線粒體擁有自身的呈環(huán)狀的雙鏈DNA分子，其復制和轉錄受到線粒體和核基因的雙重調(diào)控,。線粒體DNA（mtDNA）復制主要存在兩種模型，即鏈置換模型（the strand-displacement model）和鏈結合模型（the strand-coupled model）。鏈置換模型認為線粒體復制從特定位點起始,，H鏈先單向復制到mtDNA分子的約2/3位置,，使L鏈復制起始位點暴露，隨即引發(fā)L鏈復制,；而鏈結合模型認為線粒體復制從多個位點起始,，雙鏈同時雙向進行復制。關于線粒體復制模型仍存在一些爭論,，但這兩類復制模型都認為mtDNA中一段長約1kb的非編碼序列,，即控制區(qū)（control region）或稱D-環(huán)（D-loop）與mtDNA復制密切相關，其中含有很多控制復制的功能元件如復制引物結合位點,、復制起始位點,、復制終止位點等。在現(xiàn)有mtDNA數(shù)據(jù)庫中,，尚未發(fā)現(xiàn)正常人D-環(huán)區(qū)有大片段插入和缺失的情況,，這間接說明該區(qū)域在mtDNA復制調(diào)控中的重要作用。
近期，姚永剛課題組的畢蕊,、張阿梅,、張文等在對我國人群mtDNA D-環(huán)區(qū)突變頻譜的研究中，在一個正常人家系的mtDNA中意外發(fā)現(xiàn)其D-環(huán)存在一段50 bp的缺失（m.298_347del50）,，該缺失導致線粒體保守序列框Ⅱ（CSBⅡ）和線粒體復制起始過程中的引物結合區(qū)被移除,，而這兩個功能單元在以往的研究中被認為與mtDNA的復制起始調(diào)控有關。該50 bp缺失在研究的家系母系成員中可以遺傳,，且在不同的組織樣本如頭發(fā),、血液、唾液等都存在,，具有不同程度的異質(zhì)性,。相對于正常對照人群血液細胞的mtDNA拷貝數(shù)來說，含有缺失的家系成員的mtDNA拷貝數(shù)未見異常,，且該家系成員無相關遺傳性疾病,。這一發(fā)現(xiàn)對D-環(huán)區(qū)的這兩個復制功能單元在復制模型中是否必需提出了疑問，提示mtDNA的復制機制可能比以前認為的更為復雜,。我們推測該家系成員的mtDNA的復制可能存在其他代償途徑,。對此機制的深入研究，將有望進一步認識mtDNA復制的復雜機制,。該研究工作近期在線發(fā)表于國際知名刊物 Human Mutation,。(生物谷Bioon.com)
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生物谷推薦原文出處：
Hum Mutat. doi：10.1002/humu.21220
The acquisition of an inheritable 50-bp deletion in the human mtDNA control region does not affect the mtDNA copy number in peripheral blood cells.
Bi R, Zhang AM, Zhang W, Kong QP, Wu BL, Yang XH, Wang D, Zou Y, Zhang YP, Yao YG.
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
The mitochondrial DNA (mtDNA) control region is believed to play an important biological role in mtDNA replication. Large deletions in this region are rarely found, but when they do occur they might be expected to interfere with the replication of the molecule, thus leading to a reduction of mtDNA copy number. During a survey for mtDNA sequence variations in 5,559 individuals from the general Chinese population and 2,538 individuals with medical disorders, we identified a 50-bp deletion (m.298_347del50) in the mtDNA control region in a member of a healthy Han Chinese family belonging to haplogroup B4c1b2, as suggested by complete mtDNA genome sequencing. This deletion removes the conserved sequence block II (CSBII; region 299-315) and the replication primer location (region 317-321). However, quantification of the mtDNA copy number in this subject showed a value within a range that was observed in 20 healthy subjects without the deletion. The deletion was detected in the hair samples of the maternal relatives of the subject and exhibited variable heteroplasmy. Our current observation, together with a recent report for a benign 154-bp deletion in the mtDNA control region, suggests that the control of mtDNA replication may be more complex than we had thought. (c) 2010 Wiley-Liss, Inc.
