Y-chromosomal Adam

From Wikipedia, the free encyclopedia

In human genetics, the Y-chromosomal most recent common ancestor (Y-MRCA, informally known as Y-chromosomal Adam) is the most recent common ancestor (MRCA) from whom all currently living men are descended patrilineally. The term Y-MRCA reflects the fact that the Y chromosomes of all currently living human males are directly derived from the Y chromosome of this remote ancestor. The analogous concept of the matrilineal most recent common ancestor is known as "Mitochondrial Eve" (mt-MRCA, named for the matrilineal transmission of mtDNA), the most recent woman from whom all living humans are descended matrilineally. As with "Mitochondrial Eve", the title of "Y-chromosomal Adam" is not permanently fixed to a single individual, but can advance over the course of human history as paternal lineages become extinct.

Estimates of the time when Y-MRCA lived have also shifted as modern knowledge of human ancestry changes. In 2013, the discovery of a previously unknown Y-chromosomal haplogroup was announced, which resulted in a slight adjustment of the estimated age of the human Y-MRCA.

By definition, it is not necessary that the Y-MRCA and the mt-MRCA should have lived at the same time. While estimates as of 2014 suggested the possibility that the two individuals may well have been roughly contemporaneous (albeit with uncertainties ranging in the tens of thousands of years), the discovery of archaic Y-haplogroup has pushed back the estimated age of the Y-MRCA beyond the most likely age of the mt-MRCA. As of 2015, estimates of the age of the Y-MRCA range around 200,000 to 300,000 years ago, roughly consistent with the emergence of anatomically modern humans.

Y-chromosomal data taken from a Neanderthal from El Sidrón, Spain, produced a Y-T-MRCA of 588,000 years ago for neanderthal and Homo sapiens patrilineages, dubbed ante Adam and 275,000 years ago for Y-MRCA.

Definition

The Y-chromosomal most recent common ancestor is the most recent common ancestor of the Y-chromosomes found in currently living human males. 

Due to the definition via the "currently living" population, the identity of a MRCA, and by extension of the human Y-MRCA, is time-dependent (it depends on the moment in time intended by the term "currently"). The MRCA of a population may move forward in time as archaic lineages within the population go extinct: once a lineage has died out, it is irretrievably lost. This mechanism can thus only shift the title of Y-MRCA forward in time. Such an event could be due to the total extinction of several basal haplogroups. The same holds for the concepts of matrilineal and patrilineal MRCAs: it follows from the definition of Y-MRCA that he had at least two sons who both have unbroken lineages that have survived to the present day. If the lineages of all but one of those sons die out, then the title of Y-MRCA shifts forward from the remaining son through his patrilineal descendants, until the first descendant is reached who had at least two sons who both have living, patrilineal descendants. The title of Y-MRCA is not permanently fixed to a single individual, and the Y-MRCA for any given population would himself have been part of a population which had its own, more remote, Y-MRCA.

Although the informal name "Y-chromosomal Adam" is a reference to the biblical Adam, this should not be misconstrued as implying that the bearer of the chromosome was the only human male alive during his time. His other male contemporaries may also have descendants alive today, but not, by definition, through solely patrilineal descent; in other words, none of them have an unbroken male line of descendants (son's son's son's … son) connecting them to currently living people.

By the nature of the concept of most recent common ancestors, these estimates can only represent a terminus ante quem ("limit before which"), until the genome of the entire population has been examined (in this case, the genome of all living humans).

Age estimate

Estimates on the age of the Y-MRCA crucially depend on the most archaic known haplogroup extant in contemporary populations. As of 2018, this is haplogroup A00 (discovered in 2013). Age estimates based on this published during 2014–2015 range between 160,000 and 300,000 years, compatible with the time of emergence and early dispersal of Homo sapiens.

Method

In addition to the tendency of the title of Y-MRCA to shift forward in time, the estimate of the Y-MRCA's DNA sequence, his position in the family tree, the time when he lived, and his place of origin, are all subject to future revisions. 

