室中，他开始怀疑：孟德尔的基因是错误的吗？

Nadeau hadn’t set out to question Mendel. Instead, he wanted to know how interactions between two genes (Apobec1 and Dnd1) affected risks for testicular cancer, one of the most heritable forms of cancer. When Nadeau and his doctoral student Jennifer Zechel bred female mice carrying one normal and one mutant copy of Dnd1 with heterozygote Apobec1 males, everything appeared to follow Mendel’s rules. So far, so good. But when they reversed the breeding (a female Apobec1 heterozygote mated with a male Dnd1 heterozygote), things got weird: They found that only 27 percent of the expected offspring carried copies of mutant Apobec1, mutant Dnd1, or both, compared with the 75 percent they expected to see.

Nadeau此前并没有质疑过孟德尔的理论。相反，他只是想搞清楚两个基因(Apobec1和Dnd1)之间的相互作用会如何影响患上睾丸癌的风险——这是一种最可能遗传的癌症。当Nadeau和他的博士生Jennifer Zechel让正常的雌性老鼠和带有Apobec1与Dnd1杂合子的雄性老鼠繁殖后代的时候，所有的一切似乎都遵循了孟德尔提出的规则。至此为止一切都还好。但是当他们逆转了这种繁殖的过程 (带有Apobec1杂合子的雌性与带有Dnd1杂合子的雄性交配)时，事情就变得很奇怪了：他们发现其后代中只有27%携带了突变的Apobec1基因、突变的Dnd1基因，或者两者都有，而他们原本期望的比例是75%。

As a researcher who had spent several decades studying heredity, Nadeau was aware of myriad factors that could affect Mendel’s ratios. If a fertilized egg ended up with two mutated copies of a recessive gene, the resulting embryo might die early in development. Such embryonic lethal mutations would alter the ratio of homozygotes to heterozygotes, but it would also reduce the average number of mouse pups in each litter. Yet all of Zechel and Nadeau’s mice had standard litter sizes, and they found no evidence that embryos were dying early after fertilization.

作为一名花费了几十年时间研究遗传问题的研究人员，Nadeau意识到许多可能会影响孟德尔概率的因素。如果受精卵最终获得了两个突变的隐性基因，那么这样的胚胎可能在发育早期就会死亡。这种胚胎致死的突变会改变纯合子与杂合子的比例，但同时也会减少每窝中幼鼠的平均数量。然而， Zechel和Nadeau培育的所有老鼠都有标准的同胎生仔数，而且他们没有发现任何证据表明胚胎在受精后不久就会死亡。

Perhaps, Nadeau reasoned, the problem lay in the sperm, not the egg. He therefore bred male mice with and without the mutation to healthy mutation-free females and found no differences in the males’ fertility—something that would have become obvious if the mutation were affecting sperm formation. Step by step, Nadeau and his team eliminated every possible cause of these wonky ratios of offspring genotypes ... except one: that during fertilization, the egg and sperm were genetically biased against the mutant genotype.

Nadeau认为问题或许处在了精子上面，而不是卵子上。因此，他让发生突变和没有发生突变的雄鼠分别与没有发生突变的雌鼠进行了交配，但没有发现这些雄鼠在受精方面有什么不同——如果这种突变影响了精子的形成，那么它们的结果就会变得很明显。Nadeau和他的团队一步步地消除了所有可能导致后代夭折的基因型要素，除了一个：在受精过程中，卵子和精子在基因上对突变型基因存有偏见。

Surely, someone else must have already seen this, Nadeau reasoned, so he searched the scientific literature. Although he could find plenty of examples of unexplained offspring ratios, no one had seriously pursued genetically biased fertilization as an answer.

Nadeau做出了这样的推测——当然，其他人也已经发现了这一点——所以他搜索了科学文献。尽管他可以找到许多无法解释的后代比率的例子，但没有人认真地从基因方面研究过有偏见的受精过程。

“I don’t think we still really appreciate how common this is and how often it happens.”

“我认为我们还不知道这种现象有多普遍，以及它发生的频率。”

“Everyone just interpreted it as embryonic lethality because we see what we look for and we explain it using what we know,” Nadeau said.

