鼠疫在人類基因組上留下揮之不去的傷痕

在黑死病期間可能有助於生存的基因現在與自身免疫性疾病有關。

新聞 / 2022 年 10 月 19 日 / 自然 / 財團法人台灣紅絲帶基金會編譯

患有腺鼠疫的人，例如這本 15 世紀的瑞士手稿中所描繪的人，淋巴結腫大。

圖片來源：VCG Wilson/Corbis via Getty

當黑死病在 14 世紀中葉席捲北非和歐亞大陸時，它殺死了那裡多達一半的人口，重塑了歷史——並可能改變了人類進化的進程。

10 月 19 日發表在 Nature 上的一項研究顯示，由鼠疫耶爾森菌引起的鼠疫留下的揮之不去的疤痕可以在現代人類免疫系統的相關基因中找到。特別是四種 DNA 變異似乎在黑死病之後變得更加普遍，並且可能有助於生存。

但這些變異提供的保護可能是有代價的：今天，其中兩種與自身免疫性疾病的風險增加有關，例如克羅恩病 (Crohn’s disease) 和類風濕性關節炎。

「這是一項非常創新的工作」，費城賓夕法尼亞大學的人口遺傳學家 Ziyue Gao 說。「我們總是想知道推動人口進化的力量是什麼」。

長期影響

黑死病是人類歷史上最致命的流行病，遺傳學家長期以來一直對其起源及其對人類遷徙和免疫的影響感到好奇。「這簡直難以想像」，伊利諾伊州芝加哥大學的人口遺傳學家 Luis Barreiro 說。

Barreiro 和他的同事假設，這樣一個戲劇性的事件可能會在免疫系統的進化上留下印記。為了找出答案，他們研究了 200 多個 DNA 樣本中的遺傳變異，這些 DNA 樣本是從生活在鼠疫之前、死於鼠疫或生活一兩代人的個體的骨骼或牙齒中分離出來的。

古代DNA追踪黑死病的起源

該團隊專注於與免疫相關的基因，並在來自英國和丹麥的樣本中發現了似乎在黑死病期間被選中的四種 DNA 變體。一種變體影響了一種叫做 ERAP2 的基因的表達。攜帶這種變異的人會產生編碼 ERAP2 蛋白的全長 RNA 分子；那些缺乏它的人會製造出較短版本的 RNA。

ERAP2 蛋白由稱為巨噬細胞的特殊免疫細胞製成，可吞噬和消化細菌。它參與將細菌蛋白質切割成碎片，然後將其中一些顯示在巨噬細胞表面，作為對其他免疫細胞的信號。 Barreiro 說：「這是一種警報系統，表明正在發生感染，他們需要攻擊」。

Barreiro 和他的合作者推測，擁有全長、功能齊全的 ERAP2 蛋白可能會在黑死病期間改善免疫保護。實驗室研究支持了這一觀點：與表達截短版本的巨噬細胞相比，表達較長版本 ERAP2 的巨噬細胞能夠更有效地阻止鼠疫耶爾森氏菌複製。

但保護性 ERAP2 基因變異也是克羅恩病的已知危險因素。 Barreiro 和他的同事發現的另一種變異與類風濕性關節炎和另一種自身免疫性疾病系統性紅斑狼瘡有關。 Barreiro 說，這突出了研究可能選擇這些變體的進化壓力的相關性：「這些變體今天也可能影響對免疫相關疾病的敏感性」。

冰山一角？

德國萊比錫馬克斯普朗克進化人類學研究所的古遺傳學家約翰內斯.克勞斯說，該團隊的方法非常有效，他研究了鼠疫與免疫系統基因之間的聯繫。他指出，在 14 世紀流行的其他病原體也可能提高了 ERAP2 變體患者的生存率。

Barreiro 和他的同事希望將他們的工作擴展到包括更多樣本和更廣泛的 DNA 定序。高說，這可以揭示更多與黑死病相關的基因變異。「我想知道有多少變種被遺漏了」，她說。「這是否意味著他們只探測到了冰山一角」？

doi：https://doi.org/10.1038/d41586-022-03298-z

參考文獻：

Klunk, J. 等人。《自然》 https://doi.org/10.1038/s41586-022-05349-x (2022)。

Bubonic plague left lingering scars on the human genome

Genes that might have aided survival during the Black Death are now linked to autoimmune disorders.