The following events would change the estimate of who the individual designated as Y-MRCA was:

• Further sampling of Y chromosomes could uncover previously unknown divergent lineages. If this happens, Y-chromosome lineages would converge on an individual who lived further back in time.
• The discovery of additional deep rooting mutations in known lineages could lead to a rearrangement of the family tree.
• Revision of the Y-chromosome mutation rate (see below) can change the estimate of the time when he lived.

The time when Y-MRCA lived is determined by applying a molecular clock to human Y-chromosomes. In contrast to mitochondrial DNA (mtDNA), which has a short sequence of 16,000 base pairs, and mutates frequently, the Y chromosome is significantly longer at 60 million base pairs, and has a lower mutation rate. These features of the Y chromosome have slowed down the identification of its polymorphisms; as a consequence, they have reduced the accuracy of Y-chromosome mutation rate estimates.

Methods of estimating the age of the Y-MRCA for a population of human males whose Y-chromosomes have been sequenced are based on applying the theories of molecular evolution to the Y chromosome. Unlike the autosomes, the human Y-chromosome does not recombine often with the X chromosome during meiosis, but is usually transferred intact from father to son; however, it can recombine with the X chromosome in the pseudoautosomal regions at the ends of the Y chromosome. Mutations occur periodically within the Y chromosome, and these mutations are passed on to males in subsequent generations. 

These mutations can be used as markers to identify shared patrilineal relationships. Y chromosomes that share a specific mutation are referred to as haplogroups. Y chromosomes within a specific haplogroup are assumed to share a common patrilineal ancestor who was the first to carry the defining mutation. (This assumption could be mistaken, as it is possible for the same mutation to occur more than once.) A family tree of Y chromosomes can be constructed, with the mutations serving as branching points along lineages. The Y-MRCA is positioned at the root of the family tree, as the Y chromosomes of all living males are descended from his Y chromosome.

Researchers can reconstruct ancestral Y chromosome DNA sequences by reversing mutated DNA segments to their original condition. The most likely original or ancestral state of a DNA sequence is determined by comparing human DNA sequences with those of a closely related species, usually non-human primates such as chimpanzees and gorillas. By reversing known mutations in a Y-chromosome lineage, a hypothetical ancestral sequence for the MRCA, Y-chromosomal Adam, can be inferred. 

Determining the Y-MRCA's DNA sequence, and the time when he lived, involves identifying the human Y-chromosome lineages that are most divergent from each other—the lineages that share the fewest mutations with each other when compared to a non-human primate sequence in a phylogenetic tree. The common ancestor of the most divergent lineages is therefore the common ancestor of all lineages.

History of estimates

Early estimates of the age for the Y-MRCA published during the 1990s ranged between roughly 200 and 300 kya, Such estimates were later substantially revised downward, as in Thomson et al. 2000, which proposed an age of about 59,000. This date suggested that the Y-MRCA lived about 84,000 years after his female counterpart mt-MRCA (the matrilineal most recent common ancestor), who lived 150,000–200,000 years ago. This date also meant that Y-chromosomal Adam lived at a time very close to, and possibly after, the migration from Africa which is believed to have taken place 50,000–80,000 years ago. One explanation given for this discrepancy in the time depths of patrilineal vs. matrilineal lineages was that females have a better chance of reproducing than males due to the practice of polygyny. When a male individual has several wives, he has effectively prevented other males in the community from reproducing and passing on their Y chromosomes to subsequent generations. On the other hand, polygyny does not prevent most females in a community from passing on their mitochondrial DNA to subsequent generations. This differential reproductive success of males and females can lead to fewer male lineages relative to female lineages persisting into the future. These fewer male lineages are more sensitive to drift and would most likely coalesce on a more recent common ancestor. This would potentially explain the more recent dates associated with the Y-MRCA.

