Search This Blog

Thursday, September 4, 2025

Recent African origin of modern humans

Successive dispersals (labeled in years before present) of
  Homo erectus greatest extent (yellow)
  Homo neanderthalensis greatest extent (ochre)
  Homo sapiens (red)
Expansion of early modern humans from Africa through the Near East

The recent African origin of modern humans or the "Out of Africa" theory (OOA) is the most widely accepted paleo-anthropological model of the geographic origin and early migration of anatomically modern humans (Homo sapiens). It follows the early expansions of hominins out of Africa, accomplished by Homo erectus and then Homo neanderthalensis.

The model proposes a "single origin" of Homo sapiens in the taxonomic sense, precluding parallel evolution in other regions of traits considered anatomically modern, but not precluding multiple admixture between H. sapiens and archaic humans in Europe and Asia. H. sapiens most likely developed in the Horn of Africa between 300,000 and 200,000 years ago, although an alternative hypothesis argues that diverse morphological features of H. sapiens appeared locally in different parts of Africa and converged due to gene flow between different populations within the same period. The "recent African origin" model proposes that all modern non-African populations are substantially descended from populations of H. sapiens that left Africa after that time.

There were at least several "out-of-Africa" dispersals of modern humans, possibly beginning as early as 270,000 years ago, certainly via northern Africa and the Arabian Peninsula about 130,000 to 115,000 years ago at least. There is evidence that modern humans had reached China around 80,000 years ago. Practically all of these early waves seem to have gone extinct or retreated back, and present-day humans outside Africa descend mainly from a single expansion about 70,000–50,000 years ago, via the so-called "Southern Route". These humans spread rapidly along the coast of Asia and reached Australia by around 65,000–50,000 years ago, (though some researchers question the earlier Australian dates and place the arrival of humans there at 50,000 years ago at earliest, while others have suggested that these first settlers of Australia may represent an older wave before the more significant out of Africa migration and thus not necessarily be ancestral to the region's later inhabitants) while Europe was populated by an early offshoot which settled the Near East and Europe less than 55,000 years ago.

In the 2010s, studies in population genetics uncovered evidence of interbreeding that occurred between H. sapiens and archaic humans in Eurasia, Oceania and Africa, indicating that modern population groups, while mostly derived from early H. sapiens, are to a lesser extent also descended from regional variants of archaic humans.

Proposed waves

Layer sequence at Ksar Akil in the Levantine corridor, and discovery of two fossils of Homo sapiens, dated to 40,800 to 39,200 years BP for "Egbert", and 42,400–41,700 BP for "Ethelruda".

"Recent African origin", or Out of Africa II, refers to the migration of anatomically modern humans (Homo sapiens) out of Africa after their emergence at c. 300,000 to 200,000 years ago, in contrast to "Out of Africa I", which refers to the migration of archaic humans from Africa to Eurasia from before 1.8 and up to 0.5 million years ago. Omo-Kibish I (Omo I) from southern Ethiopia is the oldest anatomically modern Homo sapiens skeleton currently known (around 233,000 years old). There are even older Homo sapiens fossils from Jebel Irhoud in Morocco which exhibit a mixture of modern and archaic features at around 315,000 years old.

Since the beginning of the 21st century, the picture of "recent single-origin" migrations has become significantly more complex, due to the discovery of modern-archaic admixture and the increasing evidence that the "recent out-of-Africa" migration took place in waves over a long time. As of 2010, there were two main accepted dispersal routes for the out-of-Africa migration of early anatomically modern humans, the "Northern Route" (via Nile Valley and Sinai) and the "Southern Route" via the Bab-el-Mandeb strait.[38]