NEWS / 19 October 2022 / Nature

People with bubonic plague, such as those depicted in this fifteenth century Swiss manuscript, suffered from swollen lymph nodes. Credit: VCG Wilson/Corbis via Getty

When the Black Death swept through northern Africa and Eurasia in the mid-fourteenth century, it killed up to half of the human populations there, reshaped history — and potentially changed the course of human evolution.

A study published on 19 October in Nature suggests that lingering scars from the bubonic plague, which was caused by the bacterium Yersinia pestis, can be found in genes involved in the modern human immune system. Four DNA variants in particular seem to have become more common after the Black Death, and might have contributed to survival.

But the protection afforded by those variants could have come at a cost: today, two of them are associated with an increased risk of autoimmune disorders, such as Crohn’s disease and rheumatoid arthritis.

“It’s very innovative work,” says Ziyue Gao, a population geneticist at the University of Pennsylvania in Philadelphia. “We always wonder what the forces are that drive population evolution.”

Long-lasting impacts

The Black Death was the most lethal pandemic in human history, and geneticists have long been curious about its origins and its impact on human migrations and immunity. “It’s just unimaginable,” says Luis Barreiro, a human population geneticist at the University of Chicago in Illinois.

Barreiro and his colleagues hypothesized that such a dramatic event could have left its mark on the evolution of the immune system. To find out, they looked at genetic variation in more than 200 DNA samples isolated from the bones or teeth of individuals who lived before the plague, died from it or lived one or two generations later.

Ancient DNA traces origin of Black Death

The team focused on genes related to immunity and found four DNA variants that seemed to have been selected for during the Black Death in samples from both the United Kingdom and Denmark. One variant affected the expression of a gene called ERAP2. People with the variant produce a full-length version of an RNA molecule that encodes the ERAP2 protein; those who lack it make a shorter version of the RNA.

The ERAP2 protein is made by specialized immune cells called macrophages that engulf and digest bacteria. It is involved in cutting bacterial proteins into pieces, some of which are then displayed on the surface of the macrophage as a signal to other immune cells. “It’s a kind of alert system that there’s an infection going and they need to attack,” says Barreiro.

Barreiro and his collaborators speculated that having a full-length, fully functional ERAP2 protein might have improved immune protection during the Black Death. Laboratory studies backed up this idea: macrophages expressing the longer version of ERAP2 were able to keep Yersinia pestis from replicating more effectively than were macrophages expressing the truncated version.

But the protective ERAP2 gene variant is also a known risk factor for Crohn’s disease. Another of the variants Barreiro and his colleagues found is associated with rheumatoid arthritis and another autoimmune condition, systemic lupus erythematosus. This, says Barreiro, highlights the relevance of studying the evolutionary pressures that might select for these variants: “These variants can also today impact sensitivity to immune-related disorders.”

Tip of the iceberg?

The team’s approach was powerful, says Johannes Krause, a palaeogeneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who has studied links between bubonic plague and immune-system genes. He notes that other pathogens circulating in the fourteenth century could also have led to improved survival for people with the ERAP2 variant.

Barreiro and his colleagues hope to extend their work to include more samples and more extensive DNA sequencing. This, says Gao, could reveal yet more genetic variants associated with Black Death. “I’m wondering how many variants were missed,” she says. “Does that mean they’re only detecting the tip of the iceberg?”

doi: https://doi.org/10.1038/d41586-022-03298-z

References

1.Klunk, J. et al. Nature https://doi.org/10.1038/s41586-022-05349-x (2022).