The "hyper-recent" estimate of significantly below 100 kya was again corrected upward in studies of the early 2010s, which ranged at about 120 kya to 160 kya. This revision was due to the discovery of additional mutations and the rearrangement of the backbone of the Y-chromosome phylogeny following the resequencing of Haplogroup A lineages. In 2013, Francalacci et al. reported the sequencing of male-specific single-nucleotide Y-chromosome polymorphisms (MSY-SNPs) from 1204 Sardinian men, which indicated an estimate of 180,000 to 200,000 years for the common origin of all humans through paternal lineage. or again as high as 180 to 200 kya. Also in 2013, Poznik et al. reported the Y-MRCA to have lived between 120,000 and 156,000 years ago, based on genome sequencing of 69 men from 9 different populations. In addition, the same study estimated the age of Mitochondrial Eve to about 99,000 and 148,000 years. As these ranges overlap for a time-range of 28,000 years (148 to 120 kya), the results of this study have been cast in terms of the possibility that "Genetic Adam and Eve may have walked on Earth at the same time" in the popular press.

The announcement of yet another discovery of a previously unknown lineage, haplogroup A00, in 2013, resulted in another shift in the estimate for the age of Y-chromosomal. Elhaik et al. (2014) dated it to between 163,900 and 260,200 years ago (95% CI). Karmin et al. (2015) dated it to between 192,000 and 307,000 years ago (95% CI). The same study reports that non-African populations converge to a cluster of Y-MRCAs in a window close to 50kya (out-of-Africa migration), and an additional bottleneck for non-African populations at about 10kya, interpreted as reflecting cultural changes increasing the variance in male reproductive success (i.e. increased social stratification) in the Neolithic.

Family tree

 

The revised root of the y-chromosome family tree by Cruciani et al. 2011 compared with the family tree from Karafet et al. 2008. This has been further expanded by the discoveries published by Mendez et al. in 2013.

 

Initial sequencing (Karafet et al., 2008) of the human Y chromosome suggested that two most basal Y-chromosome lineages were Haplogroup A and Haplogroup BT. Haplogroup A is found at low frequencies in parts of Africa, but is common among certain hunter-gatherer groups. Haplogroup BT lineages represent the majority of African Y-chromosome lineages and virtually all non-African lineages. Y-chromosomal Adam was represented as the root of these two lineages. Haplogroup A and Haplogroup BT represented the lineages of the two male descendants of Y-chromosomal Adam. 

Cruciani et al. 2011, determined that the deepest split in the Y-chromosome tree was found between two previously reported subclades of Haplogroup A, rather than between Haplogroup A and Haplogroup BT. Subclades A1b and A1a-T are now believed to descend directly from the root of the tree and now represent the lineages of Y-chromosomal Adam's two sons. The rearrangement of the Y-chromosome family tree implies that lineages classified as Haplogroup A do not necessarily form a monophyletic clade. Haplogroup A therefore refers to a collection of lineages that do not possess the markers that define Haplogroup BT, though Haplogroup A includes the most distantly related Y chromosomes. 

The M91 and P97 mutations distinguish Haplogroup A from Haplogroup BT. Within Haplogroup A chromosomes, the M91 marker consists of a stretch of 8 T nucleobase units. In Haplogroup BT and chimpanzee chromosomes, this marker consists of 9 T nucleobase units. This pattern suggested that the 9T stretch of Haplogroup BT was the ancestral version and that Haplogroup A was formed by the deletion of one nucleobase. Haplogroups A1b and A1a were considered subclades of Haplogroup A as they both possessed the M91 with 8Ts.

But according to Cruciani et al. 2011, the region surrounding the M91 marker is a mutational hotspot prone to recurrent mutations. It is therefore possible that the 8T stretch of Haplogroup A may be the ancestral state of M91 and the 9T of Haplogroup BT may be the derived state that arose by an insertion of 1T. This would explain why subclades A1b and A1a-T, the deepest branches of Haplogroup A, both possess the same version of M91 with 8Ts. Furthermore, Cruciani et al. 2011 determined that the P97 marker, which is also used to identify Haplogroup A, possessed the ancestral state in Haplogroup A but the derived state in Haplogroup BT.

