دی‌ان‌ای میتوکندریایی

از ویکی‌پدیا، دانشنامهٔ آزاد
پرش به: ناوبری، جستجو
فارسی English
Mitochondrial DNA.
تصاویر میکروسکوپ الکترونی که mtDNA را آشکار می‌کند (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.[۱]

دی‌ان‌ای میتوکندریایی (mtDNA) نوعی DNA است که در میتوکندری سلول‌های یوکاریوتی یافت می‌شود. کار میتوکندری تبدیل انرژی شیمیایی غذا به آدنوزین تری فسفات یعنی صورتی از انرژی است که برای سلول قابل استفاده باشد.

رونویسی[ویرایش]

mtDNA به وسیلهٔ پلیمراز گاما رونویسی می‌شود که به وسیلهٔ ژنوم هسته‌ای کد می‌شود. رونویسی DNA میتوکندریایی الزاماً با تقسیم میتوکندری همراه نیست به همین دلیل ممکن است در یک میتوکندری چندین نسخه از ژنوم به طور جداگانه موجود باشد که به ان کنکاتامر (concatamer) می‌گویند.[۲]

خاستگاه[ویرایش]

به نظر می‌رسد DNA میتوکندریایی و هسته دارای ویژگیهای تکاملی متفاوتی باشند. mtDNAها از ژنوم‌های حلقوی باکتری‌هایی که توسط اجداد اولیهٔ سلول‌های یوکاریوتی امروزی در بر گرفته شده‌اند مشتق شده‌اند. این نظریه به نظریهٔ اندوسیمبیوتیک (endosymbiotic theory) معروف است. به طور تقریبی هر میتوکندری شامل ۲–۱۰ کپی از mtDNA می‌باشد.[۳] در سلول‌های ارگانیسم‌های موجود اکثریت بسیار بزرگی از پروتئین‌های موجود در میتوکندری به وسیلهٔ DNA هسته کد می‌شوند اما تصور می‌شود ژن‌های برخی از آنها دارای ریشهٔ باکتریایی هستند که در طی تکامل به سلول‌های یوکاریوتی منتقل شده‌اند.

وراثت میتوکندریایی[ویرایش]

در اغلب پر سلولی‌ها mtDNA از مادر به ارث می‌رسد. مکانیزم‌های این توارث عبارتست از یک رقیق سازی ساده (یک سلول تخم شامل ۱۰۰هزار تا یک میلیون مولکول mtDNA است در صورتی که یک اسپرم تنها شامل ۱۰۰ تا هزار عدد از انهاست)، کاهش mtDNA اسپرمی در یک تخم بارور شده و حداقل در تعداد کمی از ارگانیسم‌ها ناکامی mtDNAهای اسپرمی در ورود به تخم. فارغ از اینکه چه مکانیسمی مؤثر واقع شود این الگوی تک والدی بودن mtDNA در اکثر جانوران، گیاهان و قارچ‌ها دیده شده‌است.

وراثت ماده[ویرایش]

