High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
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DOI：
10.1126/sciadv.adi4038
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发表时间：
2023-10-27
期刊：
影响因子：
13.6
通讯作者：
Chinnery, Patrick F.
中科院分区：
文献类型：
--
作者：
Glynos, Angelos;Bozhilova, Lyuba V.;Frison, Michele;Burr, Stephen;Stewart, James B.;Chinnery, Patrick F.
异质性线粒体DNA（mtDNA）突变是遗传性疾病的主要原因，并导致常见的迟发性人类疾病。mtDNA相关疾病的迟发性和临床进展被认为是由于异质性水平的变化，但尚不清楚这种情况如何以及何时发生。在两种人类mtDNA疾病小鼠模型中进行高通量单细胞基因分型，我们看到了mtDNA异质性水平的细胞间差异，这些差异在产前出现并在整个生命过程中逐渐增加。脾细胞和非分裂的脑细胞有类似的单细胞异质性的变化，涉及线粒体DNA或细胞器的营业额作为决定细胞异质性水平的主要力量。这两种不同的线粒体DNA突变以不同的速率分离，没有选择的证据，这与体内随机遗传漂移的不同速率一致，导致具有非常高突变负荷的细胞以不同的速率积累。这为相似mtDNA突变引起的人类疾病严重程度的差异提供了解释。高通量单细胞基因分型揭示了线粒体DNA异质性在整个生命过程中的进行性体细胞嵌合现象。
Heteroplasmic mitochondrial DNA (mtDNA) mutations are a major cause of inherited disease and contribute to common late-onset human disorders. The late onset and clinical progression of mtDNA-associated disease is thought to be due to changing heteroplasmy levels, but it is not known how and when this occurs. Performing high-throughput single-cell genotyping in two mouse models of human mtDNA disease, we saw unanticipated cell-to-cell differences in mtDNA heteroplasmy levels that emerged prenatally and progressively increased throughout life. Proliferating spleen cells and nondividing brain cells had a similar single-cell heteroplasmy variance, implicating mtDNA or organelle turnover as the major force determining cell heteroplasmy levels. The two different mtDNA mutations segregated at different rates with no evidence of selection, consistent with different rates of random genetic drift in vivo, leading to the accumulation of cells with a very high mutation burden at different rates. This provides an explanation for differences in severity seen in human diseases caused by similar mtDNA mutations. High-throughput single-cell genotyping reveals progressive somatic mosaicism of mtDNA heteroplasmy throughout life.
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影响因子：
4.5
作者：
通讯作者：
--
与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
DOI：
10.1126/science.aad2459
发表时间：
2015-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gong G;Song M;Csordas G;Kelly DP;Matkovich SJ;Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
9.8
作者：
Li, Mingkun;Schoenberg, Anna;Stoneking, Mark
通讯作者：
Stoneking, Mark
DOI：
10.1126/science.aag3048
发表时间：
2018-03-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Leeman DS;Hebestreit K;Ruetz T;Webb AE;McKay A;Pollina EA;Dulken BW;Zhao X;Yeo RW;Ho TT;Mahmoudi S;Devarajan K;Passegué E;Rando TA;Frydman J;Brunet A
通讯作者：
Brunet A