My origins in time and space
Esta es mi historia
Mtdna haplogroup B
I'm mtdna haplogroup B and these are my markers
HVR-1 region:
16183 Substitution A > c 16189 Substitution T > c 16217 Substitution T > c 16519 Substitution T > c
HVR-2 region:
73 Substitution A > g 263 Substitution A > g 309 Insertion C 315 Insertion C
These are my backbone results:
2352 T > C T Negative
3594 C > T C Negative
3693 G > A G Negative
4312 C > T C Negative
4580 G > A G Negative
4833 A > G A Negative
5178 C > A C > T C Negative
7028 C > T T Positive
7055 A > C A > G A Negative
7598 G > A G Negative
8618 T > C T Negative
10086 A > G A Negative
10310 G > A G Negative
10400 C > T C Negative
10873 T > C T Negative
11251 A > G A Negative
11719 G > A A Positive
12308 A > G A Negative
12705 C > T C Negative
14766 C > T T Positive
=====================================
THIS IS MY STORY
My maternal family originated in Africa 150,000n years ago from the human mitochondrial Eve as haplogroup L
By following the herds of animals through Africa, they moved to the middle east, becoming mtdna haplogroup R
Then they had another mutation in central Asia, turning into mtdna haplogroup N
60,000 years ago a woman called Ina (My direct ancestor) had some daughters (One of them had to be my great, great, great, etc, grandmother) with a new mutation, giving birth to the mtdna haplogroup B.
After trekking along Siberia amidst the ice age as mtdna haplogroup B, my folks crossed the Straight of Bering about 12,000 years ago.
Then they went along North America, and central America until reaching Colombia, the country of my ancestors.
Mis familiares maternos se originaron de la Eva cientifica en Africa hace 150,000 años, como haplogrupo L
Pero se fueron al medio oriente, caminando o a caballo, donde se volvieron haplogrupo R.
Luego se fueron al Asia Central, donde tuvieron otra mutacion y pasaron a ser haplogrupo N
Hace 60,000 años, una mujer que han llamado Ina (mi antepasada directa) tuvo hijas con las mutaciones del mtdn haplogroup B, tambien mis antepasadas.
Unas de las antepasadas de esas hijas (mis tatatatatarabuelas) cruzaron con sus familias el Estrecho de Bering hace 12,000 años, llegando a Norteamerica donde permanecieron por algun tiempo.
Entonces se fueron en lancha o caminando a lo largo de America hasta llegar a Colombia, la tierra de mis antepasados.
Mis antepasadas tuvieron muchas descendientes y otras cuantas mutaciones hasta que un dia naci yo como mtdna haplogroup B 2
These are the pictures of my mtdna haplogroup B family
Alfinger and the conquest of Santander
Ambrosio Ehinger o Alfinger
(2) En 1529 desembarcaron en Coro-Venezuela, Ambrosio Ehinger o Alfinger (1500-1533) y Bartolomé Seyler, con 400 hombres, y el poco oro que llegaron a recolectar no compensó las terribles odiseas que vivieron en estas zonas americanas. La exploración del río Orinoco por Diego de Ordaz, antiguo camarada de Hernán Cortes; la posterior expedición de Gerónimo Dortal así como la de Sebastián de Belacazár, procedente de Quito; la de Jorge de Speyer, que recorrió las terribles Maniguas existentes entre el Orinoco y el Amazonas, y la de Phillipe Von Hutten, que duró tres años y la organizo el primer virrey del Perú don Antonio de Mendoza, constituida por una turba de malhechores, que dejó tras de sí luego de infinitas aventuras en los brazos de la jungla, junto con una ola de crímenes que termino con la conquista de la meseta de nueva Granada por Gonzalo Jiménez de Quesada, y que obedecieron al propósito de localizar el sitio del El Dorado.
 |  | |
Diego de Ordaz (1480-1532) | Philipp von Hutten (1505-1546) |
Este último logró triunfar ya que luego de vencer a los Indios Muyscas, les arrebató metales preciosos por el valor de 246.976 pesos de oro y 1815 esmeraldas de gran tamaño. Halló así mismo el verdadero sitio del hombre Dorado, visitó la laguna de Guatavita, pero no halló al famoso príncipe del mito. Un eco de la leyenda original de El dorado es la existencia de la ciudad de oro llamada Meta, buscada afanosamente por algunos de los mencionados exploradores, y por Francisco Pizarro. La desastrosa expedición de Gonzalo Pizarro por las selvas del Amazonas, tenía por objetivo llegar a la "provincia de la Canela y al Lago de El Dorado", según informo al Rey el propio don Gonzalo.
Mitochondrial Eve
Mitochondrial Eve (mt-mrca) is the name given by researchers to the woman who is defined as the matrilineal most recent common ancestor (MRCA) for all currently living
humans. Passed down from mother to offspring, derivatives of her mitochondrial DNA
(mtDNA) are now found in all living humans: all mtDNA in every living person is derived from hers. Mitochondrial Eve is the female counterpart of Y-chromosomal Adam
, the patrilineal most recent common ancestor, although they lived at different times.
Mitochondrial Eve is believed to have lived between 150,000 to 250,000 years BP
, probably in East Africa
, in the region of Tanzania
and areas to the immediate south and west.
The individual lived during a period of time when Homo sapiens were developing as a species separate from other hominid species. As an individual she lived in a small population (between 4000 and 5000 females capable of producing offspring at any given time). Mitochondrial Eve would have been roughly contemporary with humans whose fossils have been found in Ethiopia
near the Omo river
and at Hertho
. Mitochondrial Eve lived significantly earlier than the out of Africa migration which might have occurred some 95,000 – 60,000 years ago. However, Qafzeh
-type anatomically modern humans
have been noted in Western Asia as early as 125,000 years ago and their lithic culture was continuous from 200,000 years ago. Also, few archaeological sites in Asia suggest migration beyond South Asia occurred more than 76,000 years ago.
For more information on the principles involved, see matrilineal descent and genetic genealogy (matrilineal).
To find the Mitochondrial Eve of all living humans, one can start by tracing a line from every individual to his/her mother, then continue those lines from each of those mothers to their mothers and so on, effectively tracing a family tree backward in time based purely on mitochondrial lineages. Going back through time these mitochondrial lineages will converge on one maternal ancestor.
This female, nick-named 'Eve', was of interest because she bore a mitochondrial genome (mitogenome) which was the template
for all later human mitogenomes. But each human genome bears mutations that have replaced nucleotides on the original template with a different nucleotide (or in some cases added or removed nucleotides). Mitogenomes are passed from mother to offspring, with very few exceptions—only rarely will the father's mitochondrial DNA persist long enough or in sufficient enough quantity to be passed to the germ cells of the offspring. Consequently, recombination (mixing) between paternal and maternal mitogenomes is not observed as with autosomal and X-chromosomes. All complex animals can also trace their ancestry back to a mitochondrial MRCA. Chimps and humans share a mitochondrial MRCA; farther back in time, the human/chimp MRCA and Gorillas share an earlier mitochondrial MRCA.
Mitochondria becomes all but clonal (an exact copy each time they replicate) rapidly since fruitful genetic information exchange is prevented by host biology. On rare occasion, about once every 10,000 years a stable mutation occurs in a female that is passed to a female offspring and thus can be passed to subsequent generations.. At the time of the mitogenomes MRCA a mutation occurred that created a split either within one of Eve's germ cells or within the mitochondria of a developing female offspring. This mutation distinguishes between proto-L0
lineages from proto-L1
lineages, and began the two basal branches of human mitochondrial DNA, L0 and L1. It is unknown which of these lines split from the ancestral line as both early lineages accumulated multiple mutations after this split occurred but before the next major extant branches split, hence both lines are derivatives of the ancestral mitogenomic sequence.