Likely geographic origin

As current estimates on TMRCA converge with estimates for the age of anatomically modern humans and well predate the Out of Africa migration, geographical origin hypotheses continue to be limited to the African continent. 

According to Cruciani et al. 2011, 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".

Scozzari et al. (2012) agreed with 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. 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 Eve

From Wikipedia, the free encyclopedia

Haplogroup L
Possible time of origin	c. 100–230 kya
Possible place of origin	East Africa
Ancestor	n/a
Descendants	Mitochondrial macro-haplogroups L0, L1, and L5
Defining mutations	None

In human genetics, the Mitochondrial Eve (also mt-Eve, mt-MRCA) is the matrilineal most recent common ancestor (MRCA) of all currently living humans, i.e., the most recent woman from whom all living humans descend in an unbroken line purely through their mothers, and through the mothers of those mothers, back until all lines converge on one woman.

In terms of mitochondrial haplogroups, the mt-MRCA is situated at the divergence of macro-haplogroup L into L0 and L1–6. As of 2013, estimates on the age of this split ranged at around 150,000 years ago, consistent with a date later than the speciation of Homo sapiens but earlier than the recent out-of-Africa dispersal.

The male analog to the "Mitochondrial Eve" is the "Y-chromosomal Adam" (or Y-MRCA), the individual from whom all living humans are patrilineally descended. As the identity of both matrilineal and patrilineal MRCAs is dependent on genealogical history (pedigree collapse), they need not have lived at the same time. As of 2013, estimates for the age Y-MRCA are subject to substantial uncertainty, with a wide range of times from 180,000 to 580,000 years ago (with an estimated age of between 120,000 and 156,000 years ago, roughly consistent with the estimate for mt-MRCA.).

The name "Mitochondrial Eve" alludes to biblical Eve. This led to repeated misrepresentations or misconceptions in journalistic accounts on the topic. Popular science presentations of the topic usually point out such possible misconceptions by emphasizing the fact that the position of mt-MRCA is neither fixed in time (as the position of mt-MRCA moves forward in time as mitochondrial DNA (mtDNA) lineages become extinct), nor does it refer to a "first woman", nor the only living female of her time, nor the first member of a "new species".

History

Early research

Early research using molecular clock methods was done during the late 1970s to early 1980s. Allan Wilson, Mark Stoneking, Rebecca L. Cann and Wesley M. Brown found that mutation in human mtDNA was unexpectedly fast, at 0.02 substitution per base (1%) in a million years, which is 5–10 times faster than in nuclear DNA. Related work allowed for an analysis of the evolutionary relationships among gorillas, chimpanzees (common chimpanzee and bonobo) and humans. With data from 21 human individuals, Brown published the first estimate on the age of the mt-MRCA at 180,000 years ago in 1980. A statistical analysis published in 1982 was taken as evidence for recent African origin (a hypothesis which at the time was competing with Asian origin of H. sapiens).

1987 publication

By 1985, data from the mtDNA of 145 women of different populations, and of two cell lines, HeLa and GM 3043, derived from a Black American and a !Kung respectively, was available. After more than 40 revisions of the draft, the manuscript was submitted to Nature in late 1985 or early 1986 and published on 1 January 1987. The published conclusion was that all current human mtDNA originated from a single population from Africa, at the time dated to between 140,000 and 200,000 years ago.

The dating for "Eve" was a blow to the multiregional hypothesis, which was being controversially discussed at the time, and a boost to the theory of the recent origin model.

Cann, Stoneking and Wilson did not use the term "Mitochondrial Eve" or even the name "Eve" in their original paper; it appears to originate with a 1987 article in Science by Roger Lewin, headlined "The Unmasking of Mitochondrial Eve." The biblical connotation was very clear from the start. The accompanying research news in Nature had the title "Out of the garden of Eden." Wilson himself preferred the term "Lucky Mother"  and thought the use of the name Eve "regrettable." But the concept of Eve caught on with the public and was repeated in a Newsweek cover story (11 January 1988 issue featured a depiction of Adam and Eve on the cover, with the title "The Search for Adam and Eve"), and a cover story in Time on 26 January 1987.

