mtDNA

ミトコンドリアDNA, mitochondrial DNA

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/04/29 13:01:11」(JST)

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ミトコンドリアDNA（みとこんどりあディーエヌエー、mtDNA,mDNA）とは、細胞小器官であるミトコンドリア内にあるDNAのこと。ミトコンドリアが細胞内共生由来であるとする立場から、ミトコンドリアゲノムと呼ぶ場合もある。

概要

ミトコンドリアDNA は、ミトコンドリアの持つたんぱく質などに関する情報が主に含まれており、ミトコンドリアが分裂する際に複製が行われる。ミトコンドリアに必要な情報の一部は核DNAに含まれており、ミトコンドリアは細胞の外で単体では存在できない。また逆に細胞が必要とするエネルギーを、酸素を利用して取り出せるのはミトコンドリアの働きによっており、細胞それ自体もミトコンドリアなしには生存できない。これらのことはミトコンドリアが細胞内共生由来であるという仮説の傍証となっている。

一般にミトコンドリア病と呼ばれるミトコンドリアの異常によって起こる疾病も、ミトコンドリアDNAの異常に起因するものと、核DNAの異常に起因するものとがある。 ミトコンドリアDNAの遺伝子多型は、肥満しやすさの個体差に関係していると考えられている。 さらに、近年ではミトコンドリアDNAにおける変異が、がんの転移能に影響を与えているという報告もある。(Hayashi et al, 2008)

特徴

ミトコンドリアDNAは一般的にGC含量が低く(20-40%)、基本単位が数十kb程度であり、電子伝達系に関わるタンパク質、リボソームRNAやtRNAなど数十種類の遺伝子を持っている。しかしDNA分子の大きさや形状、コードされている遺伝子の数や種類などは、生物によって大きく異なる。

遺伝子地図などではミトコンドリアDNAが環状に表現されることが多い。しかし物理的に環状のミトコンドリアDNAを持つ生物は、高等動物やキネトプラスト類などごく一部に限られる。多くの生物ではDNA分子が、環状の基本構造からトイレットペーパーを引き出すかのように連続的に複製され、その結果ミトコンドリアDNAの全ての部位が二重螺旋構造であり、大部分が基本単位が何度も繰り返す線状反復構造になっている。また少数派ではあるが、常に線状のミトコンドリアDNAを持つ生物も存在している。

高等動物

ヒトを含む高等動物のミトコンドリアDNAはいずれも比較的似通っており、大きさ16 kb前後の単一の環状DNAで構成されている。遺伝子は37あり、その内訳は、呼吸鎖複合体のサブユニットが13、tRNAが22、rRNAが2となっている。遺伝子の配置は多種多様であるが、脊椎動物では魚類から哺乳類まで基本的には同じ配置になっている。線形動物、二枚貝などは遺伝子の種類がわずかに異なり、刺胞動物はゲノムが線状であるなど例外的である。

シラミ類のミトコンドリアゲノムは全く異なる構成をしており、それぞれが1ないし3の遺伝子を持つ3-4kbという小さな環状DNAが18種も存在している。

陸上植物

陸上植物のミトコンドリアDNAは数多くの反復配列を含んでおり、相同組換えによって様々な構造のDNA分子が生じている。しかし制限酵素を用いた解析によって再構築した「マスターサークル」分子を元来のミトコンドリアDNAと考えることができる。マスターサークルの大きさは最小でも200 kb前後と大きく、最大のものでは2400 kbにもなっている。高等動物のミトコンドリアDNAに含まれている遺伝子以外に、リボソームのタンパク質サブユニットをコードする遺伝子が10以上含まれており、合計の遺伝子数は100弱にもなる。また遺伝子中にグループ2イントロンが多く見出されることが特徴的である。

特徴的な生物

レクリノモナス(Reclinomonas americana)は、原始的なミトコンドリアDNAを持っていることで有名になった原生生物である。およそ70kbの環状DNAにタンパク質とRNAを合わせて98遺伝子があり、そのうち18は他のミトコンドリアDNAには全く見付からない。特に細菌と同様のRNAポリメラーゼ遺伝子群が存在する点は特徴的である。