Coalescence time is a measure of the average genetic distance of genes in the extant populations to predicted sequence of the mtDNA MRCA. The estimated time is also known as TMRCA (time to most recent common ancestor). TMRCA are useful because they can be used with other sources of information to describe ancient population structures. TMRCA can also be used to corroborate with archaeological studies to indicate possible places and cultures of humans' ancient ancestors.
The coalescence studies of human mitogenomes has produced a current best estimate (as of 2007) of the TMRCA of the L0/L1 split in modern humans to 194,300 ± 32,500 years BP. According to coalescent theory this would place the number of females in the effective population at below 5000 females. The two most recent studies of the deepest branches of mtDNA place the deepest well of diversity in Tanzania
Coalescence theory is the application of different mathematical/statistical products of gene-sequence evaluation to create statistics about a population. This process requires:
Based on the TMRCA and branching structure of the parsimony tree over time and geographic space these secondary products can be estimated:
There are many potential difficulties in calculating the TMRCA for mtDNA and the population size of the TMRCA. For the most simple analysis, the genetic distance between chimps and human, the path that goes from any extant human, though the human mitogenomic MRCA to the C/H LCA back to the chimpanzee mitogenomic MRCA and to individual chimpanzees based on an anchored LCA time. Within the region of interest single nucleotide polymorphisms (SNPs) are counted. The number of SNPs are divided by the LCA time and sequence length to arrive at a rate per site per year [rate = SNPs / (LCA Time * sequence length)]. This rate is preferably converted to rate per generations by multiply the rate by generation times. Correct rates of change strongly depend on the sequence one is examining. Therefore, one can sort SNPs by rates at sites divide that by the number of sites in the rate class and the mean rate of the rate class (see Gonder et al. 2007). Deriving the parameters for the rate equation is complex (see below).
The techniques used by different studies are important, as they reflect highly on how TMRCA can be compared.
Humans are sexually reproducing
organism
s composed of two dimorphic sexes
. Individuals with mammalian species
cannot create exact duplicates of themselves. Instead, each individual passes ~1/2 of their genetic makeup to offspring with their mate contributing the other half.In humans all of the mtDNA come from the female parent, female offspring get an equal number of X chromosomes from each parent, males get on X chromosome from the female parent and a Y from the male parent. In humans the portion of mtDNA from the male parent is very low to none, this may include, very rarely a gene-convertant (short-distant recombinant) between the male a female parent Through offspring production, individuals increase their genetic representation in the next generation, increasing the probability that more of their genes will be passed.
For MtDNA, mitochondria are passed overwhelmingly from mother to child. Female lineages effectively carry mtDNA genes. Since female or male offspring are produced randomly at a 1:1 ratio, when a mother passes a new mtNDA mutation to her offspring there is random risk that the new mtDNA mutation will be lost in the first generation (see Table on right). There is a lag time between the appearance of a mutation and probabilities above 0 that the new allele might fix, and after that time a defined distribution (see figure:Most likely time in generations to fixation).This is described by Kimura and Wright as a Markov chain
process, this process begins with 100% of an allele at absolute frequency of 1 (relative frequency = 1/2N), if the gene is excluded or fixes the Markov chain ends, but for all frequencies between 0 and 2N. For example, if the parent generation has relative frequencies of .1, .2, and .1 at absolute frequencies of 9,10, and 11, the probability of 12 individuals in the F1 generation would be 0.1*p(9->12) + 0.2*p(10->12) + 0.1*p(11->12) the calculation is performed for all possible absolute frequencies for the new generation based on frequecnies of the old generation and the new generation is replaced by to old and the process repeats This examination is called a forward-looking analysis, these predictions are based on observing population parameters while the population is evolving. It should be noted that the above is an idealization of a much more complex process. The following additional parameters should also be considered:
In molecular anthropology one is not examining a forward looking process, but the consequences of a process that has occurred in the past. In contrast to allele fixing, the coalescence is the interpretation of mutation quantification on related lineages. In sufficiently large populations, an allele that would otherwise displace all other alleles is prevented from fixing because new mutations are occurring on its own lineages. New mutations occur on the lineage before the allele fixes.
Even in large populations common lineages can be lost. At the time of mtDNA MRCA large numbers of females passed mtDNA to their female offspring, however because of genetic drift and time all of these other lineages have been excluded from the human population. Some of these other lineages had persisted for 1000s of years after mtDNA MRCA. Consequently because of coalescence there are some aspects of human evolution that are completely masked. Eve's mtDNA was not the only mtDNA when she lived, it was, in fact, one of the rarest mtDNA, because a fixation-like process masks other lineages we do not know how diverse, or how many variants existed.
The determination of coalescence time involves a set of assumptions that are subject to variance (e.g. generation times may change, mutation rates may change, male to female ratios may change, etc) that in a forward-looking investigation one could determine, but in a retrospective analysis one needs to assume. One of the most important assumptions made is the mutation rate, this mutation rate is based on the comparison of a sequence (in this case mitogenomes) between two species in which the geological age of last common ancestor is known. Population genetic diversity is measured by pairwise genetic comparison or parsimony analysis. Pairwise analysis, for example, arranges the sequences into a tree, and thus it is possible to measure the distance from any mtDNA sequence to a predicted sequence of the MRCA. With a neutral assumption, the observation of a MRCA sequence that joins the two deepest branches at a single point infers a MRCA time (TMRCA) and consequently also infers a population size probability distribution.
Calculating SNP rates between individuals of great genetic distanced (i.e. between species or genera) needs a temporal anchor, such as the geological age human-chimpanzee split, the last common ancestor (CHLCA). The CHLCA is frequently cited as an anchor for molecular TMRCA determination because Chimpanzee
s are the species most genetically similar to humans. However there are no known fossils that represent that CHLCA. White et al. (2009) suggested that errors and poor assumptions in previous studies predicted a recent LCA and that the CHLCA should be considerably older. Considering that the CHLCA vary widely, estimated mutation rates which are anchored in the CHLCA will also vary by the same relative percent. With the exception of the RFLP analysis (Cann et al. 1987), when comparing 2 TMRCA estimates for mtDNA, it is most important to remember that TMRCA is relative to the CHLCA, for example of TMRCA of 100,000 years using a 5 Ma CHLCA would become a TMRCA of 200,000 years using 10 Ma CHLCA.
In order to determine the timing of an evolutionary event such as the origins of the common ancestor of human beings living today for which the fossil record is incomplete, Zuckerkandl and Linus Pauling devised the hypothesis of the molecular clock
, which dates events based on analysis of change of molecular traits. Wilson and colleagues began applying this concept to mitochondrial DNA in the late 1970s and they found mtDNA mutates at a higher rate compared to nuclear DNA, so it gives researchers a more useful, magnified view of the diversity present in a population, and its history. Mitochondrial DNA nucleotides are variably functional. Some sites have never been observed to vary in any mammal, and some are known to vary within different samplings or the same individual. The mutation rate selected depends largely on the sites selected and the method for rate determination. Some have suggested a varying mutation rate or an inconsistent molecular clock.
The general methods of determining mutation rates, observing the appearance of new SNPs in the extant population or observing the number of mutations between two species and calculating the rates. Both methods have pitfalls. The first method is faulty because many mutations are negatively selective and over long time frames will be removed.In long term comparisons we would not see these mutations at the rate we see them in very short term comparisions On the other hand, over very long time frames mutations (particularly neutral sites) will revert, or homoplasies will make mutations harder to detect. Certain sites on MtDNA despite a high frequency of change are not used (i.e. masked) by many researchers, CRS 16129, CRS16183-16192 are two examples. Most current research is based on mutation analysis that anchored in paleontology, which means that the rate assumes that chimps and humans had a common ancestral mitogenome during a certain period of time. Gonder et al., for instance used an ancestor of 6.5 million years.
