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Mitochondrial DNA

Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles , found in most eukaryotic cells, are the powerhouse of the cell. [ 1 ] The mitoch...

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Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles, found in most eukaryotic cells, are the powerhouse of the cell.[1] The mitochondria, and thus mitochondrial DNA, are passed exclusively from mother to offspring through the egg cell.
Illustration of the location of mitochondrial DNA in human cells
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 (black dots in the upper right). (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.[2]

Mitochondrial DNA (mDNA or mtDNA) is the DNA located in the mitochondriaorganelles in a eukaryotic cell that converts chemical energy from organic compounds into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the DNA contained in a eukaryotic cell; most of the DNA is in the cell nucleus, and, in plants and algae, the DNA also is found in plastids, such as chloroplasts.[3] Mitochondrial DNA is responsible for coding of 13 essential subunits of the complex oxidative phosphorylation (OXPHOS) system which has a role in cellular energy conversion.[4]

Human mitochondrial DNA was the first significant part of the human genome to be sequenced.[5] This sequencing revealed that human mtDNA has 16,569 base pairs and encodes 13 proteins. As in other vertebrates, the human mitochondrial genetic code differs slightly from nuclear DNA.[6]

Since animal mtDNA evolves faster than nuclear genetic markers,[7][8][9] it represents a mainstay of phylogenetics and evolutionary biology. It also permits tracing the relationships of populations, and so has become important in anthropology and biogeography.

Origin

Se cree que el ADN nuclear y el mitocondrial tienen orígenes evolutivos separados , y que el ADNmt deriva de los genomas circulares de bacterias que fueron engullidas por los ancestros de las células eucariotas modernas. Esta teoría se denomina teoría endosimbiótica . En las células de los organismos actuales, la gran mayoría de las proteínas mitocondriales (aproximadamente 1500 tipos diferentes en mamíferos ) están codificadas por el ADN nuclear , pero se cree que los genes de algunas, si no de la mayoría, de ellas son de origen bacteriano, habiéndose transferido al núcleo eucariota durante la evolución . [ 10 ]

Se debaten las razones por las que las mitocondrias han conservado algunos genes. La existencia en algunas especies de orgánulos derivados de mitocondrias que carecen de genoma [ 11 ] sugiere que es posible la pérdida completa de genes, y la transferencia de genes mitocondriales al núcleo tiene varias ventajas. [ 12 ] La dificultad de dirigir productos proteicos hidrofóbicos producidos remotamente a la mitocondria es una hipótesis para explicar por qué se conservan algunos genes en el ADNmt; [ 13 ] la colocalización para la regulación redox es otra, citando la conveniencia del control localizado sobre la maquinaria mitocondrial. [ 14 ] Un análisis reciente de una amplia gama de genomas de ADNmt sugiere que ambas características pueden determinar la retención de genes mitocondriales. [ 10 ]

Estructura y diversidad del genoma

En todos los organismos, existen seis tipos principales de genoma mitocondrial, clasificados por su estructura (es decir, circular versus lineal), tamaño, presencia de intrones o estructuras similares a plásmidos , y si el material genético es una molécula singular o una colección de moléculas homogéneas o heterogéneas . [ 15 ]

En muchos organismos unicelulares (por ejemplo, el ciliado Tetrahymena y el alga verde Chlamydomonas reinhardtii ), y en casos raros también en organismos multicelulares (por ejemplo, en algunas especies de Cnidaria ), el ADNmt es ADN lineal . La mayoría de estos ADNmt lineales poseen telómeros independientes de la telomerasa (es decir, los extremos del ADN lineal) con diferentes modos de replicación, lo que los ha convertido en objetos de investigación interesantes porque muchos de estos organismos unicelulares con ADNmt lineal son patógenos conocidos . [ 16 ]

Animales

Most (bilaterian) animals have a circular mitochondrial genome. Medusozoa and calcareaclades however include species with linear mitochondrial chromosomes.[17] With a few exceptions, animals have 37 genes in their mitochondrial DNA: 13 for proteins, 22 for tRNAs, and 2 for rRNAs.[18]

Mitochondrial genomes for animals average about 16,000 base pairs in length.[18] The anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp.[19] The smallest known mitochondrial genome in animals belongs to the comb jelly Vallicula multiformis, which consist of 9,961 bp.[20]

In February 2020, a jellyfish-related parasite – Henneguya salminicola – was discovered that lacks a mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and live completely free of oxygen dependency.[21][22]

The Armadillidium vulgare has a uniquely large genome when compared to other crustacean average about 30 kB greater allowing it to be a model organism in mtDNA research[23].