これまで知られている限り最も小さなミトコンドリアDNAを持つ生物は、マラリア原虫やピロプラズマを含むアピコンプレックス門の原虫である。大きさわずか6 kbの線状ゲノムであり、電子伝達系に関わる3つのタンパク質遺伝子と、断片化されたリボソームRNA遺伝子群のみが存在している。tRNAはミトコンドリアDNA上には全く存在しないため、すべてが細胞質から輸送されていると考えられている。

キネトプラスト類のミトコンドリアでは、20kb程度の環状DNA（マキシサークル）に20前後の遺伝子が存在している以外に、1kb程度の小さな環状DNA（ミニサークル）が1万以上ある。マキシサークル上の遺伝子情報はそのままでは翻訳することができず、無数のミニサークルから転写されるガイドRNAを使ってRNA編集を行う必要がある。

コドン表

ミトコンドリアはミトコンドリア核内で保管元となるDNAから遺伝情報をmRNAに転写した後、mRNAはミトコンドリアのリボソームに移動し、アミノ酸の付いたtRNAの3塩基がmRNAのヌクレオチドと相補的に結びつくことで、tRNAが運ぶアミノ酸の配列が決まり、目的のタンパク質を合成する。これら一連の翻訳過程は細胞の遺伝子翻訳とほとんど同じであるが、共に20個のアミノ酸を規定する64個の組み合わせの内、7ヶ所に対応するアミノ酸が異なっている。

この翻訳過程でのmRNA上にあるコドンとそれが指定するアミノ酸との対応関係を示した「コドン表」を以下に示す。

第1塩基	第2塩基				第3塩基
	U	C	A	G
U	フェニルアラニン	セリン	チロシン	システイン	U
					C
	ロイシン		チロシン 終止コドン	トリプトファン 終止コドン	A
			終止コドン	トリプトファン	G
C		プロリン	ヒスチジン	アルギニン	U
					C
			グルタミン		A
					G
A	イソロイシン	トレオニン	アスパラギン	セリン	U
					C
	メチオニン イソロイシン		アスパラギン リジン	セリン アルギニン	A
	メチオニン（開始コドン）			グリシン アルギニン	G
G	バリン	アラニン	アスパラギン酸	グリシン	U
					C
			グルタミン酸		A
					G

伝達様式

ミトコンドリアは卵子の細胞質に約25万存在する。精子鞭毛基部にもわずかに存在するが、一般的に精子由来の物は受精前後に何らかの形で排除される。そのためもともとの卵子の中にあったミトコンドリアのみが細胞分裂後も引き継がれることになり、ミトコンドリアDNAは常に母性遺伝すると考えられる。父親から受け継いだという例も1例報告されているが、その患者はミトコンドリア酵素複合体の不足と重い運動機能障害を抱えている。

哺乳類の精子に含まれるミトコンドリアは、一般に受精後卵細胞の中で死滅してしまうとされる。精子由来のミトコンドリア（ミトコンドリアDNAを含む）は、後で胚の中で破壊されるようにユビキチンによる印が付けられることが1999年に報告されている。時に、例えばハイブリッド種において、このプロセスは失敗に終わる。

ミトコンドリアDNAを利用した研究

ミトコンドリアDNAは、母親から子に受け継がれる特性を生かして、家系を追跡するための研究に利用される。

有名なものにはブライアン・サイクス著『イヴの七人の娘たち(原題The Seven Daughters of Eve)』 がある。現代のヨーロッパ人はほぼ7つのクラスター（群）に分けることができ、理論的にそのクラスターの元となる配列をもたらしたのは、旧石器時代の7人の女性だと考えられる。 更にアジアやアフリカ人の遺伝子も検証したところ、現代に生きる世界中の人々の母系先祖はアフリカの1人の女性であると推定することができるという、いわゆるミトコンドリア・イブの理論も同様の分析に基づくものである。

また、Svante Pääboらは、ヨーロッパのイヌの先祖を追いかけて母系の4系統へとさかのぼる研究を発表している。

但し、ミトコンドリアDNAは母系をたどることしかできないため、人類の系統や移住の足跡をたどるためには、学問的には不十分である。そのため人類の足跡をたどるためには、父系の系統のみをたどることができるY染色体の分析と併せ検証するか、或いは人類の核DNAそのものを分析する必要がある。