Criticism and later research

Shortly after the 1987 publication, criticism of its methodology and secondary conclusions was published. Both the dating of mt-Eve and the relevance of the age of the purely matrilineal descent for population replacement was controversially discussed during the 1990s; Alan Templeton (1997) asserted that the study did "not support the hypothesis of a recent African origin for all of humanity following a split between Africans and non-Africans 100,000 years ago" and also did "not support the hypothesis of a recent global replacement of humans coming out of Africa."

Cann, Stoneking & Wilson (1987)'s placement of a relatively small population of humans in sub-Saharan Africa was consistent with the hypothesis of Cann (1982) and lent considerable support for the "recent out-of-Africa" scenario. 

In 1999 Krings et al. eliminated problems in molecular clocking postulated by Nei (1992)^{[citation needed]} when it was found that the mtDNA sequence for the same region was substantially different from the MRCA relative to any human sequence.

Although the original research did have analytical limitations, the estimate on the age of the mt-MRCA has proven robust. More recent age estimates have remained consistent with the 140–200 kya estimate published in 1987: A 2013 estimate dated Mitochondrial Eve to about 160 kya (within the reserved estimate of the original research) and Out of Africa II to about 95 kya. Another 2013 study (based on genome sequencing of 69 people from 9 different populations) reported the age of Mitochondrial Eve between 99 to 148 kya and that of the Y-MRCA between 120 and 156 kya.

Female and mitochondrial ancestry

Through random drift or selection the female-lineage will trace back to a single female, such as Mitochondrial Eve. In this example over five generations colors represent extinct matrilineal lines and black the matrilineal line descended from mtDNA MRCA.

 

Without a DNA sample, it is not possible to reconstruct the complete genetic makeup (genome) of any individual who died very long ago. By analysing descendants' DNA, however, parts of ancestral genomes are estimated by scientists. Mitochondrial DNA (mtDNA) and Y-chromosome DNA are commonly used to trace ancestry in this manner. mtDNA is generally passed un-mixed from mothers to children of both sexes, along the maternal line, or matrilineally. Matrilineal descent goes back to our mothers, to their mothers, until all female lineages converge. 

Branches are identified by one or more unique markers which give a mitochondrial "DNA signature" or "haplotype" (e.g. the CRS is a haplotype). Each marker is a DNA base-pair that has resulted from an SNP mutation. Scientists sort mitochondrial DNA results into more or less related groups, with more or less recent common ancestors. This leads to the construction of a DNA family tree where the branches are in biological terms clades, and the common ancestors such as Mitochondrial Eve sit at branching points in this tree. Major branches are said to define a haplogroup (e.g. CRS belongs to haplogroup H), and large branches containing several haplogroups are called "macro-haplogroups".

Simplified Human mitochondrial phylogeny

 

The mitochondrial clade which Mitochondrial Eve defines is the species Homo sapiens sapiens itself, or at least the current population or "chronospecies" as it exists today. In principle, earlier Eves can also be defined going beyond the species, for example one who is ancestral to both modern humanity and Neanderthals, or, further back, an "Eve" ancestral to all members of genus Homo and chimpanzees in genus Pan. According to current nomenclature, Mitochondrial Eve's haplogroup was within mitochondrial haplogroup L because this macro-haplogroup contains all surviving human mitochondrial lineages today, and she must predate the emergence of L0.

The variation of mitochondrial DNA between different people can be used to estimate the time back to a common ancestor, such as Mitochondrial Eve. This works because, along any particular line of descent, mitochondrial DNA accumulates mutations at the rate of approximately one every 3,500 years per nucleotide. A certain number of these new variants will survive into modern times and be identifiable as distinct lineages. At the same time some branches, including even very old ones, come to an end, when the last family in a distinct branch has no daughters. 