Plants and fungi

There are three different mitochondrial genome types in plants and fungi. The first type is a circular genome that has introns (type 2) and may range from 19 to 1000 kbp in length. The second genome type is a circular genome (about 20–1000 kbp) that also has a plasmid-like structure (1 kb) (type 3). The final genome type found in plants and fungi is a linear genome made up of homogeneous DNA molecules (type 5).[24][25][26]

Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes present in all eukaryotes (except for the few that have no mitochondria at all).[10] In Fungi, however, there is no single gene shared among all mitogenomes.[27] Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs.[28] However, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.[29] 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.[30]

Protists

Protists contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3, and type 5 of the plant and fungal genomes also exist in some protists, as do two unique genome types. One of these unique types is a heterogeneous collection of circular DNA molecules (type 4) while the other is a heterogeneous collection of linear molecules (type 6). Genome types 4 and 6 each range from 1–200 kbp in size.

The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum.[31][32]

Endosymbiotic gene transfer, the process by which genes that were coded in the mitochondrial genome are 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.

Replication

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand.[33] The regulation of mitochondrial DNA replication and transcription initiation is located in a single intergenic noncoding region (NCR).[33] In humans, the 1,100 base pair NCR region contains three promoters of two L-strand promoters (LSP and LSP2) and one H-strand promoter (HSP).[34] Unlike bidirectional and specific origin initiation of nuclear DNA replication, mitochondrial DNA has two strand-specific, unidirectional origins of replication of the leading H strand (OH) which located in NCR and the lagging L strand (OL) which located in the tRNA gene cluster.[35]

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.[36] 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.[37] Mitochondrial single-stranded DNA binding protein (SSB) coordinates its activity with the POLG during DNA replication.[38] All these polypeptides are encoded in the nuclear genome.

During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.[39] 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.[40] According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[39] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types."[39]

DNA repair

Although several DNA repair pathways have been reported to occur in the mitochondria, currently the base excision repair pathway is the pathway most comprehensively described.[41] Proteins that are employed in the maintenance of mitochondrial DNA are encoded by nuclear genes and translocated to the mitochondria.[41] The mitochondria of human cells are capable of repairing DNAbase pair mismatches by a pathway that is distinct from the DNA mismatch repair pathway of the nucleus.[42] This distinct mitochondrial pathway includes the activity of the Y box binding protein 1 (designated YB-1 or YBX1), that likely acts in the mismatch binding and recognition steps of mismatch repair.[42] DNA repair mechanisms specific to the mitochondria may reflect the proximity of the mitochondrial DNA to the oxidative phosphorylation system and consequently to the DNA-damaging reactive oxygen species formed during ATP production.[43]

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

Genes on the human mtDNA and their transcription

Schematic karyogram showing the human genome, with 23 chromosome pairs as well as the mitochondrial genome (to scale at bottom left, annotated "MT"). Its genome is relatively tiny compared to the rest, and its copy number per human cell varies from 0 (erythrocytes)[44] up to 1,500,000 (oocytes).[45]

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs (12S and 16S), and 14 transfer RNAs (tRNAs). The light strand encodes one subunit and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 protein subunits, all of which are involved in the oxidative phosphorylation process.[46][47]

  • The complete sequence of the human mitochondrial DNA in graphic form

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.[49] Folded tRNAs therefore act as secondary structure punctuations.[50]

