Science2014-06-13 4:39 PM

远古的犬类癌症暗示第一个犬类宿主 Transmissable Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage

论文摘要 

研究人员首次提供了一种可传播肿瘤的整个基因组序列,该肿瘤在数千年前起源于某一条狗,这种肿瘤直到现在仍然在家犬中传播。他们的努力揭示了该肿瘤最初的狗宿主特征,他们说其特征可能类似于现代的阿拉斯加雪橇狗(马拉密犬)。犬传染性性病肿瘤或CTVT是2种已知的可传播的癌症之一;它可通过转移活的癌细胞而在家犬群中传播,通常是在性交时。尽管CTVTs有一段基因组序列源于某一条狗,但它们现在在许多品种的狗中独立地存在着。然而,在该肿瘤的DNA编码内,它们的第一个宿主的基因组一直存活着。为了推断第一条作为CTVT宿主的狗的特征,Elizabeth Murchison及其同事从2条现代犬——1条澳大利亚土著营地狗及1条来自巴西的美洲卡可猎犬——中对CTVTs的基因组进行了测序。有趣的是,他们发现这2个肿瘤共享有几乎2百万个体细胞突变--这比在大多数人类肿瘤中所发现的体细胞突变要多1百多倍。可是至关重要的是,CTVT仍然保持稳定,它继续在家犬群中肆虐了数千年。通过检查DNA变异,Murchsion等人帮助澄清了CTVT第一次在犬中出现的时间--后者一直存在争议;他们估计,CTVT是在1万1000多年前(这是犬类被驯化的时间点)在一个近交群体中出现的。Murchison等人的工作揭示了世界上最老的已知癌细胞系的起源、历史及演化,它凸显了哺乳动物体细胞基因组在一个新的生态位中(在此为犬类宿主)适应并持续的能力。一则《观点栏目》文章提出了更多的见解。

Abstract 

Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy-number changes, and retrotransposon insertions. More than 10,000 genes carry nonsynonymous variants, and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived about 11,000 years ago. The cancer spawned by this individual dispersed across continents about 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.

Editor's Summary

Breaking Tumor Dogma

Canine transmissible venereal tumor (CTVT) is an unusual form of cancer because the infectious agent is not a virus or bacterium but the tumor cells themselves, which are passed from one dog to another during coitus. To explore the molecular features of the tumor and its possible origins, Murchison et al. (p. 437; see the Perspective by Parker and Ostrander) sequenced the genomes of two CTVTs and their host dogs, one from Australia and one from Brazil. Although CTVT has acquired a massive number of genomic alterations, including hundreds of times more somatic mutations than are normally found in human cancers, the tumor cell genome has remained diploid and stable. Indeed, CTVT may first have arisen in a dog that lived more than 10,000 years ago.

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