Mitochondrial Eve is the most recent common matrilineal ancestor for all modern humans. Whenever one of the two most ancient branch lines dies out, the MRCA will move to a more recent female ancestor, always the most recent mother to have more than one daughter with living maternal line descendants alive today. The number of mutations that can be found distinguishing modern people is determined by two criteria: firstly and most obviously, the time back to her, but secondly and less obviously by the varying rates at which new branches have come into existence and old branches have become extinct. By looking at the number of mutations which have been accumulated in different branches of this family tree, and looking at which geographical regions have the widest range of least related branches, the region where Eve lived can be proposed.

Popular reception and misconceptions

Newsweek reported on Mitochondrial Eve based on the Cann et al. study in January 1988, under a heading of "Scientists Explore a Controversial Theory About Man's Origins". The edition sold a record number of copies.

The popular name "mitochondrial Eve", of 1980s coinage, has contributed to a number of popular misconceptions. At first, the announcement of a "mitochondrial Eve" was even greeted with endorsement from young earth creationists, who viewed the theory as a validation of the biblical creation story.

Due to such misunderstandings, authors of popular science publications since the 1990s have been emphatic in pointing out that the name is merely a popular convention, and that the mt-MRCA was not in any way the "first woman". Her position is purely the result of genealogical history of human populations later, and as matrilineal lineages die out, the position of mt-MRCA keeps moving forward to younger individuals over time. 

In River Out of Eden (1995), Richard Dawkins discussed human ancestry in the context of a "river of genes", including an explanation of the concept of Mitochondrial Eve. The Seven Daughters of Eve (2002) presented the topic of human mitochondrial genetics to a general audience. The Real Eve: Modern Man's Journey Out of Africa" by Stephen Oppenheimer (2003) was adapted into a Discovery Channel documentary.

Not the only woman

One common misconception surrounding mitochondrial Eve is that since all women alive today descended in a direct unbroken female line from her, she must have been the only woman alive at the time. However, nuclear DNA studies indicate that the size of the ancient human population never dropped below tens of thousands. Other women living during Eve's time may have descendants alive today but not in a direct female line.

Not a fixed individual over time

The definition of mitochondrial Eve is fixed, but the woman in prehistory who fits this definition can change. That is, not only can our knowledge of when and where Mitochondrial Eve lived change due to new discoveries, but the actual mitochondrial Eve can change. The mitochondrial Eve can change, when a mother-daughter line comes to an end. It follows from the definition of Mitochondrial Eve that she had at least two daughters who both have unbroken female lineages that have survived to the present day. In every generation mitochondrial lineages end – when a woman with unique mtDNA dies with no daughters. When the mitochondrial lineages of daughters of mitochondrial Eve die out, then the title of "Mitochondrial Eve" shifts forward from the remaining daughter through her matrilineal descendants, until the first descendant is reached who had two or more daughters who together have all living humans as their matrilineal descendants. Once a lineage has died out it is irretrievably lost and this mechanism can thus only shift the title of "Mitochondrial Eve" forward in time. 

Because mtDNA mapping of humans is very incomplete, the discovery of living mtDNA lines which predate our current concept of "Mitochondrial Eve" could result in the title moving to an earlier woman. This happened to her male counterpart, "Y-chromosomal Adam," when older Y lines from Africa were discovered.

Not necessarily a contemporary of "Y-chromosomal Adam"

Sometimes mitochondrial Eve is assumed to have lived at the same time as Y-chromosomal Adam (from whom all living people are descended patrilineally), and perhaps even met and mated with him. Even if this were true, which is currently regarded as highly unlikely, this would only be a coincidence. Like mitochondrial "Eve", Y-chromosomal "Adam" probably lived in Africa. A recent study (March 2013) concluded however that "Eve" lived much later than "Adam" – some 140,000 years later. (Earlier studies considered, conversely, that "Eve" lived earlier than "Adam".) More recent studies indicate that mitochondrial Eve and Y-chromosomal Adam may indeed have lived around the same time.