در تولید مثل جنسیتی میتوکندری به طور انحصاری از مادر به ارث می‌رسد. میتوکندری موجود در اسپرم پستانداران معمولاً پس از لقاح توسط سلول تخم نابود می‌شود. علاوه بر این بیشتر میتوکندری در پایهٔ دم اسپرم حضور دارد که به منظور به پیش راندن اسپرم استفاده می‌شود و گاهی اوقات دم در ضمن فرایند لقاح نابود می‌شود. در ۱۹۹۹ این نتیجه بدست آمد که میتوکندری اسپرمی والدی (parental) توسط اوبیکوتین (ubiquitin) علامت گذاری می‌شود تا در آینده برای انهدام درون جنینی انتخاب شود.[۴] برخی تکنیک‌های لقاح مصنوعی به ویژه تزریق یک اسپرم به درون یک oocyte ممکن است با این فرایند تداخل کند. این حقیقت که mtDNA از طریق مادری به ارث می‌رسد محققان را قادر می‌سازد تا سلسلهٔ نسل مادری را در طی زمان ردیابی کنند (به طریق مشابه DNAهای کروموزوم Y که از طریق پدری به ارث می‌رسد برای دنبال کردن سلسلهٔ نسل پدری بکار می‌رود). این کار در انسانها به وسیلهٔ آنالیز توالی یک یا چند بخش از نواحی کنترل (HVR1 یا HVR2) بس متغیر (hypervariable)، مولکول mtDNA و در قالب یک تست DNA نسب شناسانه انجام می‌شود.HVR1 از حدود ۴۴۰ جفت باز (Base pair) تشکیل شده‌است. این ۴۴۰ جفت باز با نواحی کنترل افراد دیگر (اشخاص دیگر یا منابع موجود در دیتابیس) به منظور مشخص کردن شجرهٔ مادری مقایسه می‌شوند. vila et al نتایج تحقیقات نسب شناسی نوعی سگ بومی را تا درندگان منتشر کرده‌است.[۵] مفهوم حوای میتوکندریایی نیز براساس تحلیلی مشابه بنا شد تا از طریق ردیابی نسل در طول زمان ریشهٔ اولیهٔ بشر را کشف کند. از آنجا که mtDNA به طور کامل بکر نمانده و نرخ جهش سریعی دارد، می‌تواند برای بررسی روابط تکاملی ارگانیسم‌ها مفید واقع شود. در واقع می‌توان توالی mtDNAها را در گونه‌های مختلف مشخص کرد و با مقایسهٔ آنها یک درخت تکاملی ترسیم کرد. از آنجا که mtDNA از مادر به فرزند منتقل می‌شود می‌توان از ان به عنوان ابزاری مفید در تحقیقات نسب شناسی برای پیدا کردن اجداد مادری فرد استفاده کرد.

وراثت نر[ویرایش]

مشاهده شده که میتوکندری در بعضی از گونه‌ها مانند صدف‌ها می‌تواند از پدر به ارث برسد.[۶][۷] همچنین وراثت پدری میتوکندری در برخی حشرات چون مگس میوه،[۸] زنبور عسل[۹] و برخی جیرجیرک ها[۱۰] نیز گزارش شده‌است. شواهد حاکی از این هستند که توارث پدری میتوکندری در میان پستانداران بسیار نادر است. به طور مشخص نتایج ثبت شده‌ای در مورد موش‌ها موجودند که میتوکندری‌های پدری پس زده شده‌اند.[۱۱][۱۲] این مسئله در میان گوسفندان[۱۳] و همچنین گاوهای شبیه‌سازی شده یافت شده است[۱۴] و همچنین در یک مورد خاص انسانی.[۱۵]

ساختار[ویرایش]

در انسان‌ها و احتمالاً به طور کلی در همهٔ پرسلولی‌ها در هر سلول بین ۱۰۰ تا ۱۰۰۰۰ کپی متفاوت از mtDNA موجود است (سلول تخم و اسپرم استثنا هستند). در پستانداران هر مولکول mtDNA حلقوی ۲رشته‌ای شامل ۱۵۰۰۰–۱۷۰۰۰ جفت باز می‌باشد. ۲رشتهٔ mtDNA بر اساس محتوی هسته ایشان با هم متفاوت می‌شوند به طوریکه رشتهٔ با گوانین بیشتر رشتهٔ سنگین تر و رشته با سیتوزین بیشتر با عنوان رشتهٔ سبک یاد می‌شوند. در یک مجموع ۳۷ ژنی، رشتهٔ سنگین ۲۸ ژن و رشتهٔ سبک ۹ ژن را کد می‌کند. در این ۳۷ ژن ۱۳ تا برای پروتئین‌ها (پلی پپتیدها)، ۲۲تا برای tRNAها و دو تا برای زیربخش‌های کوچک و بزرگ rRNAها هستند. این الگو همچنین در میان اکثر پرسلولی‌ها مشاهده شده‌است. با این وجود در برخی از موارد یکی یا چند مورد از ۳۷ ژن غایب اند و محدودهٔ اندازهٔ mtDNAها بزرگتر است. حتی در میان گیاهان و قارچ‌ها تغییرات بزرگتری در محتوای ژنتیکی و اندازهٔ mtDNAها مشاهده شده‌است. همچنین به نظر می‌رسد یک زیرمجموعه از ژن‌ها وجود دارد که در همهٔ سلول‌های یوکاریوتی حضور دارد (به استثنای بعضی موارد که بطور کلی میتوکندری ندارند). برخی گونه‌های گیاهی مقادیر بسیار زیادی mtDNA دارند (۲۵۰۰۰۰۰ جفت باز در مولکول mtDNA) با این وجود به طرز غیرمنتظره‌ای حتی این mtDNAهای بزرگ تعداد و انواع برابری ژن در مقایسه با گیاهان با mtDNA کوچکتر دارند.[۱۶]