一例として、南アメリカのコロンビア人を調査したところ、ミトコンドリアDNAは、ほぼ全ての人がモンゴロイド系の特徴を持っていたが、Y染色体はほぼ全てがヨーロッパ系コーカソイド（特にスペイン人）に特徴的なタイプのみであった。逆に東ヨーロッパの諸民族のミトコンドリアDNAはほぼ全てコーカソイド系であったが、Y染色体及び核DNAにはモンゴロイド系の特徴を持っている人々が少なからず発見された。

ナショナルジオグラフィック協会のジェノグラフィック・プロジェクトのプロジェクト・ディレクターであるスペンサー・ウェルズ博士は、人類が最初に出アフリカを果たした時から、約5万年にも及ぶ人類の移動経路を明らかにするためにY染色体やミトコンドリアDNAなどの遺伝子データを用いて研究を行っている[1]。

「ミトコンドリアDNAハプログループ」も参照

また、犯罪の現場で毛髪が見つかったがDNA型鑑定が行なえないような場合に（自然に落ちた毛髪などは、毛根部分にDNA鑑定の対象にする組織が残っていない事がある）、ある人物を容疑者として捜査の対象に含めておくべきか、外してもよいかを決定する判断材料として、毛髪内のミトコンドリアDNA（毛髪内でもミトコンドリアDNAは残存している）が利用される。

ミトコンドリアによる系譜の研究がすすめられた時期は「遺伝的刷り込み」と呼ばれる現象が遺伝学的にまだ考慮されていなかったため、ミトコンドリア遺伝子が「母親由来のゲノムからのみ発現する遺伝子群（Maternally expressed genes、MEG）」であるとすれば、男性の身体では単に非発現状態で休眠しているだけであり、この論は齟齬を含んでいるのではないかという人があるが、父親と母親から一つずつ一対の遺伝子を受け継ぐことになっている核DNAで、一方の遺伝情報を発現させるために起こる遺伝的刷り込みが、環状のミトコンドリアDNAに対してどう関係するのかという疑問がある。

関連項目

• 細胞
• DNA
• ミトコンドリア
• ミトコンドリアDNAハプログループ

出典

参考文献

• Hayashi, J., et. al. "ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis." Science. 2008 May 2;320(5876):661-4.[2]

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Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles found in cells have often been called the powerhouse of the cell. The mitochondria, and thus mitochondrial DNA, are passed only from mother to offspring through egg cell.

Human mitochondrial DNA with the 37 genes on their respective H- and L-strands.

Electron microscopy reveals mitochondrial DNA in discrete foci. Bars: 200 nm. (A) Cytoplasmic section after immunogold labelling with anti-DNA; gold particles marking mtDNA are found near the mitochondrial membrane. (B) Whole mount view of cytoplasm after extraction with CSK buffer and immunogold labelling with anti-DNA; mtDNA (marked by gold particles) resists extraction. From Iborra et al., 2004.

Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, adenosine triphosphate (ATP). Mitochondrial DNA is only a small portion of the DNA in a eukaryotic cell; most of the DNA can be found in the cell nucleus and, in plants and algae, also in plastids such as chloroplasts.

In humans, the 16,569 base pairs of mitochondrial DNA encode for only 37 genes. Human mitochondrial DNA was the first significant part of the human genome to be sequenced. In most species, including humans, mtDNA is inherited solely from the mother.

Since animal mtDNA evolves faster than nuclear genetic markers, it represents a mainstay of phylogenetics and evolutionary biology. It also permits an examination of the relatedness of populations, and so has become important in anthropology and biogeography.

Origin

Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the circular genomes of the bacteria that were engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. Each mitochondrion is estimated to contain 2–10 mtDNA copies. In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA, but the genes for some of them, if not most, are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.

The reasons why mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages. The difficulty of targeting remotely-produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA; colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery. Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention.

Mitochondrial inheritance

In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains on average 200,000 mtDNA molecules, whereas a healthy human sperm was reported to contain on average 5 molecules ), degradation of sperm mtDNA in the male genital tract, in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental inheritance) pattern of mtDNA inheritance is found in most animals, most plants and in fungi as well.

Female inheritance

In sexual reproduction, mitochondria are normally inherited exclusively from the mother; the mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells; sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo. Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.