In addition to the temporal perspectives, there are three approaches that have been used with mtDNA to calculated the TMRCA: RFLP Analysis, HVR (D-loop approximates the MtDNA origin of replication and contains no coding sequence) and coding sequence (currently Genomic mtDNA) analysis. Restriction Fragment Length Polymorphism (RFLP) Analysis based the mutation rate on the perceived entry of humans into different parts of the world based on archaeological considerations. Hypervariable region
(HVR) analysis based the mutation rate on a distance between humans and chimpanzees. Because the mutation rate within the HVR region between humans and chimpanzees was so great, transition
:transversion
ratios were used to determine substitution rates, the ratio was established in old world monkeys (15:1)However the ratio observed in humans is higher(20:1), and in African apes is unknown, and the specific points in time when these rates have changed remains unknown. Mutations can reverse or recur on two different lineages over increased time frames and thus correction for homoplasies and reverse mutations may need to be made depending on the presumed rate at a site. Vigilant et al.(1991) corrected for this using transition to transversion ratio of 15:1 mapping the distance between chimpanzees and humans in transversions and then converting to transitions + transversions within the human population This ratio clocks the number of transversions observed was used to calculate the total number of transitions and transversions differences (169% of sites) which was divided time to determine the rate per site.
The use coding region was originally used with HVR because few had complete coding region sequence. There were suspicions that the HVR studies had missed major branches based on some earlier RFLP and coding region studies. The first study to compare genomic sequences (Ingman et al. 2000) for coalescence analysis. Coding region DNA has come under question because coding sequences are either under purifying selection to maintain structure and function, or under regional selection to evolve new capacities. Some newer studies propose using wobble positions and select HVR sites for MRCA and clade MRCA analysis. Some studies propose using these wobble positions and certain HVR sites, although deep analysis of mtDNA trees in theria
ns suggest that some wobble sites are not neutrally evolving, assessing neutrality of HVR sites deep in ape evolution is thwarted by deletions and insertions in those sites, and long branch distances (e.g. HVR1 is variously deleted in gorilla gorilla).
While genomic mtDNA studies may have weaknesses in calibrating the molecular clock, without doubt, the genomic mtDNA greatly improved the molecular phylogenetic understanding. HVR studies completely missed the basal branch of the mtDNA tree, macrohaplogroup L0 (L0) which had been intermingled with the branches of macrohaplogroup L1 (L1). Mitochondrial Eve's sequence is typically represented as the top root node of the human mitochondrial phylogenetic tree. The first split in the tree is found between L0 and L1. Because the genomic DNA resolved the two deepest branches and HVR marks an improved method for estimating TMRCA over HVR alone.
Population size estimates are one of the most important products of TMRCA determination. First, if one has a population size of X today, and Y say 10,000 years ago and Z 150,000 years ago, we can determine rates of growth in the population. Second, if Z is sufficiently large we might argue that Z was inclusive of all the similar morpho-metrically defined populations (i.e. fossil cousins) that existed at the time, but if Z is sufficiently small, one begin to look at the concept of speciation, the formation of a new species. In other words, the more that the boundaries of population size can be limited the more one is able to draw inferences about the population (its range, its location, its constituents).
Summarizing, the rate at which a new allele will eventually will displace all deeper branching clades and the time that it takes is a probabilistic function of the population structure and ploidy
based on forward looking statistics and modeling (Kimura, 1956). However estimating population size based on diversity and parsimonious trees is a backward-looking analysis. The two perspectives have markedly different results. The forward looking conclusion that TMRCA is a probabilistic function of population structure supports the inverse conclusion that population structure can be predicted, probabilistically, based on TMRCA. If TMRCA is converted to generations (TMRCA/(average generation time) = generations (Tg) then the generations to MRCA should equal 2 times the population size. Therefore . A simple example of this if TMRCA = 200,000 years, population size was constant, and generation time was 20 years, then N = 200,000/(20*2) = 5000 individuals.
For mtDNA one can expect all individuals to converge on a single point in generational time of 1/2N where Ne♀ is the average number of effectively reproducing females in the population at any given time. The relationship of TMRCA probabilities and population size is nearly linear. The relative variance is quite large and also nearly-linear (see figure Ne versus TMRCA = 200,000 years).For mtDNA TMRCA of 200,000 years and generation times of 20 years, one expects a constant population size of 1500 and 15000 individuals >95% of the time. Extrinsic factors (described above) affecting the TMRCA (e.g. inaccurate rates, inaccurate generation times, etc) and intrinsic factors can affect the accuracy of the determination.
Contrasting the forward-looking approach (above), the retrospective approach is heavily influenced by branching in several ways. The branching that creates accuracy in the TMRCA and, provided the rate determination is accurate, the points of branching within the trees increases the accuracy of size determination in population subsets. How this works, suppose we start at the present time, we see 1000s of branches, by analysis closest sister clades backwards. Each of those branches has a TMRCA and a variance. However for each interval backward one goes, the previous structure can be averaged and the standard variance decreases as a function of 1/(N^0.5). Therefore, if the tree has a great number of branches (as the mtDNA tree) the interpretation of TMRCA at given points becomes more a less a function of extrinsic variance, thus locking that portion of the tree in generations. Consequently there is more confidence about the when humans left Africa than about the time of the TMRCA.
For regions with unique sets of alleles population sizes can also be estimated. A divide and conquer strategy can be used to estimate population structure going backwards through time. A few examples from the literature, it was found that by examining the graves of the pre-westernized indigenous Andaman Islanders
that some peoples had deep mtDNA not found in other groups in surrounding regions, therefore isolation created a cluster, the cluster was estimated to be of age 65,000 years. In the Solomon Islands it was found that another isolated cluster had formed, of approximately 50,000 years in age. Both clusters represent branches of M or N lineages that are the cluster representing the mtDNA of most Exo-Africans (not of modern African origin). These clusters, by having multiple TMRCAs each statistically squeeze the time of exodus from Africa into SW Asia to a certain point, and also squeeze the female population sizes for the early settlers to a certain size. Going further backwards N and M, entered Eurasia at time point Tg. By examining both N and M we can argue their regional character (as ancient) and that archaeologically we can define time T as 100,000 (for simplicities sake), then to preserve the genetic structures population size on average is 100000/20*2 = 2500 individuals. Looking backward to 150,000 years ago that also preserved two branches LOd and LOk then that population had ~3750 females. As more of these regional branches are recognized and factored into the retrospective analysis the probability that all of these are at their low population limit decreases, and therefore the lower limits on size increase beyond the sum of cluster low limits. The branching structure however reaches a point within the human parsimonious tree that only one evident cluster remaines. At present this appears to be the time when L0k formed (~145,000 years ago) and beyond this earlier branching offers little evidence of population size.
To maintain balance with population spread and advance, the upper limit of the population size within the early period the mean estimate of early size may need to be decreased. For example, the alleles that spread to other regions, M and N to Asia with large population size cannot be excluded, and if these appear only in Asians then only the exclusion of L0 and deeper L1 branchpoints can occur. Likewise if the core population of humans was in Tanzania and the population expanded LOd, LOk into southern Africa, it becomes more difficult to exclude L0d and L0k and since L1 is protected by M and N (population sizes in Eurasia) and L0 is protected by L0d and L0k (population sizes in South Africa) neither can be excluded easily. Thus inflection of branching (or lack thereof) within a parsimonious tree plotted against time and space offers more detail on retrospective population stucture. If these branches are protected after globalization and isolation then populations that caused quasi-fixation of the MRCA must have occurred more rapidly than evident, and thus implying a smaller population size, however there are minimum constraints on lower size as one goes backwards to the MRCA (see grey area in figure), and these constraints are also notable in studies of other loci.
One of the most common measures implying structural changes are measures of selection. Selection in this context is not necessarily the same as positive selection in a competitive context. Fortuitous colonization of new territories by a small number of individuals can make unique alleles carried by those individuals appear selective to other individuals. If we apply this to humans, by creating a given in the argument that there was a place in Africa that was core to mtDNA of all humans and that there was at the geographic center of that core unique set of alleles. As the population expanded from the boundaries after the MRCA sequence had excluded all deeper branches then all the branches that expanded on the fringe would exhibit the appearance of positive selection relative to the allele that was unique to the central population. There are two measures of departure from Neutrality, the Tajima's D statistic and the D* and F* statistics of Fu and Li.