  • Posth et al. (2017) suggest that early Homo sapiens, or "another species in Africa closely related to us", might have first migrated out of Africa around 270,000 years ago based on the closer affinity within Neanderthals' mitochondrial genomes to Homo sapiens than Denisovans.
  • An interpration, with as of yet limited recognition, of a skull fragment coming from Apidima Cave in Greece dated at 210,000 years ago as a Homo sapiens specimen may also points to an early Homo sapiens migration. Finds at Misliya cave, which include a partial jawbone with eight teeth, that may belong to a Homo sapiens specimen, have been dated to around 185,000 years ago. Layers dating from between 250,000 and 140,000 years ago in the same cave contained tools of the Levallois type which could put the date of the first migration even earlier if the tools can be associated with the modern human jawbone finds.
  • An eastward dispersal from Northeast Africa to Arabia 150,000–130,000 years ago is based on the stone tools finds at Jebel Faya dated to 127,000 years ago (discovered in 2011), although fossil evidence in the area is significantly later at 85,000 years ago. Possibly related to this wave are the finds from Zhirendong cave, Southern China, dated to more than 100,000 years ago. Other evidence of modern human presence in China has been dated to 80,000 years ago.
  • The most significant out of Africa dispersal took place around 50,000–70,000 years ago via the so-called Southern Route, either before or after the Toba event, which happened between 69,000 and 77,000 years ago. This dispersal followed the southern coastline of Asia and reached Australia around 65,000–50,000 years ago or according to some research, by 50,000 years ago at earliest. Western Asia was "re-occupied" by a different derivation from this wave around 50,000 years ago and Europe was populated from Western Asia beginning around 43,000 years ago.
  • Wells (2003) describes an additional wave of migration after the southern coastal route, a northern migration into Europe about 45,000 years ago. This possibility is ruled out by Macaulay et al. (2005) and Posth et al. (2016), who argue for a single coastal dispersal, with an early offshoot into Europe.

Northern Route dispersal

Anatomically Modern Humans known archaeological remains in Europe and Africa, directly dated, calibrated carbon dates as of 2013.

Beginning 135,000 years ago, tropical Africa experienced megadroughts which drove humans from the land and towards the sea shores, and forced them to cross over to other continents.

Fossils of early Homo sapiens were found in Qafzeh and Es-Skhul Caves in Israel and have been dated to 80,000 to 120,000 years ago. These humans seem to have either become extinct or retreated back to Africa 70,000 to 80,000 years ago, possibly replaced by southbound Neanderthals escaping the colder regions of ice-age Europe. Hua Liu et al. analyzed autosomal microsatellite markers dating to about 56,000 years ago. They interpret the paleontological fossil as an isolated early offshoot that retracted back to Africa.

The discovery of stone tools in the United Arab Emirates in 2011 at the Faya-1 site in Mleiha, Sharjah, indicated the presence of modern humans at least 125,000 years ago, leading to a resurgence of the "long-neglected" North African route. This new understanding of the role of the Arabian dispersal began to change following results from archaeological and genetic studies stressing the importance of southern Arabia as a corridor for human expansions out of Africa.

In Oman, a site was discovered by Bien Joven in 2011 containing more than 100 surface scatters of stone tools belonging to the late Nubian Complex, known previously only from archaeological excavations in the Sudan. Two optically stimulated luminescence age estimates placed the Arabian Nubian Complex at approximately 106,000 years old. This provides evidence for a distinct Stone Age technocomplex in southern Arabia, around the earlier part of the Marine Isotope Stage 5.

According to Kuhlwilm and his co-authors, Neanderthals contributed genetically to modern humans then living outside of Africa around 100,000 years ago: humans which had already split off from other modern humans around 200,000 years ago, and this early wave of modern humans outside Africa also contributed genetically to the Altai Neanderthals. They found that "the ancestors of Neanderthals from the Altai Mountains and early modern humans met and interbred, possibly in the Near East, many thousands of years earlier than previously thought". According to co-author Ilan Gronau, "This actually complements archaeological evidence of the presence of early modern humans out of Africa around and before 100,000 years ago by providing the first genetic evidence of such populations." Similar genetic admixture events have been noted in other regions as well.

Southern Route dispersal

Coastal route

Red Sea crossing

By some 50–70,000 years ago, a subset of the bearers of mitochondrial haplogroup L3 migrated from East Africa into the Near East. It has been estimated that from a population of 2,000 to 5,000 individuals in Africa, only a small group, possibly as few as 150 to 1,000 people, crossed the Red Sea. The group that crossed the Red Sea travelled along the coastal route around Arabia and the Persian Plateau to India, which appears to have been the first major settling point. Wells (2003) argued for the route along the southern coastline of Asia, across about 250 kilometres (155 mi), reaching Australia by around 50,000 years ago.

Migration routes of modern humans, showing the northern route populating Western Eurasia, and the southern/coastal route populating Eastern Eurasia.

Today at the Bab-el-Mandeb straits, the Red Sea is about 20 kilometres (12 mi) wide, but 50,000 years ago sea levels were 70 m (230 ft) lower (owing to glaciation) and the water channel was much narrower. Though the straits were never completely closed, they were narrow enough to have enabled crossing using simple rafts, and there may have been islands in between. Shell middens 125,000 years old have been found in Eritrea, indicating that the diet of early humans included seafood obtained by beachcombing.

