由美国加州大学伯克利分校的一组研究人员进行了一项关于基因变异的研究，近日将其相关论文发表在《科学公共图书馆·生物》(PLoS Genetics)上，引起了Nature等媒体的关注和报道。
通过研究人群中基因变异频率与环境因素的关系，该研究发现病原体，尤其是寄生虫在人类基因变异中的作用最为重要，同时也发现，这些变异或许使得人类对自身免疫性疾病更加易感。
研究者对来自55个不同人群的超过1500人的数据进行分析，计算了不同基因的变异频率，并通过统计学模型预测了这些变异的分布。该统计学模型包含了3中能对人类基因变异产生驱使作用的因素：气候；生存策略如农业、渔业、畜牧业等；疾病。该文章的第一作者马特奥·傅马利说：“我们的目的是发现对人类基因变异影响最大的因素。”
研究者每次从模型中去除一项影响因素，来观察哪个因素对人类基因的变异影响最大。该文章的合着者拉斯莫斯·尼尔森称：“我们发现3个因素都很重要，但致病环境是最重要的。”
寄生虫在自然选择中的作用比细菌或病毒更为重要。因为细菌和病毒的进化速度较快，很快就适应了人类基因的变异，而寄生虫由于进化速度较慢，就使得人类有时间发展我们的防御系统。
研究人员找出了与病原多样性关系最为密切的103个基因，这些基因中约1/4与免疫有关，其中许多与自身免疫性疾病有关，如多发性硬化症，1型糖尿病等。
尼尔森称，一个比较合理的解释是，病原体造成的变异改变了我们的基因，使得机体的免疫系统活性增强，而当这些病原体去除以后，我们就对自身免疫病更加易感。他说“这与卫生学的假设非常吻合”，即病原体暴露去除后机体的免疫系统会处于过度激活状态。
而来自佛罗里达大学的进化生物学家布莱恩·卡拉科考斯基指出，要证明病因体与自身免疫病直接的关系，目前的证据还不足，如果作者能够证明那些帮助人类对抗病原体的基因变异也能增加对自身免疫病的易感性，这个结论会更有说服力。
同样，卡拉科考斯基也不赞同病原体因素比气候和饮食因素更重要的观点，他说“大多数免疫系统的适应就像是开关”，而对气候和饮食的适应就像是“对收音机的微调”，因此病原体的驱使作用可能仅仅是因为它更容易被检测到。
芝加哥大学的安吉拉·汉考克指出，所有的变异都是交错在一起的，很难说清楚其中某个因素的单独作用。例如，气候可能会影响病原体的分布。而且汉考克的研究表明病原体引起的变异与包括畜牧业在内的生存策略之间有关系，她说：“因为大多数动物体内的病原体也会感染人类。即便如此，病原体仍是人类接受自然选择的一个重要因素。”(生物谷Bioon.com)
doi:10.1038/nature.2011.9345
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Parasites drove human genetic variation
Adapting to pathogens was more important than climate and diet in driving natural selection.
Cassandra Willyard
Modern humans began to spread out from Africa approximately 100,000 years ago. They settled in distant lands, where they had to adapt to unfamiliar climates, find different ways to feed themselves and fight off new pathogens. A study now suggests that it was the pathogens, particularly parasitic worms, that had the biggest role in driving natural selection — but that genetic adaptation to them may also have made humans more susceptible to autoimmune diseases.
Populations separated by distance tend to drift apart genetically over time, and roughly 95% of variability between populations is a result of that drift. But the local environment plays a part too. Genetic variants that improve survival in a given region tend to become more common in the population that lives there. By looking for correlations between the frequency of different variants in a population and environmental factors such as climate, researchers can gain a better understanding of the drivers of human adaptation.
The authors of a study published last week in PLoS Genetics used data from more than 1,500 people, representing 55 distinct populations, to calculate the frequency of different genetic variants. They then developed a statistical model to predict the distribution of these variants. The model incorporates three types of environmental variable that could have exerted selective pressure on the human genome: climate; the importance of subsistence strategies such as agriculture, fishing and animal husbandry; and pathogen diversity.
“Our goal was to understand which category most shaped human genetic variation,” says Matteo Fumagalli, a genomics researcher at the University of California, Berkeley, and lead author of the paper.
The researchers removed the variables from the model one at a time, to see which would have the biggest impact on the predictive power of the model. “What we show is that all three factors are important, but the strongest factor is the pathogenic environment,” says Rasmus Nielsen, a computational biologist at Berkeley, and a co-author of the study.
Parasitic worms seemed to be a stronger driver of natural selection than viruses or bacteria. That makes some sense, says Nielsen. Bacteria and viruses, which evolve quickly, might be able to rapidly circumvent any genetic advantage gained by humans. Worms, however, evolve more slowly, giving us time to solidify our defenses.
Active immune system
The team used the model to pinpoint the 103 genes most strongly correlated with pathogenic diversity. Nearly one-quarter of those genes are involved in immunity, in everything from inflammation to pathogen recognition. Many also seem to increase susceptibility to autoimmune diseases such as multiple sclerosis, type 1 diabetes and coeliac disease.
One plausible hypothesis, Nielsen says, is that pathogen-driven adaptation changed our genes in ways that make us more susceptible to autoimmune diseases when those pathogens are absent. “There’s a tradeoff between your immune system being too active and not being active enough,” he says. So it’s possible that past pathogen exposures led to the development of more aggressive immune systems. “If the pathogen is not there, the same genes might then end up causing autoimmune disease,” he says. “It fits very well with the hygiene hypothesis” that lack of exposure to pathogens leads to an overactive immune system.
However, Bryan Kolaczkowski, an evolutionary biologist at the University of Florida in Gainesville, says that there is not yet enough evidence to make a causal link between pathogen adaptations and autoimmune disease. “It’s a reasonable speculation, but I wouldn’t say it’s a strong conclusion of this paper,” he says. The evidence would be more convincing if the authors had found that the same genetic variants that enabled us to fight off pathogens also increased our susceptibility to autoimmune diseases. Making that connection would be a good next step, he says.
Neither is Kolaczkowski convinced that pathogens are more important than climate and diet. “A lot of adaptation in the immune system is sort of these on/off switches,” he says. But adaptation to climate or diet might be more like “fine-tuning a radio” by dialling in the appropriate response, so pathogen-driven adaptation may simply be easier to detect than other kinds, he says.
Angela Hancock, a genomics researcher at the University of Chicago, Illinois, points out that all the variables are intertwined, which can make it difficult to tease out the effect of any one factor. Climate, for example, influences the distribution of pathogens. And Hancock’s research suggests that there is a link between pathogen-related adaptation and subsistence strategies that include keeping animals. That makes sense, she says, since many pathogens found in animals can infect humans. Even so, she says, “there’s no doubt that pathogens have been an important selective force in humans”.