The fact that mitochondrial DNA is maternally inherited enables genealogical researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paternally inherited, is used in an analogous way to determine the patrilineal history.) This is usually accomplished on human mitochondrial DNA by sequencing the hypervariable control regions (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a genealogical DNA test. HVR1, for example, consists of about 440 base pairs. These 440 base pairs are then compared to the control regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made to the revised Cambridge Reference Sequence. Vilà et al. have published studies tracing the matrilineal descent of domestic dogs to wolves. The concept of the Mitochondrial Eve is based on the same type of analysis, attempting to discover the origin of humanity by tracking the lineage back in time.

mtDNA is highly conserved, and its relatively slow mutation rates (compared to other DNA regions such as microsatellites) make it useful for studying the evolutionary relationships—phylogeny—of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined. However, due to the slow mutation rates it experiences, it is often hard to distinguish between closely related species to any large degree, so other methods of analysis must be used.

The mitochondrial bottleneck

Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.

Male inheritance

Main article: Paternal mtDNA transmission

Doubly uniparental inheritance of mtDNA is observed in bivalve mollusks. In those species, females have only one type of mtDNA (F), whereas males have F type mtDNA in their somatic cells, but M type of mtDNA (which can be as much as 30% divergent) in germline cells. Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies, honeybees, and periodical cicadas.

Male mitochondrial inheritance was recently discovered in Plymouth Rock chickens. Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice, where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep, and in cloned cattle. It has been found in a single case in a human male.

Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo inheritance and persistence under lab conditions.

Mitochondrial donation

Main article: Mitochondrial donation

An IVF technique known as mitochondrial donation or mitochondrial replacement therapy (MRT) results in offspring containing mtDNA from a donor female, and nuclear DNA from the mother and father. In the spindle transfer procedure, the nucleus of an egg is inserted into the cytoplasm of an egg from a donor female which has had its nucleus removed, but still contains the donor female's mtDNA. The composite egg is then fertilized with the male's sperm. The procedure is used when a woman with genetically defective mitochondria wishes to procreate and produce offspring with healthy mitochondria. The first known child to be born as a result of mitochondrial donation was a boy born to a Jordanian couple in Mexico on 6 April 2016.

Structure

Circular versus linear

In most multicellular organisms, the mtDNA - or mitogenome - is organized as a circular, covalently closed, double-stranded DNA. But in many unicellular (e.g. the ciliate Tetrahymena or the green alga Chlamydomonas reinhardtii) and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria ) the mtDNA is found as linearly organized DNA. Most of these linear mtDNAs possess telomerase independent telomeres (i.e. the ends of the linear DNA) with different modes of replication, which have made them interesting objects of research, as many of these unicellular organisms with linear mtDNA are known pathogens.

In mammals

For human mitochondrial DNA (and probably for that of metazoans in general), 100-10,000 separate copies of mtDNA are usually present per somatic cell (egg and sperm cells are exceptions). In mammals, each double-stranded circular mtDNA molecule consists of 15,000-17,000 base pairs. The two strands of mtDNA are differentiated by their nucleotide content, with a guanine-rich strand referred to as the heavy strand (or H-strand) and a cytosine-rich strand referred to as the light strand (or L-strand). The heavy strand encodes 28 genes, and the light strand encodes 9 genes for a total of 37 genes. Of the 37 genes, 13 are for proteins (polypeptides), 22 are for transfer RNA (tRNA) and two are for the small and large subunits of ribosomal RNA (rRNA). The human mitogenome contains overlapping genes (ATP8 and ATP6 as well as ND4L and ND4: see the human mitochondrial genome map), a feature that is rare in animal genomes. The 37-gene pattern is also seen among most metazoans, although in some cases one or more of these genes is absent and the mtDNA size range is greater.

The 37 genes of the Cambridge Reference Sequence for human mitochondrial DNA and their locations

