首次单独分离测序发现:同一细胞里线粒体也不同
2017/12/09
美国宾夕法尼亚大学医学院的研究人员发现了一个新方法,让研究人员能提取单个线粒体的mtDNA。该研究发现,细胞中不同线粒体DNA有很大不同,这让医生通过检测细胞状况,预测患者是否可能会患有神经系统疾病成为可能。


线粒体是具有自身DNA(mtDNA)的细胞组成部分,它为机体产生能量,并行使一些其他的功能。每个细胞中有数百到数千个线粒体个体。许多线粒体疾病起因于线粒体DNA积累的突变。例如,在结肠直肠癌、卵巢癌、乳腺癌、膀胱癌、肾癌、肺癌和胰腺肿瘤中都发现了这些突变。

这一发表在本周Cell Reports的文章揭示:单个细胞中不同线粒体之间的DNA序列有很大不同。这一论断将有助于更好地阐明许多从线粒体突变开始的疾病潜在机制,并提供有关病人如何对特定疗法作出反应的线索。

新方法允许分离单独的线粒体DNA


在显微镜下分离线粒体DNA的操作

让提取单个线粒体的mtDNA成为现实,这是通讯作者James Eberwine教授的实验室开发出了一个新方法。在比较了小鼠和人类神经元中单个线粒体中的突变后,他们发现与人类细胞相比,小鼠细胞有更多累积的突变,且突变在小鼠与人类是不同的速率积累的。

Eberwine指出,该研究说明之前科研的一个重要假设(线粒体疾病或潜在的治疗药物在细胞模型中的突变和那些发生在人类中的是平行的)存在问题。

一生中线粒体DNA突变的累积,有可能在每一个人的过程里都有些不同。这项研究讨论了同一细胞中离散线粒体DNA的相似性和差异,以及大脑中神经元和星形胶质细胞等细胞类型之间的相似性和差异性。

让医生通过检测细胞的状况预测疾病

实验图示

Eberwine 指出:“能够对单个的线粒体进行研究和对线粒体突变的动态进行比较,我们将能够计算出多少线粒体突变会导致相关疾病的风险阈值计”。例如,这些数据可以提高神经系统疾病的诊断,有可能让医生检测细胞的状况是否可能会患病,或针对患者制定一定的条件。这种情况尤其可能应用在老年人中,因为他们的线粒体DNA突变随着年龄增长而增加。

将来,研究人员计划利用这一知识寻找减缓线粒体DNA突变累积的方法,以期阻止疾病的进展。Eberwine说:“这中分离测序的新方法能够分析线粒体DNA突变的数量,是我们进一步研究需要的开始。”

参考资料

1) Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

2) First DNA sequence from a single mitochondria

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  • Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

    A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds.

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  • Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

    A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds.

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