Transcription is done by the single-subunit mitochondrial RNA polymerase (POLRMT). In association with two of accessory factors, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M), the POLRMT complex recognizes promoters and initiates transcription.[51] Transcription resulted in polycistronic transcripts that are processed in discrete mitochondrial RNA granules into individual mRNAs, tRNAs, and rRNAs.[52]

Regulation of transcription

The promoters for the initiation of the transcription of the heavy and light strands are located in the main non-coding region of the mtDNA called the displacement loop, the D-loop.[46] There is evidence that the transcription of the mitochondrial rRNAs is regulated by the heavy-strand promoter 1 (HSP1), and the transcription of the polycistronic transcripts coding for the protein subunits are regulated by HSP2.[46]

Measurement of the levels of the mtDNA-encoded RNAs in bovine tissues has shown that there are major differences in the expression of the mitochondrial RNAs relative to total tissue RNA.[53] Among the 12 tissues examined the highest level of expression was observed in the heart, followed by brain and steroidogenic tissue samples.[53]

As demonstrated by the effect of the trophic hormone ACTH on adrenal cortex cells, the expression of the mitochondrial genes may be strongly regulated by external factors, apparently to enhance the synthesis of mitochondrial proteins necessary for energy production.[53] Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.[53]

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 has been reported to contain on average 5 molecules),[54][55] degradation of sperm mtDNA in the male genital tract and 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 also in fungi.[56]

In a study published in 2018, human babies were reported to inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy,[57] a finding that has been rejected by other scientists.[58][59][60]

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, mitochondria are present solely in the midpiece, which is used for propelling the sperm cells, and sometimes the midpiece, along with 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.[61] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.

The fact that mitochondrial DNA is mostly 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 . [ 62 ] HVR1, for example, consists of about 440 base pairs. These 440 base pairs are compared to the same regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made with the revised Cambridge Reference Sequence . Vilà et al. have published studies tracing the matrilineal descent of domestic dogs from wolves. [ 63 ] El concepto de la Eva mitocondrial se basa en el mismo tipo de análisis, tratando de descubrir el origen de la humanidad rastreando el linaje hacia atrás en el tiempo.

El cuello de botella mitocondrial

Se espera que las entidades sujetas a herencia uniparental y con poca o ninguna recombinación estén sujetas al trinquete de Muller , la acumulación de mutaciones deletéreas hasta la pérdida de funcionalidad. Las poblaciones animales de mitocondrias evitan esto mediante un proceso de desarrollo conocido como cuello de botella del ADNmt . El cuello de botella aprovecha los procesos aleatorios en la célula para aumentar la variabilidad célula a célula en la carga mutante a medida que se desarrolla un organismo: un solo óvulo con cierta proporción de ADNmt mutante produce un embrión en el que diferentes células tienen diferentes cargas mutantes. La selección a nivel celular puede entonces actuar para eliminar aquellas células con más ADNmt mutante, lo que lleva a una estabilización o reducción de la carga mutante entre generaciones. El mecanismo subyacente al cuello de botella es objeto de debate, [ 64 ] [ 65 ] [ 66 ] [ 67 ] y un metaestudio matemático y experimental reciente proporciona evidencia de una combinación de la partición aleatoria de ADNmt en las divisiones celulares y el recambio aleatorio de moléculas de ADNmt dentro de la célula. [ 40 ]

Herencia masculina

Male mitochondrial DNA inheritance has been discovered in Plymouth Rock chickens.[68] Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice,[69][70] where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep,[71] and in cloned cattle.[72] Rare cases of male mitochondrial inheritance have been documented in humans.[73][74][75][57] 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.

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 mtDNA (which can be as much as 30% divergent) in germline cells.[76] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies,[77][78]honeybees,[79] and periodical cicadas.[80]

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.[81] 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.[82]

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.[83] mtDNA does not accumulate any more oxidative base damage than nuclear DNA.[84] 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.[85] mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin.[86] 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.[87] The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins,[88] which may have an effect on organism metabolism and/or fitness.