In the 1970s, early molecular biologist noted that some aspects of mitochondrial DNA, curiously, had a faster rate of evolution than the protein sequences commonly used at the time, and this might be useful in determining rates of evolution between individuals and species. In 1980, W.M. Brown, looking at the relative variation between human and other species, recognizes there was a constriction in the human population 180,000 years ago. A year later Brown and Wilson were looking at RFLP
fragments and determined the human population expanded more recently than other ape populations and noted that humans had the mtDNA diversity that was comparable to isolated subspecies of other apes. This study was followed by a more complete study by Cann et al. (1987) of RFLP fragments in larger numbers of Africans with early estimates of the TMRCA at 215 +/- 75 kya. Because these studies did not obtain SNP no rate estimate as described above could be made. Instead they used paleoanthropological evidence for human settlement in New Guinea, Australia and the New World allowing them to estimate the sequence divergence rate was 2 to 4% per million years(at the RFLP level). A hypothetical ancestor, type a, linked to all other extant sequences with a divergence rate of 0.57% would mean the TMRCA existed between 142,500 and 285,000 years ago. Another hypothetical ancestor c contained no known African ancestors and was between 90,000 and 180,000 years ago. Based on these and other early indirect studies Takahata estimated that the Ne, female was between 3,500 and 4,600 individuals.
In 1989, Linda Vigilant of A.C. Wilson
's group used PCR to amplify a region of hypervariability called the D-loop from the single hairs of southern African hunter-gatherers (!kung-San are a click speaking tribe of Namibia and neighboring Botswana). Sequencing this region was advantageous because the larger density of mutations meant they need only to sequence a few hundred nucleotides to obtain enough sequence to reliably demonstrate the level of diversity of humans, in addition at the time it was believed that this rapid rate of evolution was due to the d-loop regions neutrality. Two years later they used the same technique and an estimated chimp/human last common ancestor (CHLCA) of 4 to 6 million years to produced human mtDNA-TMRCA between 166,000 and 249,000 years. With more recent paleoanthrpological studies in Africa this CHLCA appears unlikely, and the use of the more likely 6 to 10 million year CHLCA would place this ancestor between 249,000 and 415,000 years.
Despite the improvements in the technique the approach was troubled. First, within the D-loop, 'hypervariable' region there are sites which evolve extremely rapidly it was later noted that the sequence was not evolving completely neutral manner. Other problems included an indirect method for deriving the mutation rate between chimps and humans, a C/H LCA that more recent than currently postulated. This did not determine the 'Vigilant' TMRCA 'date range' was incorrect, but that the range was likely wider than indicated in the publication.
Between 1991 and 2000 a number of additional studies were conducted, including studies that compared RFLP with HVR and partial genomic sequences with HVR. It became increasingly clear that there were problems with the phylogenetics created with HVR sequences. Other than the hyper-hypervariable sites, there appear to have been problems over how the base of the mtDNA tree was defined.
Advances in sequencing made it possible to sequence large numbers of genomic mitochondrial DNA (mitogenome). In 2000, Max Ingman analyzed the genomic sequences and provided the first sequences of the 53 mitogenomes. The TMRCA for humans was of 171,500 ± 50,000 years were less than previous studies, but not significantly so. The studies presented with an 'exodus' time from Africa in non-Africans of 52,000 years +/- 27,500 years (Both TMRCA are based on the Chimp human LCA of 5 million years). From this it can be inferred that Mitochondrial Eve had at least two daughters who survived to have their own children. Today L0 is restricted to African populations, whereas L1 is the ancestral haplogroup of all non-Africans, as well as most Africans. Mitochondrial Eve's sequence can be approximated by comparing a sequence from L0 with a sequence from L1. By reconciling the mutations in L0 and L1. The mtDNA sequences of contemporary human populations will generally differ from Mitochondrial Eve's sequence by about 50 mutations.
Despite some agreement with this date in some anthropological circles, there was concern that this date was too recent. A growing body of evidence from the Levant (Skhul and Qafzeh
), India, and China (LiuJiang) and Australia (Mungo Lake- LM3) that humans had migrated from Africa well before 52 kya.
Considering the C/H LCA calibration of the molecular clock, a higher-set confidence range (6.5 my C/H LCA) places the upper limit of confidence at 139,000 years ago. Of particular concern, however, is the recent finding that the oldest individuals at Skhul cave (Israel) are 100,000 to 135,000 years and the high end of Ingman's exoafrican TMRCA is 107,000. However, Tattersall and Schwartz (2008) recognize that some examples of late archaic homo sapiens may be better placed in other taxa as the Levant may not have been an early site of human occupation out of Africa. Rightmire (2009) associates archaic humans from Jebel Irhoud
(Morroco 160,000) in a Mousterian tool context with the early Skhul fossils and if this dating is correct (real date not less than the estimate) then it distances both Jebel Irhoud and the oldest Skhul fossils from the geographic limits of the constrict population. Because of the sample size this study failed to see evidence of selection or population size growth; however, coalescence theory predicts that under neutral models, current population size in Africa is far too great to explain coalescence as recent as 171,500 years ago without some selection.
Consequently, Gonder et al. (2006) group undertook mitogenomic sequencing in areas of Africa were previous studies indicated deep diversity. This new study found new lineages of African mtDNA and more importantly narrowed the region within Africa in which humans ancestors likely arose. This new study indicated that the TMRCA likely occurred between 160,000 to 226,000 years ago (but dates between 130,000 and 280,000 cannot be ruled out, the Chimp-Human mtDNA MRCA time was anchored at 6.5 million years). This improved study however is not without criticism, the authors pointed out that by one measure selection is acting on all mtDNA (except in the proposed core region, Tanzania) and another measure found non-neutrality in the evolution of all mtDNA. Since this study a number of papers have been published that try to explain the appearance of excessive numbers of coding region mutations relative to expectations, one hypothesis is that these are the result of 'purifying selection' that occurred as people migrated. Another hypothesis is that these occurred as a consequence of selective pressure. A subsequent study has stated the following concerning the age estimates We used the rate of 5138 years per coding region single nucleotide polymorphism to translate the age estimate in mutations into ages in years. It is worth noting that age estimates in years should be cautiously interpreted because the actual mutation rate in years per mutation remains an open debate in the literature.
The Khoisan population was closely examined in 2008, adding many more sequences. Behar et al.(2008) determined that other than the L0d and LOk mitogenomes in Khoisan, other genomes in the Khoisan appear to be the result of recent admixture, consequently they estimated that Khoisans separated from the core interbreeding population after both the L0d and L0k clades had formed, about 144,000 years ago +/-11,000 years. In as much as their evidence suggested very low geneflow between non-Khoisan females and Khoisan females for 10,000s of years it was no longer possible for a population constriction to fix mtDNA in both groups, the period of constrained population size had effectively ended.
The background for the interpretation of the mtDNA TMRCA are the numerous studies showing human-like fossils and bone remnants in Africa and Eurasia. These studies progress in concert with modern molecular genetics, with sequencing of ancient bone remnants becoming more common-place, particularly for Neandertals. Prior to the sequencing of the first Neandertal mtDNA, the TMRCA and PMRCA for modern humans set ancient humans apart from Neandertals. The current sequence of a number of Neanderthal mtDNA has reaffirmed that in the genus homo's recent past the female lineages of Neandertals and Humans existed in non-crossbreeding populations. Thus the implication of recent African origins 20 years ago set off one of the biggest battles in paleoanthropology, setting major players, such as Milford Wolpoff against molecular paleontologist such as AC Wilson.