Gene	Type	Product	Positions in the mitogenome	Strand
MT-ATP8	protein coding	ATP synthase, Fo subunit 8 (complex V)	08,366-08,572 (overlap with MT-ATP6)	H
MT-ATP6	protein coding	ATP synthase, Fo subunit 6 (complex V)	08,527-09,207 (overlap with MT-ATP8)	H
MT-CO1	protein coding	Cytochrome c oxidase, subunit 1 (complex IV)	05,904-07,445	H
MT-CO2	protein coding	Cytochrome c oxidase, subunit 2 (complex IV)	07,586-08,269	H
MT-CO3	protein coding	Cytochrome c oxidase, subunit 3 (complex IV)	09,207-09,990	H
MT-CYB	protein coding	Cytochrome b (complex III)	14,747-15,887	H
MT-ND1	protein coding	NADH dehydrogenase, subunit 1 (complex I)	03,307-04,262	H
MT-ND2	protein coding	NADH dehydrogenase, subunit 2 (complex I)	04,470-05,511	H
MT-ND3	protein coding	NADH dehydrogenase, subunit 3 (complex I)	10,059-10,404	H
MT-ND4L	protein coding	NADH dehydrogenase, subunit 4L (complex I)	10,470-10,766	H
MT-ND4	protein coding	NADH dehydrogenase, subunit 4 (complex I)	10,760-12,137 (overlap with MT-ND4L)	H
MT-ND5	protein coding	NADH dehydrogenase, subunit 5 (complex I)	12,337-14,148	H
MT-ND6	protein coding	NADH dehydrogenase, subunit 6 (complex I)	14,149-14,673	L
MT-RNR2	protein coding	Humanin	—	—
MT-TA	transfer RNA	tRNA-Alanine (Ala or A)	05,587-05,655	L
MT-TR	transfer RNA	tRNA-Arginine (Arg or R)	10,405-10,469	H
MT-TN	transfer RNA	tRNA-Asparagine (Asn or N)	05,657-05,729	L
MT-TD	transfer RNA	tRNA-Aspartic acid (Asp or D)	07,518-07,585	H
MT-TC	transfer RNA	tRNA-Cysteine (Cys or C)	05,761-05,826	L
MT-TE	transfer RNA	tRNA-Glutamic acid (Glu or E)	14,674-14,742	L
MT-TQ	transfer RNA	tRNA-Glutamine (Gln or Q)	04,329-04,400	L
MT-TG	transfer RNA	tRNA-Glycine (Gly or G)	09,991-10,058	H
MT-TH	transfer RNA	tRNA-Histidine (His or H)	12,138-12,206	H
MT-TI	transfer RNA	tRNA-Isoleucine (Ile or I)	04,263-04,331	H
MT-TL1	transfer RNA	tRNA-Leucine (Leu-UUR or L)	03,230-03,304	H
MT-TL2	transfer RNA	tRNA-Leucine (Leu-CUN or L)	12,266-12,336	H
MT-TK	transfer RNA	tRNA-Lysine (Lys or K)	08,295-08,364	H
MT-TM	transfer RNA	tRNA-Methionine (Met or M)	04,402-04,469	H
MT-TF	transfer RNA	tRNA-Phenylalanine (Phe or F)	00,577-00,647	H
MT-TP	transfer RNA	tRNA-Proline (Pro or P)	15,956-16,023	L
MT-TS1	transfer RNA	tRNA-Serine (Ser-UCN or S)	07,446-07,514	L
MT-TS2	transfer RNA	tRNA-Serine (Ser-AGY or S)	12,207-12,265	H
MT-TT	transfer RNA	tRNA-Threonine (Thr or T)	15,888-15,953	H
MT-TW	transfer RNA	tRNA-Tryptophan (Trp or W)	05,512-05,579	H
MT-TY	transfer RNA	tRNA-Tyrosine (Tyr or Y)	05,826-05,891	L
MT-TV	transfer RNA	tRNA-Valine (Val or V)	01,602-01,670	H
MT-RNR1	ribosomal RNA	Small subunit : SSU (12S)	00,648-01,601	H
MT-RNR2	ribosomal RNA	Large subunit : LSU (16S)	01,671-03,229	H

In plants

Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all). Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs. Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs. The genome of the mitochondrion of the cucumber (Cucumis sativus) consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their replication.

In protists

The smallest mitochondrial genome sequenced to date is the 5967 bp mtDNA of the parasite Plasmodium falciparum.

Genome diversity

There are six main genome types found in mitochondrial genomes. These genome types were classified by “Kolesnikov & Gerasimov (2012)" and differ in various ways such as a circular versus linear genome, genome size, the presence of introns or plasmid like structures, and whether the genetic material is a singular molecule or collection of homogeneous or heterogeneous molecules.

Animals

There is only one mitochondrial genome type found in animal cells. This genome contains one circular molecule with between 11-28kbp of genetic material (type 1).

Plants and fungi

There are three different genome types found in plants and fungi. The first type is a circular genome that has introns (type 2) and may range from 19-1000kpb in length. The second genome type is a circular genome (about 20–1000kbp) that also has a plasmid-like structure (1kb) (type 3). The final genome type that can be found in plant and fungi is a linear genome made up of homogeneous DNA molecules (type 5).