Toba eruption

The dating of the Southern Dispersal is a matter of dispute. It may have happened either pre- or post-Toba, a catastrophic volcanic eruption that took place between 69,000 and 77,000 years ago at the site of present-day Lake Toba in Sumatra, Indonesia. Stone tools discovered below the layers of ash deposited in India may point to a pre-Toba dispersal but the source of the tools is disputed. An indication for post-Toba is haplo-group L3, that originated before the dispersal of humans out of Africa and can be dated to 60,000–70,000 years ago, "suggesting that humanity left Africa a few thousand years after Toba". Some research showing slower than expected genetic mutations in human DNA was published in 2012, indicating a revised dating for the migration to between 90,000 and 130,000 years ago. Some more recent research suggests a migration out-of-Africa of around 50,000-65,000 years ago of the ancestors of modern non-African populations, similar to most previous estimates.

West Asia

Following the fossils dating 80,000 to 120,000 years ago from Qafzeh and Es-Skhul Caves in Israel there are no H. sapiens fossils in the Levant until the Manot 1 fossil from Manot Cave in Israel, dated to 54,700 years ago, though the dating was questioned by Groucutt et al. (2015). The lack of fossils and stone tool industries that can be safely associated with modern humans in the Levant has been taken to suggest that modern humans were outcompeted by Neanderthals until around 55,000 years ago, who would have placed a barrier on modern human dispersal out of Africa through the Northern Route. Climate reconstructions also support a Southern Route dispersal of modern humans as the Bab-el-Mandeb strait experienced a climate more conductive to human migration than the northern landbridge to the Levant during the major human dispersal out of Africa.

A 2023 study proposed that Eurasians and Africans genetically diverged ~100,000 years ago. Main Eurasians then lived in the Saudi Peninsula, genetically isolated from at least 85 kya, before expanding north 54 kya. For reference, Homo sapiens and Neanderthals diverged ~500 kya.

Oceania

Fossils from Lake Mungo, Australia, have been dated to about 42,000 years ago. Other fossils from a site called Madjedbebe have been dated to at least 65,000 years ago, though some researchers doubt this early estimate and date the Madjedbebe fossils at about 50,000 years ago at the oldest.

Phylogenetic data suggests that an early Eastern Eurasian (Eastern non-African) meta-population trifurcated somewhere in eastern South Asia, and gave rise to the Australo-Papuans, the Ancient Ancestral South Indians (AASI), as well as East/Southeast Asians, although Papuans may have also received some gene flow from an earlier group (xOoA), around 2%, next to additional archaic admixture in the Sahul region.

According to one study, Papuans could have either formed from a mixture between an East Eurasian lineage and lineage basal to West and East Asians, or as a sister lineage of East Asians with or without a minor basal OoA or xOoA contribution.

A Holocene hunter-gatherer sample (Leang_Panninge) from South Sulawesi was found to be genetically in between East-Eurasians and Australo-Papuans. The sample could be modeled as ~50% Papuan-related and ~50% Basal-East Asian-related (Andamanese Onge or Tianyuan). The authors concluded that Basal-East Asian ancestry was far more widespread and the peopling of Insular Southeast Asia and Oceania was more complex than previously anticipated.

East and Southeast Asia

In China, the Liujiang man (Chinese: 柳江人) is among the earliest modern humans found in East Asia. The date most commonly attributed to the remains is 67,000 years ago. High rates of variability yielded by various dating techniques carried out by different researchers place the most widely accepted range of dates with 67,000 BP as a minimum, but do not rule out dates as old as 159,000 BP. Liu, Martinón-Torres et al. (2015) claim that modern human teeth have been found in China dating to at least 80,000 years ago.

Tianyuan man from China has a probable date range between 38,000 and 42,000 years ago, while Liujiang man from the same region has a probable date range between 67,000 and 159,000 years ago. According to 2013 DNA tests, Tianyuan man is related "to many present-day Asians and Native Americans". Tianyuan is similar in morphology to Liujiang man, and some Jōmon period modern humans found in Japan, as well as modern East and Southeast Asians.

A 2021 study about the population history of Eastern Eurasia, concluded that distinctive Basal-East Asian (East-Eurasian) ancestry originated in Mainland Southeast Asia at ~50,000BC from a distinct southern Himalayan route, and expanded through multiple migration waves southwards and northwards respectively.

