線粒體擁有自身的呈環(huán)狀的雙鏈DNA分子,，其復(fù)制和轉(zhuǎn)錄受到線粒體和核基因的雙重調(diào)控,。線粒體DNA（mtDNA）復(fù)制主要存在兩種模型，即鏈置換模型（the strand-displacement model）和鏈結(jié)合模型（the strand-coupled model）,。鏈置換模型認(rèn)為線粒體復(fù)制從特定位點(diǎn)起始,，H鏈先單向復(fù)制到mtDNA分子的約2/3位置,，使L鏈復(fù)制起始位點(diǎn)暴露,，隨即引發(fā)L鏈復(fù)制；而鏈結(jié)合模型認(rèn)為線粒體復(fù)制從多個(gè)位點(diǎn)起始,，雙鏈同時(shí)雙向進(jìn)行復(fù)制,。關(guān)于線粒體復(fù)制模型仍存在一些爭論，但這兩類復(fù)制模型都認(rèn)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(fù)制密切相關(guān),，其中含有很多控制復(fù)制的功能元件如復(fù)制引物結(jié)合位點(diǎn)、復(fù)制起始位點(diǎn),、復(fù)制終止位點(diǎn)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(fù)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(gè)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(dǎo)致線粒體保守序列框Ⅱ（CSBⅡ）和線粒體復(fù)制起始過程中的引物結(jié)合區(qū)被移除,，而這兩個(gè)功能單元在以往的研究中被認(rèn)為與mtDNA的復(fù)制起始調(diào)控有關(guān)。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(xì)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(guān)遺傳性疾病,。這一發(fā)現(xiàn)對D-環(huán)區(qū)的這兩個(gè)復(fù)制功能單元在復(fù)制模型中是否必需提出了疑問，提示mtDNA的復(fù)制機(jī)制可能比以前認(rèn)為的更為復(fù)雜,。我們推測該家系成員的mtDNA的復(fù)制可能存在其他代償途徑,。對此機(jī)制的深入研究，將有望進(jìn)一步認(rèn)識(shí)mtDNA復(fù)制的復(fù)雜機(jī)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)
更多閱讀
PLoS ONE：古代野牛的線粒體DNA基因組
Cell：線粒體DNA復(fù)制酶結(jié)構(gòu)
JBC：缺陷線粒體或能延緩衰老
Genomics：人類線粒體基因簇的進(jìn)化
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.