Protists

Protists contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3 and type 5 mentioned in the plant and fungal genomes also exists in some protist, as well as two unique genome types. The first of these is a heterogeneous collection of circular DNA molecules (type 4) and the final genome type found in protists is a heterogeneous collection of linear molecules (type 6). Genome types 4 and 6 both range from 1–200kbp in size.

Endosymbiotic gene transfer, the process of genes that were coded in the mitochondrial genome being transferred to the cell's main genome likely explains why more complex organisms, such as humans, have smaller mitochondrial genomes than simpler organisms, such as protists.

Genome Type	Kingdom	Introns	Size	Shape	Description
1	Animal	No	11–28kbp	Circular	Single molecule
2	Fungi, Plant, Protista	Yes	19–1000kbp	Circular	Single molecule
3	Fungi, Plant, Protista	No	20–1000kbp	Circular	Large molecule and small plasmid like structures
4	Protista	No	1–200kbp	Circular	Heterogeneous group of molecules
5	Fungi, Plant, Protista	No	1–200kbp	Linear	Homogeneous group of molecules
6	Protista	No	1–200kbp	Linear	Heterogeneous group of molecules

Replication

Mitochondrial DNA is replicated by the DNA polymerase gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the POLG gene and two 55 kDa accessory subunits encoded by the POLG2 gene. The replisome machinery is formed by DNA polymerase, TWINKLE and mitochondrial SSB proteins. TWINKLE is a helicase, which unwinds short stretches of dsDNA in the 5′ to 3′ direction.

During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. The resulting reduction in per-cell copy number of mtDNA plays a role in the mitochondrial bottleneck, exploiting cell-to-cell variability to ameliorate the inheritance of damaging mutations. At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm. In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types.

Transcription

In animal mitochondria, each DNA strand is transcribed continuously and produces a polycistronic RNA molecule. Between most (but not all) protein-coding regions, tRNAs are present (see the human mitochondrial genome map). During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. With the mitochondrial RNA processing, individual mRNA, rRNA, and tRNA sequences are released from the primary transcript. Folded tRNAs therefore act as secondary structure punctuations.

Mutations and disease

Human mitochondrial DNA with groups of protein-, rRNA- and tRNA-encoding genes.

The involvement of mitochondrial DNA in several human diseases.

Susceptibility

The concept that mtDNA is particularly susceptible to reactive oxygen species generated by the respiratory chain due to its proximity remains controversial. mtDNA does not accumulate any more oxidative base damage than nuclear DNA. It has been reported that at least some types of oxidative DNA damage are repaired more efficiently in mitochondria than they are in the nucleus. mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin. Moreover, mitochondria evolved a unique mechanism which maintains mtDNA integrity through degradation of excessively damaged genomes followed by replication of intact/repaired mtDNA. This mechanism is not present in the nucleus and is enabled by multiple copies of mtDNA present in mitochondria The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins, which may have an effect on organism metabolism and/or fitness.

Genetic illness

Further information: Mitochondrial disease

Mutations of mitochondrial DNA can lead to a number of illnesses including exercise intolerance and Kearns–Sayre syndrome (KSS), which causes a person to lose full function of heart, eye, and muscle movements. Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies. Particularly in the context of disease, the proportion of mutant mtDNA molecules in a cell is termed heteroplasmy. The within-cell and between-cell distributions of heteroplasmy dictate the onset and severity of disease and are influenced by complicated stochastic processes within the cell and during development.

Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.

Mutations in nuclear genes that encode proteins that mitochondria use can also contribute to mitochondrial diseases. These diseases do not follow mitochondrial inheritance patterns, but instead follow Mendelian inheritance patterns.

Use in disease diagnosis

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy.