According to a 2024 study, Southeast Asia was the "demographic center of expansion" after some Out of African migrants returned to Africa, evident by the presence of basal Y-chromosome Eurasian lineages (C, D, F, K) in the region.

Americas

Genetic studies concluded that Native Americans descended from a single founding population that initially split from a Basal-East Asian source population in Mainland Southeast Asia around 36,000 years ago, at the same time at which the proper Jōmon people split from Basal-East Asians, either together with Ancestral Native Americans or during a separate expansion wave. They also show that the basal northern and southern Native American branches, to which all other Indigenous peoples belong, diverged around 16,000 years ago. An indigenous American sample from 16,000BC in Idaho, which is craniometrically similar to modern Native Americans as well as Paleosiberians, was found to have largely East-Eurasian ancestry and showed high affinity with contemporary East Asians, as well as Jōmon period samples of Japan, confirming that Ancestral Native Americans split from an East-Eurasian source population in Eastern Siberia.

Europe

According to Macaulay et al. (2005), an early offshoot from the southern dispersal with haplogroup N followed the Nile from East Africa, heading northwards and crossing into Asia through the Sinai. This group then branched, some moving into Europe and others heading east into Asia. This hypothesis is supported by the relatively late date of the arrival of modern humans in Europe as well as by archaeological and DNA evidence. Based on an analysis of 55 human mitochondrial genomes (mtDNAs) of hunter-gatherers, Posth et al. (2016) argue for a "rapid single dispersal of all non-Africans less than 55,000 years ago". By 45,000 years ago, modern humans are known to have reached northwestern Europe.

Genetic reconstruction

Mitochondrial haplogroups

Within Africa

Map of early diversification of modern humans according to mitochondrial population genetics (see: Haplogroup L).

The first lineage to branch off from Mitochondrial Eve was L0. This haplogroup is found in high proportions among the San of Southern Africa and the Sandawe of East Africa. It is also found among the Mbuti people. These groups branched off early in human history and have remained relatively genetically isolated since then. Haplogroups L1, L2, and L3 are descendants of L1–L6, and are largely confined to Africa. The macro haplogroups M and N, which are the lineages of the rest of the world outside Africa, descend from L3. L3 is about 70,000 years old, while haplogroups M and N are about 65–55,000 years old. The relationship between such gene trees and demographic history is still debated when applied to dispersals.

Of all the lineages present in Africa, the female descendants of only one lineage, mtDNA haplogroup L3, are found outside Africa. If there had been several migrations, one would expect descendants of more than one lineage to be found. L3's female descendants, the M and N haplogroup lineages, are found in very low frequencies in Africa (although haplogroup M1 populations are very ancient and diversified in North and North-east Africa) and appear to be more recent arrivals. A possible explanation is that these mutations occurred in East Africa shortly before the exodus and became the dominant haplogroups thereafter by means of the founder effect. Alternatively, the mutations may have arisen shortly afterwards.

Southern Route and haplogroups M and N

Results from mtDNA collected from aboriginal Malaysians called Orang Asli indicate that the haplogroups M and N share characteristics with original African groups from approximately 85,000 years ago, and share characteristics with sub-haplogroups found in coastal south-east Asian regions, such as Australasia, the Indian subcontinent and throughout continental Asia, which had dispersed and separated from their African progenitor approximately 65,000 years ago. This southern coastal dispersal would have occurred before the dispersal through the Levant approximately 45,000 years ago. This hypothesis attempts to explain why haplogroup N is predominant in Europe and why haplogroup M is absent in Europe. Evidence of the coastal migration is thought to have been destroyed by the rise in sea levels during the Holocene epoch. Alternatively, a small European founder population that had expressed haplogroup M and N at first, could have lost haplogroup M through random genetic drift resulting from a bottleneck (i.e. a founder effect).

The group that crossed the Red Sea travelled along the coastal route around Arabia and Persia until reaching India. Haplogroup M is found in high frequencies along the southern coastal regions of Pakistan and India and it has the greatest diversity in India, indicating that it is here where the mutation may have occurred. Sixty percent of the Indian population belong to Haplogroup M. The indigenous people of the Andaman Islands also belong to the M lineage. The Andamanese are thought to be offshoots of some of the earliest inhabitants in Asia because of their long isolation from the mainland. They are evidence of the coastal route of early settlers that extends from India to Thailand and Indonesia all the way to eastern New Guinea. Since M is found in high frequencies in highlanders from New Guinea and the Andamanese and New Guineans have dark skin and Afro-textured hair, some scientists think they are all part of the same wave of migrants who departed across the Red Sea ~60,000 years ago in the Great Coastal Migration. The proportion of haplogroup M increases eastwards from Arabia to India; in eastern India, M outnumbers N by a ratio of 3:1. Crossing into Southeast Asia, haplogroup N (mostly in the form of derivatives of its R subclade) reappears as the predominant lineage. M is predominant in East Asia, but amongst Indigenous Australians, N is the more common lineage. This haphazard distribution of Haplogroup N from Europe to Australia can be explained by founder effects and population bottlenecks.

