由美國加州大學伯克利分校的一組研究人員進行了一項關于基因變異的研究,，近日將其相關論文發(fā)表在《科學公共圖書館·生物》(PLoS Genetics)上，引起了Nature等媒體的關注和報道,。

通過研究人群中基因變異頻率與環(huán)境因素的關系,，該研究發(fā)現(xiàn)病原體,，尤其是寄生蟲在人類基因變異中的作用最為重要，同時也發(fā)現(xiàn),，這些變異或許使得人類對自身免疫性疾病更加易感,。

研究者對來自55個不同人群的超過1500人的數(shù)據(jù)進行分析,，計算了不同基因的變異頻率,，并通過統(tǒng)計學模型預測了這些變異的分布,。該統(tǒng)計學模型包含了3中能對人類基因變異產(chǎn)生驅使作用的因素：氣候,；生存策略如農(nóng)業(yè),、漁業(yè)、畜牧業(yè)等,；疾病,。該文章的第一作者馬特奧·傅馬利說：“我們的目的是發(fā)現(xiàn)對人類基因變異影響最大的因素,。”

研究者每次從模型中去除一項影響因素,，來觀察哪個因素對人類基因的變異影響最大,。該文章的合著者拉斯莫斯·尼爾森稱：“我們發(fā)現(xiàn)3個因素都很重要，但致病環(huán)境是最重要的,。”

寄生蟲在自然選擇中的作用比細菌或病毒更為重要,。因為細菌和病毒的進化速度較快，很快就適應了人類基因的變異,，而寄生蟲由于進化速度較慢,，就使得人類有時間發(fā)展我們的防御系統(tǒng)。

研究人員找出了與病原多樣性關系最為密切的103個基因,，這些基因中約1/4與免疫有關,，其中許多與自身免疫性疾病有關，如多發(fā)性硬化癥,，1型糖尿病等。

尼爾森稱,，一個比較合理的解釋是,，病原體造成的變異改變了我們的基因，使得機體的免疫系統(tǒng)活性增強,，而當這些病原體去除以后，我們就對自身免疫病更加易感,。他說“這與衛(wèi)生學的假設非常吻合”,，即病原體暴露去除后機體的免疫系統(tǒng)會處于過度激活狀態(tài),。

而來自佛羅里達大學的進化生物學家布萊恩·卡拉科考斯基指出，要證明病因體與自身免疫病直接的關系,，目前的證據(jù)還不足,，如果作者能夠證明那些幫助人類對抗病原體的基因變異也能增加對自身免疫病的易感性,，這個結論會更有說服力,。

同樣，卡拉科考斯基也不贊同病原體因素比氣候和飲食因素更重要的觀點,，他說“大多數(shù)免疫系統(tǒng)的適應就像是開關”,，而對氣候和飲食的適應就像是“對收音機的微調(diào)”，因此病原體的驅使作用可能僅僅是因為它更容易被檢測到,。

芝加哥大學的安吉拉·漢考克指出,，所有的變異都是交錯在一起的，很難說清楚其中某個因素的單獨作用,。例如,，氣候可能會影響病原體的分布,。而且漢考克的研究表明病原體引起的變異與包括畜牧業(yè)在內(nèi)的生存策略之間有關系,，她說：“因為大多數(shù)動物體內(nèi)的病原體也會感染人類,。即便如此,，病原體仍是人類接受自然選擇的一個重要因素,。”(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”.