ژن‌ها[ویرایش]

زنجیرهٔ انتقال[ویرایش]

ژنوم میتوکندریایی شامل ۱۳ ژن کد کنندهٔ پروتئین است. بسیاری از این ژن‌ها زنجیرهٔ انتقال را کد می‌کنند.

دسته‌ها ژن‌ها
NADH dehydrogenase
(complex I)
MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6
Coenzyme Q - cytochrome c reductase/Cytochrome b
(complex III)
MT-CYB
سیتوکروم اکسیداز
(complex IV)
MT-CO1, MT-CO2, MT-CO3
ای‌تی‌پی سینتیز MT-ATP6, MT-ATP8

rRNA[ویرایش]

rRNA میتوکندریایی توسط MT-RNR1 (12s) و MT-RNR2 (16s) کد می‌شود.

tRNA[ویرایش]

ژن‌های زیر tRNA را کد می‌کنند:

اسید آمینه 3-Letter 1-Letter MT DNA
آلانین Ala A MT-TA
آرژینین Arg R MT-TR
آسپاراژین Asn N MT-TN
اسید آسپارتیک Asp D MT-TD
Cysteine Cys C MT-TC
اسید گلوتامیک Glu E MT-TE
گلوتامین Gln Q MT-TQ
گلیسین Gly G MT-TG
هیستیدین His H MT-TH
ایزولوسین Ile I MT-TI
لوسین Leu L MT-TL1, MT-TL2
لیزین Lys K MT-TK
متیونین Met M MT-TM
فنیل‌آلانین Phe F MT-TF
پرولین Pro P MT-TP
سرین Ser S MT-TS1, MT-TS2
ترئونین Thr T MT-TT
تریپتوفان Trp W MT-TW
تیروزین Tyr Y MT-TY
والین Val V MT-TV

جهش[ویرایش]

نقش mtDNA در برخی از بیماری‌های انسانی

بیماری‌های ژنتیکی[ویرایش]

جهش در mtDNA می‌تواند منجر به شماری از بیماری‌های ژنتیکی مانند exercise intolerance و سندروم کرنز-سایر (kss) شود که می‌تواند سبب کاهش کارکرد قلب، چشم‌ها و حرکات ماهیچه شود. برخی شواهد حاکی از انند که این نقص‌ها نقش اساسی در فرایند پیری دارند.[۱۷]

کاربرد در شناسایی[ویرایش]