Not the most recent ancestor shared by all humans

Mitochondrial Eve is the most recent common matrilineal ancestor, not the most recent common ancestor. Since the mtDNA is inherited maternally and recombination is either rare or absent, it is relatively easy to track the ancestry of the lineages back to a MRCA; however, this MRCA is valid only when discussing mitochondrial DNA. An approximate sequence from newest to oldest can list various important points in the ancestry of modern human populations:

• The human MRCA. Monte Carlo simulations suggest the MRCA was born surprisingly recently, perhaps even within the last 5,000 years, even for people born on different continents.
• The identical ancestors point. Just a few thousand years before the most recent single ancestor shared by all living humans was the time at which all humans who were then alive either left no descendants alive today or were common ancestors of all humans alive today. In other words, "each present-day human has exactly the same set of genealogical ancestors" alive at the "identical ancestors point" in time. This is far more recent than when Mitochondrial Eve lived.
• Mitochondrial Eve, the most recent female-line common ancestor of all living people.
• "Y-chromosomal Adam", the most recent male-line common ancestor of all living people.

Huntingtin

From Wikipedia, the free encyclopedia

 

HTT
Available structures PDB Ortholog search: PDBe RCSB

Identifiers
Aliases	HTT, HD, IT15, huntingtin, LOMARS
External IDs	OMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT

Gene location (Human) Chr. Chromosome 4 (human) Band 4p16.3 Start 3,041,422 bp End 3,243,960 bp

RNA expression pattern More reference expression data

Gene ontology
Orthologs
Species	Human	Mouse
Entrez	3064	15194
Ensembl	ENSG00000197386	ENSMUSG00000029104
UniProt	P42858	P42859
RefSeq (mRNA)	NM_002111	NM_010414
RefSeq (protein)	NP_002102	NP_034544
Location (UCSC)	Chr 4: 3.04 – 3.24 Mb	Chr 5: 34.76 – 34.91 Mb

The huntingtin gene, also called the HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene, which codes for a protein called the huntingtin protein. The gene and its product are under heavy investigation as part of Huntington's disease clinical research and the suggested role for huntingtin in long-term memory storage.

It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), it contains more than 36 glutamine residues (highest reported repeat length is about 250). Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.

The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may or may not be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between seven and 35 repeats.

The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.

Protein

Function

The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents. Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined. From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules. These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the trafficking of materials into a cell. Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.

Interactions

Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125). Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.

Interacting Protein	PolyQ length dependence	Function
α-adaptin C/HYPJ	Yes	Endocytosis
Akt/PKB	No	Kinase
CBP	Yes	Transcriptional co-activator with acetyltransferase activity
CA150	No	Transcriptional activator
CIP4	Yes	cdc42-dependent signal transduction
CtBP	Yes	Transcription factor
FIP2	Not known	Cell morphogenesis
Grb2	Not known	Growth factor receptor binding protein
HAP1	Yes	Membrane trafficking
HAP40	Not known	Unknown
HIP1	Yes	Endocytosis, proapoptotic
HIP14/HYP-H	Yes	Trafficking, endocytosis
N-CoR	Yes	Nuclear receptor co-repressor
NF-κB	Not known	Transcription factor
p53	No	Transcription factor
PACSIN1	Yes	Endocytosis, actin cytoskeleton
PSD-95	Yes	Postsynaptic Density 95
RasGAP	Not known	Ras GTPase activating protein
SH3GL3	Yes	Endocytosis
SIN3A	Yes	Transcriptional repressor
Sp1	Yes	Transcription factor

Huntingtin has also been shown to interact with:

• HIP2,
• MAP3K10,
• OPTN,
• PRPF40A,
• RASA1,
• SETD2,
• TRIP10,
• ZDHHC17.

Mitochondrial dysfunction

Mutant Huntingtin protein plays a key role in mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress. Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology.

Clinical significance

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats

Repeat count	Classification	Disease status
<26 span="">	Normal	Unaffected
27–35	Intermediate	Unaffected
36–40	Reduced penetrance	+/- Affected
>40	Full penetrance	Affected

Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein. These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects. However, 36 or more residues produce an erroneous form of Htt, "mHtt" (standing for mutant Htt). Reduced penetrance is found in counts 36-39.

Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease. Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons. Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin. This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.

As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.