Autosomal DNA

The earliest-branching non-African paternal lineages (C, D, F) after the out-of-Africa event (a), and their deepest divergence among modern day East or Southeast Asia (b), suggesting rapid coastal expansions. Simplified Y-chromosome tree is shown as reference for colours.

A 2002 study of African, European, and Asian populations found greater genetic diversity among Africans than among Eurasians, and that genetic diversity among Eurasians is largely a subset of that among Africans, supporting the out-of-Africa model. A large study by Coop et al. (2009) found evidence for natural selection in autosomal DNA outside of Africa. The study distinguishes non-African sweeps (notably KITLG variants associated with skin color), West-Eurasian sweeps (SLC24A5) and East-Asian sweeps (MC1R, relevant to skin color). Based on this evidence, the study concluded that human populations encountered novel selective pressures as they expanded out of Africa.[102] MC1R and its relation to skin color had already been discussed by Harding et al. (2000), p. 1355. According to this study, Papua New Guineans continued to be exposed to selection for dark skin color so that, although these groups are distinct from Africans in other places, the allele for dark skin color shared by contemporary Africans, Andamanese and New Guineans is an archaism. Endicott et al. (2003) suggest convergent evolution. A 2014 study by Gurdasani et al. indicates that the higher genetic diversity in Africa was further increased in some regions by relatively recent Eurasian migrations affecting parts of Africa.

Pathogen DNA

Another promising route towards reconstructing human genetic genealogy is via the JC virus (JCV), a type of human polyomavirus which is carried by 70–90 percent of humans and which is usually transmitted vertically, from parents to offspring, suggesting codivergence with human populations. For this reason, JCV has been used as a genetic marker for human evolution and migration. This method does not appear to be reliable for the migration out of Africa; in contrast to human genetics, JCV strains associated with African populations are not basal. From this Shackelton et al. (2006) conclude that either a basal African strain of JCV has become extinct or that the original infection with JCV post-dates the migration from Africa.

Admixture of archaic and modern humans

Evidence for archaic human species (descended from Homo heidelbergensis) having interbred with modern humans outside of Africa, was discovered in the 2010s. This concerns primarily Neanderthal admixture in all modern populations except for Sub-Saharan Africans but evidence has also been presented for Denisova hominin admixture in Australasia (i.e. in Melanesians, Aboriginal Australians and some Negritos). The rate of Neanderthal admixture to European and Asian populations as of 2017 has been estimated at between about 2–3%.

Archaic admixture in some Sub-Saharan African populations hunter-gatherer groups (Biaka Pygmies and San), derived from archaic hominins that broke away from the modern human lineage around 700,000 years ago, was discovered in 2011. The rate of admixture was estimated at 2%. Admixture from archaic hominins of still earlier divergence times, estimated at 1.2 to 1.3 million years ago, was found in Pygmies, Hadza and five Sandawe in 2012.

From an analysis of Mucin 7, a highly divergent haplotype that has an estimated coalescence time with other variants around 4.5 million years BP and is specific to African populations, it is inferred to have been derived from interbreeding between African modern and archaic humans.

A study published in 2020 found that the Yoruba and Mende populations of West Africa derive between 2% and 19% of their genome from an as-yet unidentified archaic hominin population that likely diverged before the split of modern humans and the ancestors of Neanderthals and Denisovans.

Stone tools

In addition to genetic analysis, Petraglia et al. also examines the small stone tools (microlithic materials) from the Indian subcontinent and explains the expansion of population based on the reconstruction of paleoenvironment. He proposed that the stone tools could be dated to 35 ka in South Asia, and the new technology might be influenced by environmental change and population pressure.

History of the theory

Classical paleoanthropology

The frontispiece to Huxley's Evidence as to Man's Place in Nature (1863): the image compares the skeleton of a human to other apes.
The possibility of an origin of L3 in Asia was proposed by Cabrera et al. (2018).
a: Exit of the L3 precursor to Eurasia. b: Return to Africa and expansion to Asia of basal L3 lineages with subsequent differentiation in both continents.