Nadeau说:“每个人都只是把它解释为胚胎的致死率，因为我们只看到了我们所寻找的东西，我们用我们知道的东西来解释它。”

One of those examples Nadeau found was from the lab of the cancer researcher Roseline Godbout at the University of Alberta. Godbout studied the role of a protein called DDX1 in the development of retinoblastoma, a highly heritable childhood cancer. Mice that were missing one functional copy of the DDX1 gene (but with another, fully functional gene as backup) seemed normal and healthy. When Godbout and Devon Germain, now a postdoctoral fellow at the Max F. Perutz Laboratories in Vienna, bred such heterozygote males and females, they found that none of the offspring lacked both copies of DDX1, even though simple Mendelian math would suggest 25 percent of them should. Given the gene’s importance to DNA replication, however, this wasn’t surprising: The homozygotes without DDX1 presumably died after conception. Godbout and Germain also found lower-than-expected numbers of homozygote offspring with two copies of DDX1. A complicated series of mating experiments led the scientists to propose that their results came from a rare mutation that had occurred in the DDX1 gene during their experiments.

Nadeau发现的一个例子来自于阿尔伯塔大学的癌症研究人员Roseline Godbout的实验室。Godbout研究了一种名为“DDX1”的蛋白质在成视网膜细胞瘤中的作用，这是一种具有高度遗传性的儿童癌症。缺少了DDX1基因的一种功能性副本的小鼠(与之对比的是另一个具有完全功能性基因的备份组)看起来是正常的和健康的。当Godbout和现为维也纳马克斯·F. 佩尔茨实验室的博士后研究员的Devon Germain培育出了这种杂合子雄鼠和雌鼠时，他们发现没有一只后代缺乏两种DDX1的副本，即使简单的门德曼数学也会给出25%的结果。然而，考虑到该基因对DNA复制的重要性，这一结果并不令人吃惊：没有DDX1的纯合子可能在怀孕后死亡。Godbout和Germain还发现带有DDX1两份副本的同卵后代的数量要低于预期。一系列复杂的交配实验让科学家们提出了一种解释：他们的研究结果来自于在他们的实验中于 DDX1基因上发生的一种罕见的突变。

Nadeau wasn’t convinced. He wrote to Godbout to ask how her lab had verified that the “knockout” homozygotes without DDX1 genes had died as embryos. They hadn’t. He also asked whether they had considered genetically biased fertilization, wherein the egg preferred to fuse with a sperm of the opposite DDX1 genotype.

Nadeau对此并不信服。他写信给Godbout，询问她的实验室是如何验证不带有DDX1基因的被淘汰的杂合子已经在胚胎时期死亡。他们无法回答这个问题。他还询问了他们是否考虑过基因层面上有偏见的受精过程——在这种情况下，卵子更倾向于与DDX1基因型的精子结合。

“We really thought it was just a weird pattern of inheritance,” Germain recalled. “We hadn’t thought about nonrandom fertilization.”

Germain回忆说:“我们真的认为这只是一种奇怪的遗传模式。我们没有考虑过非随机受精的问题。”

Later, on a whim, Germain decided to review all the raw data from his experiments. As he looked over the results, he remembered Godbout’s questions that had been prompted by Nadeau’s email. The more he looked at the data, the more that genetically biased fertilization looked like “the most plausible explanation,” he said.

后来，Germain突发奇想，决定回顾他的实验中的所有原始数据。当他查看结果时，他想起了Nadeau的电子邮件中向Godbout提出的问题。他说，他对这些数据进行越多的研究，就越认为基因层面上有偏见的受精过程看起来是“最可信的解释”。

Frustrated at how few scientists had seriously considered genetically biased fertilization as an explanation for their results, Nadeau wrote up his hypothesis in “Can Gametes Woo?,” an article published in October in Genetics. His goal, he said, was to spur more research into this area and determine if and how egg-and-sperm interactions can alter fertilization.

因为很少有科学家认真考虑用基因层面上有偏见的受精过程来解释他们的结果而倍感沮丧的Nadeau在《配子们会相互吸引吗？》这篇发表于10月份《遗传学》杂志上的文章中提出了他的假设。他说：他的目标是推动这一领域的更多研究，并确定卵子和精子之间的相互作用是否以及如何改变受精。

“We’ve been blinded by our preconceptions. It’s a different way to think about fertilization with very different implications about the process of fertilization,” Nadeau says.