Genetic illness

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.[89] 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[90] and are influenced by complicated stochastic processes within the cell and during development.[40][91]

Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.[92]

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.[93]

Use in disease diagnosis

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy.[94][95] mtDNA alterations can be detected in the bio-fluids of patients with cancer.[96] mtDNA is characterized by the high rate of polymorphisms and mutations. Some of these are increasingly recognized as an important cause of human pathology such as oxidative phosphorylation (OXPHOS) disorders, maternally inherited diabetes and deafness (MIDD), Type 2 diabetes mellitus, Neurodegenerative disease, heart failure, and cancer.

Relationship with ageing

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction. [ 97 ] 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 (eg, by reducing antioxidant defenses) in worms increase, rather than decrease, their longevity. [ 83 ] 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. [ 98 ] 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. [ 99 ] However, this concept was conclusively disproved when it was demonstrated that mice, which were genetically altered to accumulate mtDNA mutations at an accelerated rate to age prematurely, but their tissues do not produce more ROS as predicted by the 'Vicious Cycle' hypothesis. [ 100 ] 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. [ 101 ] The application of a mitochondrial-specific ROS scavenger, which lead to a significant longevity of the mice studied, [ 102 ] suggests that mitochondria may still be well-implicated in ageing. Extensive research is being conducted to further investigate this link and methods to combat ageing. Presently, gene therapy and nutraceutical supplementation are popular areas of ongoing research. [ 103 ] [ 104 ] Bjelakovic et al. analizaron los resultados de 78 estudios entre 1977 y 2012, que involucraron a un total de 296.707 participantes, y concluyeron que los suplementos antioxidantes no reducen la mortalidad por todas las causas ni prolongan la esperanza de vida, mientras que algunos de ellos, como el betacaroteno, la vitamina E y las dosis más altas de vitamina A, pueden incluso aumentar la mortalidad. [ 105 ] In a recent study, it was shown that dietary restriction can reverse ageing alterations by affecting the accumulation of mtDNA damage in several organs of rats. For example, dietary restriction prevented age-related accumulation of mtDNA damage in the cortex and decreased it in the lung and testis.[106]

Neurodegenerative diseases

Increased mtDNA damage is a feature of several neurodegenerative diseases.

The brains of individuals with Alzheimer's disease have elevated levels of oxidative DNA damage in both nuclear DNA and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA.[107] It has been proposed that aged mitochondria is the critical factor in the origin of neurodegeneration in Alzheimer's disease.[108] Analysis of the brains of AD patients suggested an impaired function of the DNA repair pathway, which would cause reduce the overall quality of mtDNA.[109]

In Huntington's disease, mutant huntingtin protein causes mitochondrial dysfunction involving inhibition of mitochondrialelectron transport, higher levels of reactive oxygen species and increased oxidative stress.[110] Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington's disease pathology.[111]

The DNA oxidation product 8-oxoguanine (8-oxoG) is a well-established marker of oxidative DNA damage. In persons with amyotrophic lateral sclerosis (ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal motor neurons are impaired.[112] Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the etiology of ALS.

Correlation of the mtDNA base composition with animal life spans

Animal species mtDNA base composition was retrieved from the MitoAge database and compared to their maximum life span from AnAge database.

Durante la última década, un grupo de investigación israelí liderado por el profesor Vadim Fraifeld ha demostrado que existen correlaciones fuertes y significativas entre la composición de bases del ADNmt y la longevidad máxima específica de cada especie animal. [ 113 ] [ 114 ] [ 115 ] Como se demuestra en su trabajo, un mayor contenido de guanina + citosina del ADNmt ( GC% ) se asocia fuertemente con una mayor longevidad máxima en todas las especies animales. Una observación adicional es que la correlación del GC% del ADNmt con la longevidad máxima es independiente de la conocida correlación entre la tasa metabólica de las especies animales y la longevidad máxima. El GC% del ADNmt y la tasa metabólica basal explican las diferencias en la longevidad máxima de las especies animales de manera multiplicativa (es decir, longevidad máxima de la especie = su GC% del ADNmt * tasa metabólica). [ 114 ] Para apoyar a la comunidad científica en la realización de análisis comparativos entre las características del ADNmt y la longevidad en los animales, se creó una base de datos dedicada llamada MitoAge . [ 116 ]

El espectro mutacional del ADN mitocondrial es sensible a los rasgos de la historia de vida específicos de cada especie.