Relationship with aging

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction. In essence, mutations in mtDNA upset a careful balance of reactive oxygen species (ROS) production and enzymatic ROS scavenging (by enzymes like superoxide dismutase, catalase, glutathione peroxidase and others). However, some mutations that increase ROS production (e.g., by reducing antioxidant defenses) in worms increase, rather than decrease, their longevity. Also, naked mole rats, rodents about the size of mice, live about eight times longer than mice despite having reduced, compared to mice, antioxidant defenses and increased oxidative damage to biomolecules. Once, there was thought to be a positive feedback loop at work (a 'Vicious Cycle'); as mitochondrial DNA accumulates genetic damage caused by free radicals, the mitochondria lose function and leak free radicals into the cytosol. A decrease in mitochondrial function reduces overall metabolic efficiency. However, this concept was conclusively disproved when it was demonstrated that mice, which were genetically altered to accumulate mtDNA mutations at accelerated rate do age prematurely, but their tissues do not produce more ROS as predicted by the 'Vicious Cycle' hypothesis. Supporting a link between longevity and mitochondrial DNA, some studies have found correlations between biochemical properties of the mitochondrial DNA and the longevity of species. Extensive research is being conducted to further investigate this link and methods to combat aging. Presently, gene therapy and nutraceutical supplementation are popular areas of ongoing research. Bjelakovic et al. analyzed the results of 78 studies between 1977 and 2012, involving a total of 296,707 participants, and concluded that antioxidant supplements do not reduce all-cause mortality nor extend lifespan, while some of them, such as beta carotene, vitamin E, and higher doses of vitamin A, may actually increase mortality.

Relationship with non-B (non-canonical) DNA structures

Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms and cloverleaf-like elements. Moreover, there is data supporting the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM.

Use in identification

For use in human identification, see Human mitochondrial DNA.

Unlike nuclear DNA, which is inherited from both parents and in which genes are rearranged in the process of recombination, there is usually no change in mtDNA from parent to offspring. Although mtDNA also recombines, it does so with copies of itself within the same mitochondrion. Because of this and because the mutation rate of animal mtDNA is higher than that of nuclear DNA, mtDNA is a powerful tool for tracking ancestry through females (matrilineage) and has been used in this role to track the ancestry of many species back hundreds of generations.

The rapid mutation rate (in animals) makes mtDNA useful for assessing genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships; see phylogenetics) among different species. To do this, biologists determine and then compare the mtDNA sequences from different individuals or species. Data from the comparisons is used to construct a network of relationships among the sequences, which provides an estimate of the relationships among the individuals or species from which the mtDNAs were taken. mtDNA can be used to estimate the relationship between both closely related and distantly related species. Due to the high mutation rate of mtDNA in animals, the 3rd positions of the codons change relatively rapidly, and thus provide information about the genetic distances among closely related individuals or species. On the other hand, the substitution rate of mt-proteins is very low, thus amino acid changes accumulate slowly (with corresponding slow changes at 1st and 2nd codon positions) and thus they provide information about the genetic distances of distantly related species. Statistical models that treat substitution rates among codon positions separately, can thus be used to simultaneously estimate phylogenies that contain both closely and distantly related species

Mitochondrial DNA was admitted into evidence for the first time ever in 1996 during State of Tennessee v. Paul Ware.

In the 1998 court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer, mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time. The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5).

Mitochondrial DNA was first admitted into evidence in California in the successful prosecution of David Westerfield for the 2002 kidnapping and murder of 7-year-old Danielle van Dam in San Diego: it was used for both human and dog identification. This was the first trial in the U.S. to admit canine DNA.

History

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive threads inside mitochondria, and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.

Mitochondrial sequence databases

Several specialized databases have been founded to collect mitochondrial genome sequences and other information. Although most of them focus on sequence data, some of them include phylogenetic or functional information.

• MitoSatPlant: Mitochondrial microsatellites database of viridiplantae.
• MitoBreak: the mitochondrial DNA breakpoints database.
• MitoFish and MitoAnnotator: a mitochondrial genome database of fish. See also Cawthorn et al.
• MitoZoa 2.0: a database for comparative and evolutionary analyses of mitochondrial genomes in Metazoa. (no longer available)
• InterMitoBase: an annotated database and analysis platform of protein-protein interactions for human mitochondria. (apparently last updated in 2010, but still available)
• Mitome: a database for comparative mitochondrial genomics in metazoan animals (no longer available)
• MitoRes: a resource of nuclear-encoded mitochondrial genes and their products in metazoa (apparently no longer being updated)

Mitochondrial mutation databases

Several specialized databases exist that report polymorphisms and mutations in the human mitochondrial DNA, together with the assessment of their pathogenicity.

• MITOMAP: A compendium of polymorphisms and mutations in human mitochondrial DNA [3].
• MitImpact: A collection of pre-computed pathogenicity predictions for all nucleotide changes that cause non-synonymous substitutions in human mitochondrial protein coding genes [4].