Nadeau说:“我们被我们的偏见蒙蔽了。这是一种不同的思考方式，对受精的过程有着非常不同的影响。”

Other scientists, such as Manier at George Washington University, say that Nadeau’s hypothesis is intriguing and even plausible, but they point out that no one has any evidence about how it could happen. Nadeau agrees and points to two possibilities.

其他科学家——比如乔治华盛顿大学的Manier——认为Nadeau的假设很有趣，甚至是可信的，但他们指出：没有人有任何证据表明它是如何发生的。Nadeau也同意这一点，并指出了两种可能性。

“Females are going to have a vested interest in the outcome of fertilization.”

“在受精的结果中，雌性存在着既得利益。”

The first involves the metabolism of B vitamins such as folic acid, which form important signaling molecules on sperm and eggs. Research in Nadeau’s lab has shown that these molecules play an outsize role in fertilization, and he believes abnormalities in certain signaling genes may alter how much sperm and egg attract each other.

第一种是维生素B的新陈代谢，比如叶酸，它在精子和卵子中形成重要的信号分子。Nadeau实验室的研究表明，这些分子在受精过程中发挥了巨大的作用，他认为某些信号基因的异常可能会改变精子和卵子之间的相互吸引方式。

A competing hypothesis builds on the fact that sperm are often present in the female reproductive tract before the final set of cell divisions that produce the egg. Signals from the sperm could influence these cell divisions and bias the identity of the cell that becomes the egg.

一种关于相互竞争的假说是基于这样一个事实，即精子通常是在最后一组细胞分裂产生卵子之前出现在雌性生殖道中。精子发出的信号可能会影响这些细胞的分裂，并使成为卵子的这些细胞的身份出现偏差。

Whatever the mechanism might be, this work challenges the standard view of female physiology as passive during fertilization. “Females were seen as passive objects with no choice, but females are going to have a vested interest in the outcome of fertilization,” said Renee Firman, an evolutionary biologist at the University of Western Australia. “We still have a long way to go to understand this process, but I don’t think we still really appreciate how common this is and how often it happens.”

无论这一机制是怎样的，这项工作都挑战了雌性生理在受精过程中处于被动状态的标准观点。西澳大利亚大学的进化生物学家Renee Firman说：“雌性被认为是被动的对象，它没有选择，但雌性在受精的结果中却有着既得利益。我们还有很长的路要走，才能最终理解这一过程，但我不认为我们真正了解这一过程有多普遍，以及它发生的频率。”

Finding data to support or refute this hypothesis could be challenging, Manier said. It will depend on showing that genes within the sperm affect their surface molecules, and that the egg can sense these differences. Such results will require detailed biochemical studies of individual sperm cells and sequencing information about their genome.

Manier说：找到支持或驳斥这一假设的数据可能是一种挑战。这将取决于精子内的基因是否会影响它们的表面分子，以及卵子能够感知到这些差异。这样的结果将需要对单个精子细胞进行详细的生化研究，并对它们的基因组进行测序。

Nadeau is prepared for skeptics—he’s encountered many at conferences when he presents the results of his mouse studies and his hypothesis for what’s going on. Critics often approach him after the talk and begin asking him questions. Whether they walk away convinced is unclear, but Nadeau feels they are much less certain that biased fertilization doesn’t happen. To Harmit Malik, a geneticist and virologist at the Fred Hutchinson Cancer Research Center, the situation is the ultimate Sherlock Holmesian solution.

Nadeau在为回应质疑做着准备——当他在会议上展示其小白鼠研究的结果和假设时，便遇到了许多质疑之声。在他的演讲结束后，批评之声便会出现，并开始向他提问。他们是否是在被说服之后离开的，目前还不清楚，但Nadeau觉得他们已经不那么肯定有偏见的受精过程不会发生了。对弗雷德钦森癌症研究中心的遗传学家和病毒学家Harmit Malik来说，这种情况是最终的夏洛克·福尔摩斯式的解决方案了。

“If you’ve eliminated the impossible, then what remains, however unlikely, must be the truth,” he quipped.

他打趣道：“如果你已经消除了不可能，那么剩下的——无论它多么不可能——都必然是事实”。