However, despite the compatibility of TMRCAs/PMRCAs from Neandertals and Humans with a multiple species model, other genetic studies ambiguously supported this theory. Y chromosomal studies produced a TMRCA, at less than 50,000 years, this estimate occurred after humans had expanded. Studies of other loci presented with a wide variety of fixation times, from 0 to 2 million years. Others studies did not adequately sample in Africa and presented ambiguous PMRCA or PMRCA on other continents. Francisco Ayala tried to discredit the coalescent population size by arguing that the HLA-DRB1 locus had a TMRCA of 10s of millions of years.
One early oversight of many early studies is that the fixation of alleles (the object of coalescent theory study) is not a discrete mathematical function, it is a probabilistic function, and it is highly dependent on the ploidy being studied.
Takahata (1999) was the first molecular anthropologist to point out that conclusions drawn from single locus studies suffer from the large randomness of the fixation process. Schaffner (2004) has cleared up this issue by demonstrating the 3 sets of fixation ranges, haploid, X-linked and diploid where TMCRAs for different loci are expected to fall. Takahata (1993) estimated the effective human population size at 11,000 individuals, and Schaffner working on an improved set of X-linked markers from low recombination regions of the X-chromosome identified an effective size of approximately 12,000 individuals. PDHA1 falls on the edge of fixation times for X-linked chromosome. For autosomes, the MX1 locus and the HLA loci appear to preserve past diversity in the human population. With few exceptions however X-linked and autosomes appear to coalesce under a common populationsize, these exceptions, most of the quasi-neutral loci studied so far fall within the expected distributions of TMRCAs that can be anticipated by the 2N rule.
Just as mitochondria are inherited matrilineally, Y-chromosomes are inherited patrilineally. Y chromosomal TMRCA, the time of the Y-chromosomal Adam
, lie in the 42 to 110ky range, which is a little less than half the TMRCA of mtDNA. Importantly, the genetic evidence suggests that the most recent patriarch of all humanity is much more recent than the most recent matriarch, suggesting that 'Adam' and 'Eve' were not alive at the same time. While 'Eve' is believed to be alive 140,000 years ago, 'Adam' lived only 60,000 years ago. According to Wilder et al. (2004), the lower TMRCA of Y is due to an effective population size of males 1/2 that of females over most of human evolution. However, even with a reduced effective population size, given humans expanded out of Africa >60,000 years ago, the effective population of males would have to have been a small fraction of that of females to neutrally explain the recent fixation (see graph on right). A recent study of X-chromosome suggests that different rates of male sperm production between humans and chimps has altered the molecular clock in sex chromosomes.
The term bottleneck has been used to describe the population structure that created mtDNA Eve. The appearance of a bottleneck was a consequence of the appearance of a 'big bang' of HVR branching about the time humans first left Africa. From that point back to the TMRCA was less than 100,000 years and the population size estimate was below 5000 effective females. Looking backwards in time this is what might be called a retrograde bottleneck, however it is an artifact of fixation process, since the last quasi-fixation event (the event which initiated with mtDNA Eve and extended to the extant population) conceals the population size from all points earlier than that mutation (see figure Retrograde look at bottlenecks). The work done on Neanderthal sequencing (Green 2007) has identified little evidence of Neanderthal contribution to humans, moreover it describes an effective size of the population when humans and Neanderthals split was about 3000 individuals. Taken in the light of Schaffner's and Takahata's effective populations sizes, 3000 <>e, female <>e, male < 4000 does not appear to represent a magnitude shift downward from the average size. Taking a null hypothesis, prior to and after the mtDNA MRCA population sizes appear to reflect long-term small population structure up until 70,000~150,000 years ago, not a brief constricting bottleneck, but a long period of constrained size followed by an expansion.
Statistics does not require an alternative, bottleneck, hypothesis prior to the expansion, however, a bottleneck may have existed. If the population size were at 11,000 to 12,000 individuals, the Ne for mtDNA and Y in particular, is below the expected median TMRCAs (See image Above and on the left). The difference between X-linked/Autosome TMRCA and mtDNA/Y TMRCA is the former covers and averages events that occur over a 1+ million year time frames whereas the haploid TMRCA reflect more recent time frames. Y chromosome and mtDNA may be more representative of population structure immediately prior to expansion. The ability to mesh mtDNA coalescence and Y coalescence depend on a better understanding of male to female ratios in the late stone age and agreement TMRCA of Y chromosome, which is currently the subject of much critique. If these two loci could be treated together, they would likely fall significantly below the X-linked and Autosomal population sizes.
Moreover, the TMRCA calculations above frequently assume there have been no structural changes in Africa, even though the population size of Africa currently is several magnitudes higher than the predicted effective size by mitogenomic, Y , X-lined or autosomal DNA. Some models assumed much of the growth occurred recently, however inflection of lineage growth is evident in the mtDNA trees at approximately 100 to 150 thousand years ago. This becomes more so evident if the population assumption of Gonder. et al. (2007), that all lineages are under selection except a few in Tanzania, then the growth in human population size between 140 and 60kya may have effectively ended a constriction that could reasonably have excluded deep branches within the human mtDNA population. If so, this requires much lower population sizes to achieve fixation within a bottleneck, sizes 1/2 to 1/3 the effective sizes postulated by Shaffner and Takahata, might best fit the observations. The mtDNA TMRCA distribution is marginally within the statistical limits for haploid fixation even considering high effective number of females (See graph: Most probable number of effective females based on TMRCA). The Y-chromosomal TMRCA, however, is not (see left most part of above graph). Others have postulated that by some form of selection (hegemony, cultural, or genetic), the Y chromosome swept the population, and, if so, this would negate a joint treatment . The problem with this hypothesis however is that; if the TMRCA for Y occurred after mtDNA entered greater Africa or Eurasia as a consequence of expansion, then Y could have expanded from anywhere (Central Africa, North Africa, Eurasia). However, Y diversity is greatest in Southern Africa, within the two earliest demographic branches observed with mtDNA in Behar et al. 2009 suggesting the earliest branch in Y should be about 150,000 mtDNA years in age. This points to disagreement between calibrations/interpretation of the Y-chromosomal molecular clock and mtDNA molecular clock.
The principal philosophical battle between strict Out of Africa and Multiregional Evolution hypotheses revolves around the placement of humans at times during human evolution the singly interpretable result of mtDNA coalescence determined the battleground that would follow its presentation.
The strict Out of Africa model places humans in SSA or even more strictly, ~10,000 interbreeding individuals in a defined domain in sub-Saharan Africa. With this model, because all humans are in this domain as other hominids continue to evolve Eurasia and parts of Africa evolution occurred independently at some point when homo sapiens beings effectively became a new species of the archaic homo sapiens. As part of this model specific events happen, population remains in a contained region, and at some point expands, expands out of Africa, expands to most parts of Africa, and since other hominids are no longer apparent, probably took part in a global-'competitive' displacement.
The strict multiregional hypothesis on-the-other-hand has humans spread broadly across Africa, Eurasia, parts of Oceania. Humans interbreed overtime across long ranges, but modern humans primarily represent evolution in-situ. As part of this model the ice age ends allowing people to travel, agriculture increase population size, but people have largely evolved in place. Massive migrations and displacement would not explain genetic makeup.
If we assume that there were humans in NE China, central China, southern China, Sumatra, Flores Island, Europe, the Levant, North Africa and Subsaharan Africa, and assuming there were no other humans other (e.g. Narmada India) then effective sizes per known regions was about 103 effective females. In an area like sub-Saharan Africa this would mean that the density of humans would be on the order of individuals per 1000s of square miles.
The Out of Africa hypothesis asserts that human populations originated in a contained region and fits better the predicted population sizes, the more recent information on mtDNA found in Tanzania, and the evidence for an early branch that separated L0d and L0k from other L0 and L1 is suggestive of the power small migrations have on isolating peoples, this further argues for a contained geographic region in origin of modern humans. This constraint compresses population density by 2 magnitudes over the multiregional model and is comparable to densities of stone age peoples. Largely other genetic data support mtDNA, and thus multiregionalism has faded from the forefront of human evolution hypothesis and has been replaced by mostly Out of Africa hypothesis.
