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时间:2017/12/23 21:29:20  作者:  来源:  浏览:0  评论:0
内容摘要: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 t...
New evidence challenges the oldest law of genetics.



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.


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.


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.


“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.


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.


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


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.


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.


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.


“We’ve been blinded by our preconceptions.”


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.


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


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?


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.


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.


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


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


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.


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


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.


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.


“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.


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.


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


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.


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.


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.


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.






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