The cladistic relationship of humans with the African apes was suggested by Charles Darwin after studying the behaviour of African apes, one of which was displayed at the London Zoo. The anatomist Thomas Huxley had also supported the hypothesis and suggested that African apes have a close evolutionary relationship with humans. These views were opposed by the German biologist Ernst Haeckel, who was a proponent of the out-of-Asia theory. Haeckel argued that humans were more closely related to the primates of South-east Asia and rejected Darwin's African hypothesis.

In The Descent of Man, Darwin speculated that humans had descended from apes, which still had small brains but walked upright, freeing their hands for uses which favoured intelligence; he thought such apes were African:

In each great region of the world the living mammals are closely related to the extinct species of the same region. It is, therefore, probable that Africa was formerly inhabited by extinct apes closely allied to the gorilla and chimpanzee; and as these two species are now man's nearest allies, it is somewhat more probable that our early progenitors lived on the African continent than elsewhere. But it is useless to speculate on this subject, for an ape nearly as large as a man, namely the Dryopithecus of Lartet, which was closely allied to the anthropomorphous Hylobates, existed in Europe during the Upper Miocene period; and since so remote a period the earth has certainly undergone many great revolutions, and there has been ample time for migration on the largest scale.

— Charles Darwin, Descent of Man

In 1871, there were hardly any human fossils of ancient hominins available. Almost fifty years later, Darwin's speculation was supported when anthropologists began finding fossils of ancient small-brained hominins in several areas of Africa (list of hominina fossils). The hypothesis of recent (as opposed to archaic) African origin developed in the 20th century. The "recent African origin" of modern humans means "single origin" (monogenism) and has been used in various contexts as an antonym to polygenism. The debate in anthropology had swung in favour of monogenism by the mid-20th century. Isolated proponents of polygenism held forth in the mid-20th century, such as Carleton Coon, who thought as late as 1962 that H. sapiens arose five times from H. erectus in five places.

Multiregional origin hypothesis

The historical alternative to the recent origin model is the multiregional origin of modern humans, initially proposed by Milford Wolpoff in the 1980s. This view proposes that the derivation of anatomically modern human populations from H. erectus at the beginning of the Pleistocene 1.8 million years BP, has taken place within a continuous world population. The hypothesis necessarily rejects the assumption of an infertility barrier between ancient Eurasian and African populations of Homo. The hypothesis was controversially debated during the late 1980s and the 1990s. The now-current terminology of "recent-origin" and "Out of Africa" became current in the context of this debate in the 1990s. Originally seen as an antithetical alternative to the recent origin model, the multiregional hypothesis in its original "strong" form is obsolete, while its various modified weaker variants have become variants of a view of "recent origin" combined with archaic admixture. Stringer (2014) distinguishes the original or "classic" Multiregional model as having existed from 1984 (its formulation) until 2003, to a "weak" post-2003 variant that has "shifted close to that of the Assimilation Model".

Mitochondrial analyses

In the 1980s, Allan Wilson together with Rebecca L. Cann and Mark Stoneking worked on genetic dating of the matrilineal most recent common ancestor of modern human populations (dubbed "Mitochondrial Eve"). To identify informative genetic markers for tracking human evolutionary history, Wilson concentrated on mitochondrial DNA (mtDNA), which is maternally inherited. This DNA material mutates quickly, making it easy to plot changes over relatively short times. With his discovery that human mtDNA is genetically much less diverse than chimpanzee mtDNA, Wilson concluded that modern human populations had diverged recently from a single population while older human species such as Neanderthals and Homo erectus had become extinct. With the advent of archaeogenetics in the 1990s, the dating of mitochondrial and Y-chromosomal haplogroups became possible with some confidence. By 1999, estimates ranged around 150,000 years for the mt-MRCA and 60,000 to 70,000 years for the migration out of Africa.

From 2000 to 2003, there was controversy about the mitochondrial DNA of "Mungo Man 3" (LM3) and its possible bearing on the multiregional hypothesis. LM3 was found to have more than the expected number of sequence differences when compared to modern human DNA (CRS). Comparison of the mitochondrial DNA with that of ancient and modern aborigines, led to the conclusion that Mungo Man fell outside the range of genetic variation seen in Aboriginal Australians and was used to support the multiregional origin hypothesis. A reanalysis of LM3 and other ancient specimens from the area published in 2016, showed it to be akin to modern Aboriginal Australian sequences, inconsistent with the results of the earlier study.