Homo sapiens
is assumed to have speciated from Homo heidelbergensis
in the period of 200–160 kya. The fact that Mitochondrial Eve happens to be dated to precisely this period has been taken as evidence of a population bottleneck
(e.g. Toba catastrophe theory
) giving rise to the human species. There are, however, many ways such family trees can be constructed. A tree can be constructed based on any gene, not just the mitochondrial DNA. When different such trees including the mtDNA tree are compared, no population bottleneck is found because different trees show different coalescent
points. The inconsistencies between coalescent points indicate that there had been numerous gene interchanges between population groups around the world, even after the first exodus out of Africa. This idea forms the basis of Alan Templeton
's 'Out of Africa Again and Again' theory.
The Mitochondrial DNA provides another support for the Out of Africa hypothesis in the form of gene diversity. One finding not subject to interpretation is that the greatest diversity of mitochondrial DNA sequences exists among Africans. This diversity is believed to have accumulated because humans have been living longer in Africa than anywhere. Family trees (or "phylogenies
") constructed on the basis of mitochondrial DNA comparisons show that the living humans whose mitochondrial lineages branched earliest from the tree (L0
) are prevalent among the San and the Mbuti
people. The subsequent branches of L1
, L2
and L3
are also largely confined to Africa, while only the macrogroups M
and N
, descended from L3, participated in the ancient migration(s) out of Africa.
Mitochondrial Eve is the most recent common matrilineal
ancestor, not the MRCA
. Since the mtDNA are 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 only valid when discussing mitochondrial DNA. Ironically mtDNA are not human, they are organelles that live within our cells, so it is better to say these are human-mitochondrial Most Recent Common Ancestor. Despite the recent fixation of the mtDNA genome in humans, other genes have evolved that were broadly selective in the human population, these genes have swept through the human population, two such genes have been identified on the X-chromosome.
Other studies have indicated the overwhelming majority of humans have a recent common ancestor within the last 5000 years (albeit between any two individuals it may not be the same ancestor), however the genetic relationship between well diverged individuals may not reflect the theoretical relationship, as geographic and cultural barriers may slow geneflow. Gene flow is not fluid in humans, genes are passed in units called chromosomes, which undergo limited number of recombination on each unit per generation, therefore a common ancestor genealogically may not indicate the passage of DNA from that ancestor to the two divergent individuals. Whereas since mtDNA does not undergo this dilution via recombination, we can argue that the majority of mtDNA sequence (that which has not undergone mutation) from mtDNA ~16000 nts came from a single individual >150,000 years ago. A more recent common ancestor for all Males is the much larger Y chromosome (however it codes for very few genes).
Allan Wilson
's naming Mitochondrial Eve after Eve
of the Genesis creation account
has led to some misunderstandings among the general public. A common misconception is that Mitochondrial Eve was the only living human female of her time.
Indeed, not only were many women alive at the same time as Mitochondrial Eve but many of them have living descendants through their sons. While the mtDNA of these women is gone, their Nuclear genes are present in today's population.
What distinguishes Mitochondrial Eve (and her matrilineal ancestors) from all her female contemporaries is that she has a purely matrilineal line of descent to all humans alive today, whereas all her female contemporaries with descendants alive today have at least one male in every line of descent. Because mitochondrial DNA is only passed through matrilineal descent, all humans alive today have mitochondrial DNA that is traceable back to Mitochondrial Eve.
Furthermore, it can be shown that every female contemporary of Mitochondrial Eve either has no living descendant today or is an ancestor to all living people. Starting with 'the' MRCA at around 3,000 years ago, one can trace all ancestors of the MRCA backward in time. At every ancestral generation, more and more ancestors (via both paternal and maternal lines) of MRCA are found. These ancestors are by definition also common ancestors of all living people. Eventually, there will be a point in the past where all humans can be divided into two groups: those who left no descendants today and those who are common ancestors of all living humans today. This point in time is termed the identical ancestors point and is estimated to be between 5,000 and 15,000 years ago. Since Mitochondrial Eve is estimated to have lived more than a hundred thousand years before the identical ancestors point, every woman contemporary to her is either not an ancestor of any living people, or a common ancestor of all living people.
World population
The term world population commonly refers to the total number of living humans on Earth at a given time. As of , the Earth's population is estimated by the United States Census Bureau to be billion. The world population has been growing continuously since the end of the Black Death around 1400...
humans. Passed down from mother to offspring, derivatives of her mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within cells that convert the energy from food into a form that cells can use...
(mtDNA) are now found in all living humans: all mtDNA in every living person is derived from hers. Mitochondrial Eve is the female counterpart of Y-chromosomal Adam
Y-chromosomal Adam
In human genetics, Y-chromosomal Adam is the patrilineal human most recent common ancestor from whom all Y chromosomes in living men are descended...
, the patrilineal most recent common ancestor, although they lived at different times.
Mitochondrial Eve is believed to have lived between 150,000 to 250,000 years BP
Before Present
Before Present years is a time scale used in archaeology, geology, and other scientific disciplines to specify when events in the past occurred. Because the "present" time changes, standard practice is to use 1 January 1950 as the arbitrary origin of the age scale...
, probably in East Africa
East Africa
East Africa or Eastern Africa is the easterly region of the African continent, variably defined by geography or geopolitics. In the UN scheme of geographic regions, 19 territories constitute Eastern Africa:...
, in the region of Tanzania
Tanzania
The United Republic of Tanzania is a country in central East Africa bordered by Kenya and Uganda to the north, Rwanda, Burundi and the Democratic Republic of the Congo to the west, and Zambia, Malawi and Mozambique to the south. The country's eastern borders lie on the Indian Ocean.The United...
and areas to the immediate south and west.
The individual lived during a period of time when Homo sapiens were developing as a species separate from other hominid species. As an individual she lived in a small population (between 4000 and 5000 females capable of producing offspring at any given time). Mitochondrial Eve would have been roughly contemporary with humans whose fossils have been found in Ethiopia
Ethiopia
Ethiopia , officially the Federal Democratic Republic of Ethiopia, is a landlocked country situated in the Horn of Africa. Ethiopia is bordered by Eritrea to the north, Sudan to the west, Kenya to the south, Somalia to the east and Djibouti to the northeast. Its size is 1,100,000 km² with an...
near the Omo river
Omo remains
The Omo remains are a collection of hominid bones, discovered between 1967 and 1974 at the Kibish sites near the Omo River, Omo National Park, in south-western Ethiopia. The bones were recovered by a scientific team from the Kenya National Museums directed by Richard Leakey and others. The remains...
and at Hertho
Homo sapiens idaltu
Homo sapiens idaltu is an extinct subspecies of Homo sapiens that lived almost 160,000 years ago in Pleistocene Africa. is from the Saho-Afar word meaning "elder or first born"....
. Mitochondrial Eve lived significantly earlier than the out of Africa migration which might have occurred some 95,000 – 60,000 years ago. However, Qafzeh
Qafzeh
The Jebel Qafzeh remains or Qafzeh-Skhul early modern humans were discovered at the paleoanthropological site Qafzeh near Mount Precipice south of Nazareth, Israel. Since 1933, 12 significant fossilised human skeletons have been found at the main rock shelter and nearby Skhul cave...
-type anatomically modern humans
Anatomically modern humans
Anatomically modern human or early modern human in paleoanthropology refers to early individuals of Homo sapiens with an appearance similar to that of modern humans....
have been noted in Western Asia as early as 125,000 years ago and their lithic culture was continuous from 200,000 years ago. Also, few archaeological sites in Asia suggest migration beyond South Asia occurred more than 76,000 years ago.