در انسان‌ها mtDNA، تعداد ۱۶۵۶۹ بلوک سازندهٔ DNA (جفت‌های باز) را شامل می‌شود[۱۸] که نمایش دهندهٔ بخشی از مجموع DNA موجود در سلول است. برخلاف DNA هسته که از هر دو والد به ارث می‌رسد و در ان ژن‌ها در طی فرایند نوترکیبی چینشی تازه می‌یابند در mtDNA معمولاً از والد به فرزند تغییری مشاهده نمی‌شود. با این وجود mtDNA نیز دچار نوترکیبی می‌شود و این کار را با کپی‌هایی از خودش در یک میتوکندری واحد انجام می‌دهد. به این دلیل و نیز به دلیل اینکه در حیوانات mtDNA نرخ جهش بالاتری نسبت به DNA هسته دارد[۱۹] مولکول mtDNA ابزاری قوی برای ردیابی نسل‌ها از طریق مادری است و از این طریق برای جستجوی اجداد بسیاری از گونه‌ها در طول صدها نسل بکار می‌رود. mtDNA انسان همچنین می‌تواند برای شناسایی افراد بکار رود.[۲۰] مراکز پزشکی قانونی گاهی اوقات مقایسه‌های mtDNA را برای شناسایی بقایای انسانی و به ویژه شناسایی بقایای اسکلت‌های قدیمی به کار می‌برند. گرچه mtDNA برخلاف DNA هسته تنها مختص به یک شخص نیست اما می‌توان با استفاده مشترک از ان و شواهد دیگر (مانند شواهد ریخت‌شناسی، شواهد مکانی و...) عمل شناسایی را انجام داد. همچنین به عنوان گواهی سلبی نیز عمل می‌کند.[۲۱] بسیاری از محققان معتقدند mtDNA نسبت به DNA هسته‌ای ابزار بهتری برای شناسایی بقایای اسکلت‌های قدیمی است زیرا به دلیل وجود کپی‌های زیاد از mtDNA در سلول احتمال بدست آوردن یک نمونهٔ مفید افزایش می‌یابد و به این خاطر که یک همسانی با یک ارتباط زنده بسیار محتمل است حتی اگر فواصل نسلی مادری زیادی آنها را از هم جدا کند. جسد یک تبهکار معروف آمریکایی از همین طریق و به وسیلهٔ مقایسهٔ mtDNA او با یکی از اعقاب مسیر دختری وی مشخص شد.[۲۲] همین‌طور نشخیص هویت برخی از اعضای خاندان سلطنتی روسیه به وسیله مقایسه با اقوام مادری آنها.[۲۳] میزان کم جمعیت مؤثر و نرخ جهش سریع (در حیوانات) mtDNA را برای یافتن روابط ژنتیکی بین افراد و گروه‌ها در یک گونهٔ خاص و همچنین شناسایی و دسته‌بندی فیلوژنی بین گونه‌های مختلف ابزاری مناسب ساخته‌است البته مشروط به اینکه این گونه‌ها ارتباطشان از هم خیلی دور نباشد. این کار به این شکل صورت می‌گیرد که ابتدا توالی mtDNA افراد یا گونه‌های مختلف مشخص می‌شود و آنگاه بر حسب رابطه‌ای که این توالی‌ها با هم دارند شبکه‌ای ایجاد می‌شود که درخت فیلوژنتیک نام دارد.

تاریخچه[ویرایش]

mtDNA در ۱۹۶۰ توسط مارگریت ام.کی. ناس و سیلوان ام. کی ناس و به وسیلهٔ میکروسکوپ الکترونی[۲۴] و همچنین توسط الن هاسلبروز، هانس تاپی و گاتفرید شاتز به وسیلهٔ ازمایش‌های بیوشیمیایی روی بخش‌های به شدت خالص شدهٔ میتوکندری کشف گردید.[۲۵]

جستارهای وابسته[ویرایش]

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  23. Paleo-DNA Laboratory - Forensic Services
  24. Gill P, Ivanov PL, Kimpton C, et al. (February 1994). «Identification of the remains of the Romanov family by DNA analysis». Nat. Genet. 6 (2): 130–5. doi:10.1038/ng0294-130. PMID 8162066.
  25. The details of the tests were published at Gil et al. , 'Identification of the Remains' The Duke of Fife was officially named as the source of the comparison sample of mtDNA in Ivanov, 'Mitochondrial DNA', p. 419.
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.[1]

Mitochondrial DNA (mtDNA or mDNA)[2] 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 the plastids, like 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.[3]

Since mtDNA evolves relatively slowly compared to other 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.