Y-chromosome analyses

Map of Y-chromosome haplogroups – dominant haplogroups in pre-colonial populations with proposed migrations routes

The Y chromosome, which is paternally inherited, does not go through much recombination and thus stays largely the same after inheritance. Similar to Mitochondrial Eve, this could be studied to track the male most recent common ancestor ("Y-chromosomal Adam" or Y-MRCA).

The most basal lineages have been detected in West, Northwest and Central Africa, suggesting plausibility for the Y-MRCA living in the general region of "Central-Northwest Africa".

A Stanford University School of Medicine study was done by comparing Y-chromosome sequences and mtDNA in 69 men from different geographic regions and constructing a family tree. It was found that the Y-MRCA lived between 120,000 and 156,000, and the Mitochondrial Eve lived between 99,000 and 148,000 years ago, which not only predates some proposed waves of migration, but also meant that both lived in the African continent around the same time period.

Another study finds a plausible placement in "the north-western quadrant of the African continent" for the emergence of the A1b haplogroup. The 2013 report of haplogroup A00 found among the Mbo people of western present-day Cameroon is also compatible with this picture.

The revision of Y-chromosomal phylogeny since 2011 has affected estimates for the likely geographical origin of Y-MRCA as well as estimates on time depth. By the same reasoning, future discovery of presently-unknown archaic haplogroups in living people would again lead to such revisions. In particular, the possible presence of between 1% and 4% Neanderthal-derived DNA in Eurasian genomes implies that the (unlikely) event of a discovery of a single living Eurasian male exhibiting a Neanderthal patrilineal line would immediately push back T-MRCA ("time to MRCA") to at least twice its current estimate. However, the discovery of a Neanderthal Y-chromosome by Mendez et al. was tempered by a 2016 study that suggests the extinction of Neanderthal patrilineages, as the lineage inferred from the Neanderthal sequence is outside of the range of contemporary human genetic variation. Questions of geographical origin would become part of the debate on Neanderthal evolution from Homo erectus.

Mitochondrial DNA

From Wikipedia, the free encyclopedia
Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles, found in most eukaryotic cells, are the powerhouse of the cell. The mitochondria, and thus mitochondrial DNA, are passed exclusively from mother to offspring through the egg cell.
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.

Mitochondrial DNA (mDNA or mtDNA) is the DNA located in the mitochondria organelles in a eukaryotic cell that converts chemical energy from food 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. 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.

Human mitochondrial DNA was the first significant part of the human genome to be sequenced. 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.

Since animal mtDNA evolves faster than nuclear genetic markers, 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

Nuclear and mitochondrial DNA are thought to have separate evolutionary origins, with the mtDNA derived from the circular genomes of bacteria engulfed by the ancestors of modern eukaryotic cells. This theory is called the endosymbiotic theory. In the cells of extant organisms, the vast majority of the proteins in the mitochondria (numbering approximately 1500 different types in mammals) are coded by nuclear DNA, but the genes for some, if not most, of them are thought to be of bacterial origin, having been transferred to the eukaryotic nucleus during evolution.

The reasons 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.

Genome structure and diversity

Across all organisms, there are six main mitochondrial genome types, classified by structure (i.e. circular versus linear), size, presence of introns or plasmid like structures, and whether the genetic material is a singular molecule or collection of homogeneous or heterogeneous molecules.

In many unicellular organisms (e.g., the ciliate Tetrahymena and the green alga Chlamydomonas reinhardtii), and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria), the mtDNA is linear 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 because many of these unicellular organisms with linear mtDNA are known pathogens.

Animals

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

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

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.

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).

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). In Fungi, however, there is no single gene shared among all mitogenomes. 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.

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.

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.

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

Replication

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The regulation of mitochondrial DNA replication and transcription initiation is located in a single intergenic noncoding region (NCR). In human, the 1,100 base pairs NCR region contains three promoters of two L-strand promoters (LSP and LSP2) and one H-strand promoter (HSP). 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.

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. 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. 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. According to Justin St. John and colleagues, "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."

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. Proteins that are employed in the maintenance of mitochondrial DNA are encoded by nuclear genes and translocated to the mitochondria. The mitochondria of human cells are capable of repairing DNA base pair mismatches by a pathway that is distinct from the DNA mismatch repair pathway of the nucleus. 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. 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.