Matrilineal descent
For more information on the principles involved, see matrilineal descent and genetic genealogy (matrilineal).
To find the Mitochondrial Eve of all living humans, one can start by tracing a line from every individual to his/her mother, then continue those lines from each of those mothers to their mothers and so on, effectively tracing a family tree backward in time based purely on mitochondrial lineages. Going back through time these mitochondrial lineages will converge on one maternal ancestor.
This female, nick-named 'Eve', was of interest because she bore a mitochondrial genome (mitogenome) which was the template
Template
Template may mean:*a stencil, pattern or overlay used in graphic arts and sewing to replicate letters, shapes or designs...
for all later human mitogenomes. But each human genome bears mutations that have replaced nucleotides on the original template with a different nucleotide (or in some cases added or removed nucleotides). Mitogenomes are passed from mother to offspring, with very few exceptions—only rarely will the father's mitochondrial DNA persist long enough or in sufficient enough quantity to be passed to the germ cells of the offspring. Consequently, recombination (mixing) between paternal and maternal mitogenomes is not observed as with autosomal and X-chromosomes. All complex animals can also trace their ancestry back to a mitochondrial MRCA. Chimps and humans share a mitochondrial MRCA; farther back in time, the human/chimp MRCA and Gorillas share an earlier mitochondrial MRCA.
Mitochondria becomes all but clonal (an exact copy each time they replicate) rapidly since fruitful genetic information exchange is prevented by host biology. On rare occasion, about once every 10,000 years a stable mutation occurs in a female that is passed to a female offspring and thus can be passed to subsequent generations.. At the time of the mitogenomes MRCA a mutation occurred that created a split either within one of Eve's germ cells or within the mitochondria of a developing female offspring. This mutation distinguishes between proto-L0
Haplogroup L0 (mtDNA)
In human mitochondrial genetics, Haplogroup L0 is a human mitochondrial DNA haplogroup.-Origin:L0 is one of two branches from the of the most recent common ancestor, MRCA, for the shared human maternal lineage. This ancestor is estimated to have lived in Southern Africa or East Africa...
lineages from proto-L1
Haplogroup L1 (mtDNA)
In human mitochondrial genetics, Haplogroup L1 is a human mitochondrial DNA haplogroup.-Origin:Haplogroup L1 is believed to have first appeared in East Africa approximately 150,000 to 170,000 years ago. Haplogroup L1 is a daughter of Mitochondrial Eve like haplogroup L0...
lineages, and began the two basal branches of human mitochondrial DNA, L0 and L1. It is unknown which of these lines split from the ancestral line as both early lineages accumulated multiple mutations after this split occurred but before the next major extant branches split, hence both lines are derivatives of the ancestral mitogenomic sequence.
Coalescence Analysis
Coalescence time is a measure of the average genetic distance of genes in the extant populations to predicted sequence of the mtDNA MRCA. The estimated time is also known as TMRCA (time to most recent common ancestor). TMRCA are useful because they can be used with other sources of information to describe ancient population structures. TMRCA can also be used to corroborate with archaeological studies to indicate possible places and cultures of humans' ancient ancestors.
The coalescence studies of human mitogenomes has produced a current best estimate (as of 2007) of the TMRCA of the L0/L1 split in modern humans to 194,300 ± 32,500 years BP. According to coalescent theory this would place the number of females in the effective population at below 5000 females. The two most recent studies of the deepest branches of mtDNA place the deepest well of diversity in Tanzania
Estimating MRCAs
Coalescence theory is the application of different mathematical/statistical products of gene-sequence evaluation to create statistics about a population. This process requires:
- the determination of nucleotide evolution rate;
- the estimation of population diversityGenetic diversityGenetic diversity is a level of biodiversity that refers to the total number of genetic characteristics in the genetic makeup of a species. It is distinguished from genetic variability, which describes the tendency of genetic characteristics to vary....
;
- for parsimony trees - estimation within the deepest branches
- for pairwise comparisonPaired difference testIn statistics, a paired difference test is a type of location test that is used when comparing two sets of measurements to assess whether their population means differ...
- within or between the most diverse geographic regions- knowledge of inter-fertility patterns;
- for TMRCA estimation - the average temporal distance between generations.
- for estimation of total population size based on haploids - effective female to effective male ratios
- for hypothesis validation - rates of transmigration and minimum population densities
- a method for determining neutralityNearly neutral theory of molecular evolutionThe nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for slightly advantageous or deleterious mutations at the molecular level...
or correcting for non-neutrality.
- a method for determining neutrality
Based on the TMRCA and branching structure of the parsimony tree over time and geographic space these secondary products can be estimated:
- The average population size throughout the from the TMRCA to present
- The complex structure of the population can be estimated.
- Place of the MRCA (PMRCA).
There are many potential difficulties in calculating the TMRCA for mtDNA and the population size of the TMRCA. For the most simple analysis, the genetic distance between chimps and human, the path that goes from any extant human, though the human mitogenomic MRCA to the C/H LCA back to the chimpanzee mitogenomic MRCA and to individual chimpanzees based on an anchored LCA time. Within the region of interest single nucleotide polymorphisms (SNPs) are counted. The number of SNPs are divided by the LCA time and sequence length to arrive at a rate per site per year [rate = SNPs / (LCA Time * sequence length)]. This rate is preferably converted to rate per generations by multiply the rate by generation times. Correct rates of change strongly depend on the sequence one is examining. Therefore, one can sort SNPs by rates at sites divide that by the number of sites in the rate class and the mean rate of the rate class (see Gonder et al. 2007). Deriving the parameters for the rate equation is complex (see below).
The techniques used by different studies are important, as they reflect highly on how TMRCA can be compared.
Coalescent ancestry of mtDNA
| # of offspring | | Number of females | ||||
|---|---|---|---|---|---|
| 0♀ | 1♀ | 2♀ | 3♀ | 4♀ | |
| 0 | 100% | ||||
| 1 | 50.0 | 50.0 | |||
| 2 | 25.0 | 50.0 | 25 | ||
| 3 | 12.5 | 37.5 | 37.5 | 12.5 | |
| 4 | 6.25 | 25.0 | 37.5 | 25.0 | 6.25 |
Humans are sexually reproducing
Sexual reproduction
Sexual reproduction is characterized by processes that pass a combination of genetic material to offspring, resulting in diversity. The main two processes are: meiosis, involving the halving of the number of chromosomes; and fertilization, involving the fusion of two gametes and the restoration...
organism
Organism
In biology, an organism is any living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homeostasis as a stable whole...
s composed of two dimorphic sexes
Sexual dimorphism
Sexual dimorphism is the systematic difference in form between individuals of different sex in the same species. Examples include colour , size, and the presence or absence of parts of the body used in courtship displays or fights, such as ornamental feathers, horns, antlers or tusks.-Examples:In...
. Individuals with mammalian species
Species
In biology, a species is:* a taxonomic rank or* a unit at that rank ....
cannot create exact duplicates of themselves. Instead, each individual passes ~1/2 of their genetic makeup to offspring with their mate contributing the other half.In humans all of the mtDNA come from the female parent, female offspring get an equal number of X chromosomes from each parent, males get on X chromosome from the female parent and a Y from the male parent. In humans the portion of mtDNA from the male parent is very low to none, this may include, very rarely a gene-convertant (short-distant recombinant) between the male a female parent Through offspring production, individuals increase their genetic representation in the next generation, increasing the probability that more of their genes will be passed.