De novo mutations arise either due to mistakes during DNA replication or due to unrepaired damage caused in turn by endogenous and exogenous mutagens. It has been long believed that mtDNA can be particularly sensitive to damage caused by reactive oxygen species (ROS), however, G>T substitutions, the hallmark of the oxidative damage in the nuclear genome, are very rare in mtDNA and do not increase with age. Comparing the mtDNA mutational spectra of hundreds of mammalian species, it has been recently demonstrated that species with extended lifespans have an increased rate of A>G substitutions on single-stranded heavy chains. [ 117 ] This discovery led to the hypothesis that A>G is a mitochondria-specific marker of age-associated oxidative damage. This finding provides a mutational (contrary to the selective one) explanation for the observation that long-lived species have GC-rich mtDNA: long-lived species become GC-rich simply because of their biased process of mutagenesis. La asociación entre el espectro mutacional del ADN mitocondrial y los rasgos de la historia de vida específicos de cada especie en mamíferos abre la posibilidad de vincular estos factores y descubrir nuevos mutágenos específicos de la historia de vida en diferentes grupos de organismos.

Relación con estructuras de ADN no canónicas (no B)

Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms, and cloverleaf-like elements.[118] Moreover, data supports 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.[119]

Use in forensics

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 mother 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,[120] 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.

Las pruebas de ADN mitocondrial (ADNmt) pueden ser utilizadas por científicos forenses en casos donde el ADN nuclear está gravemente degradado. Las células autosómicas solo tienen dos copias de ADN nuclear, pero pueden tener cientos de copias de ADNmt debido a las múltiples mitocondrias presentes en cada célula. Esto significa que la evidencia altamente degradada que no sería útil para el análisis STR podría utilizarse en el análisis de ADNmt. El ADNmt puede estar presente en huesos, dientes o cabello, que podrían ser los únicos restos que queden en caso de degradación severa. A diferencia del análisis STR, la secuenciación de ADNmt se ha realizado tradicionalmente mediante la secuenciación de Sanger, desarrollada por Frederick Sanger en la década de 1970. La secuenciación de Sanger, el método más antiguo y ampliamente utilizado, sigue siendo el estándar de oro en la tipificación forense de ADNmt, validando la secuenciación masivamente paralela (MPS). [ 121 ] [ 122 ] Anderson et al sequenced and reported the first mitochondrial genome in 1981, the Cambridge Reference Sequence (CRS), [ 123 ] which was later revised and renamed in 1999 as the revised Cambridge Reference Sequence (rCRS). [ 124 ] A Reconstructed Sapiens Reference Sequence (RSRS) has since been proposed to replace the rCRS. [ 125 ] The known sequence and questioned sequence are both compared to the Revised Cambridge Reference Sequence to generate their respective haplotypes. If the known sample sequence and questioned sequence originated from the same matriline, one would expect to see identical sequences and identical differences from the rCRS. [ 126 ] Cases arise where there are no known samples to collect and the unknown sequence can be searched in a database such as EMPOP. EMPOP, acrónimo del proyecto de base de datos de población de ADN mitocondrial del grupo europeo de perfiles de ADN (EDNAP), es la base de datos de ADN forense más grande, con más de 63.400 mitotipos con control de calidad en su versión actual, V.14. [ 127 ] El Grupo de Trabajo Científico sobre Métodos de Análisis de ADN recomienda tres conclusiones para describir las diferencias entre una secuencia de ADNmt conocida y una secuencia de ADNmt cuestionada: exclusión para dos o más diferencias entre las secuencias, inconcluso si hay una diferencia de nucleótido, o imposibilidad de excluir si no hay diferencias de nucleótido entre las dos secuencias. [ 128 ]

The rapid mutation rate (in animals) makes mtDNA useful for assessing the 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[92]

Mitochondrial DNA was admitted into evidence for the first time ever in a United States courtroom in 1996 during State of Tennessee v. Paul Ware.[129]