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) up to 1,500,000 (oocytes).

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.

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 (overlap with MT-ND4) 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

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.

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. Transcription resulted in polycistronic transcripts that are processed in discrete mitochondrial RNA granules into individual mRNAs, tRNAs, and rRNAs.

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. 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.

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. Among the 12 tissues examined the highest level of expression was observed in the heart, followed by brain and steroidogenic tissue samples.

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. Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.

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), 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.

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

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. 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. 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. 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.

The mitochondrial bottleneck

Entities subject to 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 through a developmental process known as the mtDNA bottleneck. The bottleneck exploits random processes in the cell to increase 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 in which 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 the random partitioning of mtDNAs at cell divisions and the random turnover of mtDNA molecules within the cell.

Male inheritance

Male mitochondrial DNA inheritance has been 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. Rare cases of male mitochondrial inheritance have been documented in humans. 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. Paternally inherited mitochondria have additionally been reported in some insects such as fruit flieshoneybees, and periodical cicadas.

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.

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

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. mtDNA alterations can be detected in the bio-fluids of patients with cancer. 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. 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 an accelerated rate to 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. The application of a mitochondrial-specific ROS scavenger, which lead to a significant longevity of the mice studied, 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. 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. 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.

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. It has been proposed that aged mitochondria is the critical factor in the origin of neurodegeneration in Alzheimer's disease. 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.

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

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. 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.

Over the past decade, an Israeli research group led by Professor Vadim Fraifeld has shown that strong and significant correlations exist between the mtDNA base composition and animal species-specific maximum life spans. As demonstrated in their work, higher mtDNA guanine + cytosine content (GC%) strongly associates with longer maximum life spans across animal species. An additional observation is that the mtDNA GC% correlation with the maximum life spans is independent of the well-known correlation between animal species' metabolic rate and maximum life spans. The mtDNA GC% and resting metabolic rate explain the differences in animal species' maximum life spans in a multiplicative manner (i.e., species maximum life span = their mtDNA GC% * metabolic rate). To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built named MitoAge.

mtDNA mutational spectrum is sensitive to species-specific life-history traits

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. 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. An association between mtDNA mutational spectrum and species-specific life-history traits in mammals opens a possibility to link these factors together discovering new life-history-specific mutagens in different groups of organisms.

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, 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.

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 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.

mtDNA testing can be used by forensic scientists in cases where nuclear DNA is severely degraded. Autosomal cells only have two copies of nuclear DNA but can have hundreds of copies of mtDNA due to the multiple mitochondria present in each cell. This means highly degraded evidence that would not be beneficial for STR analysis could be used in mtDNA analysis. mtDNA may be present in bones, teeth, or hair, which could be the only remains left in the case of severe degradation. In contrast to STR analysis, mtDNA sequencing uses Sanger sequencing. 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. Cases arise where there are no known samples to collect and the unknown sequence can be searched in a database such as EMPOP. The Scientific Working Group on DNA Analysis Methods recommends three conclusions for describing the differences between a known mtDNA sequence and a questioned mtDNA sequence: exclusion for two or more differences between the sequences, inconclusive if there is one nucleotide difference, or inability to exclude if there are no nucleotide differences between the two sequences.

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

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.

In the 1998 United States 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, 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. This was the first trial in the U.S. to admit canine DNA.

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.

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.

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 nuclear genomes. 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.

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.

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.

  • AmtDB: a database of ancient human mitochondrial genomes.
  • InterMitoBase: an annotated database and analysis platform of protein-protein interactions for human mitochondria. (apparently last updated in 2010, but still available)
  • MitoBreak: the mitochondrial DNA breakpoints database.
  • MitoFish and MitoAnnotator: a mitochondrial genome database of fish. See also Cawthorn et al.
  • 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)
  • MitoSatPlant: Mitochondrial microsatellites database of viridiplantae.
  • MitoZoa 2.0: a database for comparative and evolutionary analyses of mitochondrial genomes in Metazoa. (no longer available)

MtDNA-phenotype association databases

Genome-wide association studies can reveal associations of mtDNA genes and their mutations with phenotypes including lifespan and disease risks. In 2021, the largest, UK Biobank-based, genome-wide association study of mitochondrial DNA unveiled 260 new associations with phenotypes including lifespan and disease risks for e.g. type 2 diabetes.

Mitochondrial mutation databases

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

Recent African origin of modern humans

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Recent_African_origin_of_modern_humans   Successive dispersals (l...