Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.
Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.
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人类结肠上皮和疾病中线粒体突变光谱的比较：缺乏在细胞线粒体DNA点突变中纯化选择的证据。
DOI：
10.1371/journal.pgen.1003082
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Turnbull DM
中科院分区：
文献类型：
--
作者：
Greaves LC;Elson JL;Nooteboom M;Grady JP;Taylor GA;Taylor RW;Mathers JC;Kirkwood TB;Turnbull DM
据预测，人类衰老是由细胞和组织中分子损伤的积累引起的。体细胞线粒体DNA（mtDNA）突变已在许多衰老组织中被证实，并已被证明与细胞线粒体功能障碍有关。目前还不清楚是否有选择性的限制，这已被证明发生在生殖系中，对这些mtDNA突变的发生和扩展在个体体细胞。在这里，我们比较了在老年人结肠中观察到的突变模式和谱与在一般人群中观察到的突变（种系变异）以及与原发性mtDNA疾病相关的突变。使用计算程序MutPred预测蛋白编码突变的致病性，并比较三组获得的分数。我们发现，与衰老相关的突变随机分布在整个基因组中，比一般人群更频繁地出现非同义突变或移码突变，并且比人群变异更具致病性。与原发性mtDNA疾病相关的突变比衰老或群体突变的致病性更高。这些数据提供了很少的证据，任何选择性限制的发生和扩展的线粒体DNA突变在人体衰老过程中的人体结肠的体细胞在一般人群中看到的种系突变。线粒体DNA编码线粒体呼吸链的基本组成部分，并且严格地母系遗传，使其容易受到有害突变的积累。为了避免这种情况，mtDNA受到瓶颈现象的影响，只有少量的mtDNA分子被传递到卵母细胞前体。然后这些被扩增到成熟卵母细胞中所需数量的mtDNA分子，这意味着任何突变都可能丢失或迅速固定。纯化选择被认为是防止种系中致病性mtDNA突变的重要保护机制，因为这对mtDNA稳定性至关重要。目前尚不清楚在体细胞组织中是否存在这种保护机制。为了研究这一点，我们比较了老化人类结肠细胞中存在的突变谱与通过母体生殖系传递的那些群体变异和导致原发性mtDNA疾病的mtDNA突变。我们发现，致病性mtDNA突变是目前在一个显着更高的频率在人类结肠的体细胞中的变体，通过种系，显示在这里研究的体细胞组织中的纯化选择的证据很少，但在种系中的这种选择机制的有力证据。
Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population. Mitochondrial DNA encodes essential components of the mitochondrial respiratory chain and is strictly maternally inherited, making it vulnerable to the accumulation of deleterious mutations. To avoid this, mtDNA is subjected to a bottleneck phenomenon whereby only a small number of mtDNA molecules are passed on to the oocyte precursor. These are then amplified to the required number of mtDNA molecules in the mature oocyte, meaning that any mutations may be either lost or rapidly fixed. Purifying selection is thought to be an important protective mechanism against pathogenic mtDNA mutations in the germline, as this is essential for mtDNA stability. It is unknown whether there are any such protective mechanisms in the somatic tissues. To investigate this we have compared the spectrum of mutations present in ageing human colonocytes with those population variants passed through the maternal germline and mtDNA mutations responsible for primary mtDNA disease. We show that pathogenic mtDNA mutations are present at a significantly higher frequency in the somatic cells of the human colon in contrast to variants that have passed though the germline, showing little evidence for purifying selection in the somatic tissues studied here, but strong evidence of this selective mechanism in the germline.
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影响因子：
56.9
作者：
Fan, Weiwei;Waymire, Katrina G.;Wallace, Douglas C.
通讯作者：
Wallace, Douglas C.
影响因子：
14.9
作者：
CORTOPASSI, GA;ARNHEIM, N
通讯作者：
ARNHEIM, N
DOI：
10.1073/pnas.0505903103
发表时间：
2006-01-17
影响因子：
11.1
作者：
Greaves, LC;Preston, SL;McDonald, SAC
通讯作者：
McDonald, SAC
影响因子：
2.8
作者：
Alston, Charlotte L.;Morak, Monika;Taylor, Robert W.
通讯作者：
Taylor, Robert W.
影响因子：
30.8
作者：
Cree, Lynsey M.;Samuels, David C.;Chinnery, Patrick F.
通讯作者：
Chinnery, Patrick F.