See also

• Archaeogenetics of the Near East
• Clade
• CoRR hypothesis
• Haplogroup
• Heteroplasmy
• Human mitochondrial DNA haplogroup
• Human mitochondrial genetics
• Mitochondrial disease
• Mitochondrial DNA (journal)
• Mitochondrial Eve
• Mitochondrial rCRS
• Paternal mtDNA transmission
• Single origin theory
• Supercluster (genetic)
• TIM/TOM complex
• Genetic history of Africa
• Genetic history of Europe
• Genetic history of the British Isles
• Genetic history of the Iberian Peninsula
• Genetic history of indigenous peoples of the Americas
• Genetic history of Italy
• Genetic history of North Africa
• Genetics and archaeogenetics of South Asia

References

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. ミトコンドリアの構造、機能、および遺伝学 mitochondrial structure function and genetics
• 2. 単一遺伝子性疾患の非メンデル遺伝のパターン non mendelian inheritance patterns of monogenic diseases
• 3. メンデル遺伝の概要 overview of mendelian inheritance
• 4. 先天異常の遺伝学的および環境的原因 genetic and environmental causes of birth defects
• 5. ミトコンドリア細胞症における腎病変 renal involvement in the mitochondrial cytopathies

English Journal

• Retinoblastoma Protein Knockdown Favors Oxidative Metabolism and Glucose and Fatty Acid Disposal in Muscle Cells.

• Petrov PD1, Ribot J1, López-Mejía IC2, Fajas L2, Palou A1, Bonet ML1.
• Journal of cellular physiology.J Cell Physiol.2016 Mar;231(3):708-18. doi: 10.1002/jcp.25121.
• Deficiency in the retinoblastoma protein (Rb) favors leanness and a healthy metabolic profile in mice largely attributed to activation of oxidative metabolism in white and brown adipose tissues. Less is known about Rb modulation of skeletal muscle metabolism. This was studied here by transiently kno
• PMID 26241807

• The development of a hexaplex-conventional PCR for identification of six animal and plant species in foodstuffs.

• Safdar M1, Junejo Y2.
• Food chemistry.Food Chem.2016 Feb 1;192:745-9. doi: 10.1016/j.foodchem.2015.07.082. Epub 2015 Jul 21.
• A hexaplex-conventional PCR assay was developed for identification of five meat and one plant species origins in foodstuffs simultaneously. The method merges the use of horse (Equus caballus), soybean (Glycine max), sheep (Ovis aries), poultry (Meleagris meleagris), pork (Sus scrofa), and cow (Bos t
• PMID 26304406

• Detection of adulterated murine components in meat products by TaqMan© real-time PCR.

• Fang X1, Zhang C2.
• Food chemistry.Food Chem.2016 Feb 1;192:485-90. doi: 10.1016/j.foodchem.2015.07.020. Epub 2015 Jul 8.
• Using murine meat to substitute mutton has been identified as a new type of meat fraud in China, yet no detection method for murine species has been reported. Here, three kinds of rodent were used as target species to establish a murine-specific real-time PCR method of detection. The mitochondrial c
• PMID 26304376

Japanese Journal

• Common genetic heritage and admixture among Indian population groups as revealed by mtDNA markers

• MEITEI Sanjenbam Yaiphaba,MEITEI Khangembam Somibabu,MURRY Benrithung [他]
• Anthropological science 120(3), 227-234, 2012-12
• NAID 40019526109

• The mtDNA rps3 locus has been invaded by a group ？ intron in some species of Grosmannia

• Rudski Shelly M.,Hausner Georg
• Mycoscience 53(6), 471-475, 2012-11
• NAID 40019496158

• 動物遺存体の古DNA分析 : イヌ,オオカミ,家畜ブタのミトコンドリアDNA解析を中心に (特集 古DNAの解析は考古学に何をもたらすか)

• 石黒 直隆
• 月刊考古学ジャーナル (633), 19-23, 2012-10
• NAID 40019495341

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★リンクテーブル★

リンク元	「mitochondrial DNA」「ミトコンドリアDNA」

「mitochondrial DNA」

　　[★] ミトコンドリアDNA mtDNA

「ミトコンドリアDNA」

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英

mitochondrial DNA、mtDNA