It should not be confused with messenger RNA.

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.[4] 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.[5]

The reasons why mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome[6] suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages.[7] The difficulty of targeting remotely-produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA;[8] colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery.[9] Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention.[5]

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[10][11] ), 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.[12] 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 accomplished on human mitochondrial DNA by sequencing one or more of the hypervariable control regions (HVR1 or HVR2) of the mitochondrial DNA, as with a genealogical DNA test. HVR1 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.[13] 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 inexorable 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,[14][15][16][17] 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.[18]

Male inheritance

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.[19] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies,[20][21] honeybees,[22] and periodical cicadas.[23]

Male mitochondrial inheritance was recently discovered in Plymouth Rock chickens.[24] Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice,[25][26] where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep,[27] and in cloned cattle.[28] It has been found in a single case in a human male.[29]

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.

Three-parent inheritance

An artificial reproductive process known as Three Parent In Vitro Fertilization (TPIVF) results in offspring containing mtDNA from a donor female, and nuclear DNA from another female and a male. In the process, 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.[30]

Structure

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.[31]

For human mitochondrial DNA (and probably for that of metazoans in general), 100-10,000 separate copies of mtDNA are usually present per cell (egg and sperm cells are exceptions). In mammals, each double-stranded circular mtDNA molecule consists of 15,000-17,000[32] 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 light strand encodes 28 genes, and the heavy strand encodes 9 genes for a total of 37 genes.[33] 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). This pattern is also seen among most metazoans, although in some cases one or more of the 37 genes is absent and the mtDNA size range is greater. Even greater 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 mtDNAs (as many as 2,500,000 base pairs per mtDNA molecule) but, surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.[34]

As far as transcription concerns, at least in animals, each strand is transcribed continuously and produces a polycistronic RNA molecule. In the human mitogenome, ATP8 and ATP6 as well as ND4L and ND4 are overlapping genes. Between most (but not all) protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.[35]

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.[36]

The smallest mitochondrial genome sequenced to date is the 5967bp mtDNA of the parasite Plasmodium falciparum;[37] some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing 11.3Mb.[38]

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.[39] 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.[40]

During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.[41] 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.[18] At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[41] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types.[41]

Mutations

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.[42] mtDNA does not accumulate any more oxidative base damage than nuclear DNA.[43] 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.[44] mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin.[45] 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 [46] The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins,[47] 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.[48] 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 [49] and are influenced by complicated stochastic processes within the cell and during development.[18][50]

Use in disease diagnosis

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy.[51][52]

Relationship with aging

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction.[53] 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.[42] 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.[54] 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.[55] 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.[56] 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.[57] 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.[58][59] 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.[60]

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.[61] 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.[62]

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,[63] 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 accummulate 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[35]

Mitochondrial DNA was admitted into evidence for the first time ever in 1996 during State of Tennessee v. Paul Ware.[64]

In the 1998 court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer,[65] mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time.[66][67] The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5).[citation needed]

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.[68] This was the first trial in the U.S. to admit canine DNA.[69]

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,[70] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.[71]

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.[72]
  • MitoBreak: the mitochondrial DNA breakpoints database.[73]
  • MitoFish and MitoAnnotator: a mitochondrial genome database of fish.[74] See also Cawthorn et al.[75]
  • MitoZoa 2.0: a database for comparative and evolutionary analyses of mitochondrial genomes in Metazoa.[76]
  • InterMitoBase: an annotated database and analysis platform of protein-protein interactions for human mitochondria.[77]
  • Mitome: a database for comparative mitochondrial genomics in metazoan animals[78] (no longer available)
  • MitoRes: a resource of nuclear-encoded mitochondrial genes and their products in metazoa[79] (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

References

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