In the 1998 United States court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer,[130] mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time.[131][132] The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5).[133]

Mitochondrial DNA was first admitted into evidence in California, United States, 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.[134] This was the first trial in the U.S. to admit canine DNA.[135]

The remains of King Richard III, who died in 1485, were identified by comparing his mtDNA with that of two matrilineal descendants of his sister who were alive in 2013, 527 years after he died.[136]

Use in evolutionary biology and systematic biology

MtDNA is conserved across eukaryotic organisms given the critical role of mitochondria in cellular respiration. However, due to less efficient DNA repair (compared to nuclear DNA), it has a relatively high mutation rate (but slow compared to other DNA regions such as microsatellites) which makes 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.

For instance, while most nuclear genes are nearly identical between humans and chimpanzees, their mitochondrial genomes are 9.8% different. Human and gorilla mitochondrial genomes are 11.8% different, suggesting that humans may be more closely related to chimpanzees than gorillas.[137]

mtDNA in nuclear DNA

Whole genome sequences of more than 66,000 people revealed that most of them had some mitochondrial DNA inserted into their nucleargenomes. More than 90% of these nuclear-mitochondrial segments (NUMTs) were inserted after humans diverged from the other apes. Results indicate such transfers currently occur as frequently as once in every ≈4,000 human births.[138]

It appears that organellar DNA is much more often transferred to nuclear DNA than previously thought. This observation also supports the idea of the endosymbiont theory that eukaryotes have evolved from endosymbionts which turned into organelles while transferring most of their DNA to the nucleus so that the organellar genome shrunk in the process.[138]

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,[139] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.[140]

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.

  • AmtDB: a database of ancient human mitochondrial genomes.[141]
  • InterMitoBase : una base de datos anotada y plataforma de análisis de interacciones proteína-proteína para mitocondrias humanas. [ 142 ] (aparentemente actualizada por última vez en 2010, pero aún disponible)
  • MitoBreak : la base de datos de puntos de ruptura del ADN mitocondrial. [ 143 ]
  • MitoFish y MitoAnnotator : una base de datos del genoma mitocondrial de peces. [ 144 ] Véase también Cawthorn et al. [ 145 ]
  • Mitome: una base de datos para genómica mitocondrial comparativa en animales metazoos [ 146 ] (ya no está disponible)
  • MitoRes: un recurso de genes mitocondriales codificados en el núcleo y sus productos en metazoos [ 147 ] (aparentemente ya no se actualiza)
  • MitoSatPlant : Base de datos de microsatélites mitocondriales de viridiplantae. [ 148 ]
  • MitoZoa 2.0: una base de datos para análisis comparativos y evolutivos de genomas mitocondriales en metazoos. [ 149 ] (ya no está disponible)

Bases de datos de asociación entre ADN mitocondrial y fenotipo

Los estudios de asociación de genoma completo pueden revelar asociaciones de genes de ADN mitocondrial y sus mutaciones con fenotipos , incluyendo la esperanza de vida y los riesgos de enfermedades. En 2021, el mayor estudio de asociación de genoma completo de ADN mitocondrial, basado en el Biobanco del Reino Unido , reveló 260 nuevas asociaciones con fenotipos, incluyendo la esperanza de vida y los riesgos de enfermedades, por ejemplo, la diabetes tipo 2. [ 150 ] [ 151 ]

bases de datos de mutaciones mitocondriales

Existen varias bases de datos especializadas que informan sobre polimorfismos y mutaciones en el ADN mitocondrial humano, junto con la evaluación de su patogenicidad.

  • MitImpact : Una colección de predicciones de patogenicidad precalculadas para todos los cambios de nucleótidos que causan sustituciones no sinónimas en genes humanos que codifican proteínas mitocondriales. MitImpact 3D - Laboratorio de bioinformática IRCCS-CSS .
  • MITOMAP : Un compendio de polimorfismos y mutaciones en el ADN mitocondrial humano WebHome < MITOMAP < Foswiki .

Véase también

Referencias

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