For MtDNA, mitochondria are passed overwhelmingly from mother to child. Female lineages effectively carry mtDNA genes. Since female or male offspring are produced randomly at a 1:1 ratio, when a mother passes a new mtNDA mutation to her offspring there is random risk that the new mtDNA mutation will be lost in the first generation (see Table on right). There is a lag time between the appearance of a mutation and probabilities above 0 that the new allele might fix, and after that time a defined distribution (see figure:Most likely time in generations to fixation).This is described by Kimura and Wright as a Markov chain
Markov chain
In mathematics, a Markov chain, named after Andrey Markov, is a random process where all information about the future is contained in the present state . To be more exact, the process has the Markov property, meaning that future states depend only on the present state, and are independent of past...
process, this process begins with 100% of an allele at absolute frequency of 1 (relative frequency = 1/2N), if the gene is excluded or fixes the Markov chain ends, but for all frequencies between 0 and 2N. For example, if the parent generation has relative frequencies of .1, .2, and .1 at absolute frequencies of 9,10, and 11, the probability of 12 individuals in the F1 generation would be 0.1*p(9->12) + 0.2*p(10->12) + 0.1*p(11->12) the calculation is performed for all possible absolute frequencies for the new generation based on frequecnies of the old generation and the new generation is replaced by to old and the process repeats This examination is called a forward-looking analysis, these predictions are based on observing population parameters while the population is evolving. It should be noted that the above is an idealization of a much more complex process. The following additional parameters should also be considered:
- progeny distributions (what is the random likelihood a female will have 0,1,2,3,4,5,....N progeny?
- variation in selection
- variations in population size
In molecular anthropology one is not examining a forward looking process, but the consequences of a process that has occurred in the past. In contrast to allele fixing, the coalescence is the interpretation of mutation quantification on related lineages. In sufficiently large populations, an allele that would otherwise displace all other alleles is prevented from fixing because new mutations are occurring on its own lineages. New mutations occur on the lineage before the allele fixes.
Even in large populations common lineages can be lost. At the time of mtDNA MRCA large numbers of females passed mtDNA to their female offspring, however because of genetic drift and time all of these other lineages have been excluded from the human population. Some of these other lineages had persisted for 1000s of years after mtDNA MRCA. Consequently because of coalescence there are some aspects of human evolution that are completely masked. Eve's mtDNA was not the only mtDNA when she lived, it was, in fact, one of the rarest mtDNA, because a fixation-like process masks other lineages we do not know how diverse, or how many variants existed.
The determination of coalescence time involves a set of assumptions that are subject to variance (e.g. generation times may change, mutation rates may change, male to female ratios may change, etc) that in a forward-looking investigation one could determine, but in a retrospective analysis one needs to assume. One of the most important assumptions made is the mutation rate, this mutation rate is based on the comparison of a sequence (in this case mitogenomes) between two species in which the geological age of last common ancestor is known. Population genetic diversity is measured by pairwise genetic comparison or parsimony analysis. Pairwise analysis, for example, arranges the sequences into a tree, and thus it is possible to measure the distance from any mtDNA sequence to a predicted sequence of the MRCA. With a neutral assumption, the observation of a MRCA sequence that joins the two deepest branches at a single point infers a MRCA time (TMRCA) and consequently also infers a population size probability distribution.
Referencing the mutation rate
Calculating SNP rates between individuals of great genetic distanced (i.e. between species or genera) needs a temporal anchor, such as the geological age human-chimpanzee split, the last common ancestor (CHLCA). The CHLCA is frequently cited as an anchor for molecular TMRCA determination because Chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s are the species most genetically similar to humans. However there are no known fossils that represent that CHLCA. White et al. (2009) suggested that errors and poor assumptions in previous studies predicted a recent LCA and that the CHLCA should be considerably older. Considering that the CHLCA vary widely, estimated mutation rates which are anchored in the CHLCA will also vary by the same relative percent. With the exception of the RFLP analysis (Cann et al. 1987), when comparing 2 TMRCA estimates for mtDNA, it is most important to remember that TMRCA is relative to the CHLCA, for example of TMRCA of 100,000 years using a 5 Ma CHLCA would become a TMRCA of 200,000 years using 10 Ma CHLCA.
Anthropoid mitochondrial clock
In order to determine the timing of an evolutionary event such as the origins of the common ancestor of human beings living today for which the fossil record is incomplete, Zuckerkandl and Linus Pauling devised the hypothesis of the molecular clock
Molecular clock
The molecular clock is a technique in molecular evolution which uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...
, which dates events based on analysis of change of molecular traits. Wilson and colleagues began applying this concept to mitochondrial DNA in the late 1970s and they found mtDNA mutates at a higher rate compared to nuclear DNA, so it gives researchers a more useful, magnified view of the diversity present in a population, and its history. Mitochondrial DNA nucleotides are variably functional. Some sites have never been observed to vary in any mammal, and some are known to vary within different samplings or the same individual. The mutation rate selected depends largely on the sites selected and the method for rate determination. Some have suggested a varying mutation rate or an inconsistent molecular clock.
| Study | SequenceType | CHLCA | Referencing method |
|---|---|---|---|
| Cann et al. (1987) | (RFLP) | - | Archaeologically defined exoAfrican migrations |
| Vigilant et al.(1991) | HVR | 4 to 6 Ma | CH Transversions, using a (15:1) macaque transitionto transversion ratio |
| Ingman et al.(2000) | Genomic(Not HVR) | 5 Ma | CH genomic comparison |
| Gonder et al.(2006) | Genomic(Not HVR) | 6.0 Ma(+ 0.5 Ma) | CH, Rate class defined |
| Soares et al.(2009) | Genomic | 6.5Ma(+ 0.5 Ma) | CH, Corrected for purifying selection |
| Chimpanzee to Human = CH, LCA = Last Common Ancestor | |||
The general methods of determining mutation rates, observing the appearance of new SNPs in the extant population or observing the number of mutations between two species and calculating the rates. Both methods have pitfalls. The first method is faulty because many mutations are negatively selective and over long time frames will be removed.In long term comparisons we would not see these mutations at the rate we see them in very short term comparisions On the other hand, over very long time frames mutations (particularly neutral sites) will revert, or homoplasies will make mutations harder to detect. Certain sites on MtDNA despite a high frequency of change are not used (i.e. masked) by many researchers, CRS 16129, CRS16183-16192 are two examples. Most current research is based on mutation analysis that anchored in paleontology, which means that the rate assumes that chimps and humans had a common ancestral mitogenome during a certain period of time. Gonder et al., for instance used an ancestor of 6.5 million years.
In addition to the temporal perspectives, there are three approaches that have been used with mtDNA to calculated the TMRCA: RFLP Analysis, HVR (D-loop approximates the MtDNA origin of replication and contains no coding sequence) and coding sequence (currently Genomic mtDNA) analysis. Restriction Fragment Length Polymorphism (RFLP) Analysis based the mutation rate on the perceived entry of humans into different parts of the world based on archaeological considerations. Hypervariable region
Hypervariable region
A hypervariable region is a location within nuclear DNA or the D-loop of mitochondrial DNA in which base pairs of nucleotides repeat or have substitutions...
(HVR) analysis based the mutation rate on a distance between humans and chimpanzees. Because the mutation rate within the HVR region between humans and chimpanzees was so great, transition
Transition (genetics)
In genetics, a transition is a mutation changing a purine to another purine nucleotide or a pyrimidine to another pyrimidine nucleotide . Approximately two out of every three single nucleotide polymorphisms are transitions....
:transversion
Transversion
In molecular biology, transversion refers to the substitution of a purine for a pyrimidine or vice versa. It can only be reverted by a spontaneous reversion...
ratios were used to determine substitution rates, the ratio was established in old world monkeys (15:1)However the ratio observed in humans is higher(20:1), and in African apes is unknown, and the specific points in time when these rates have changed remains unknown. Mutations can reverse or recur on two different lineages over increased time frames and thus correction for homoplasies and reverse mutations may need to be made depending on the presumed rate at a site. Vigilant et al.(1991) corrected for this using transition to transversion ratio of 15:1 mapping the distance between chimpanzees and humans in transversions and then converting to transitions + transversions within the human population This ratio clocks the number of transversions observed was used to calculate the total number of transitions and transversions differences (169% of sites) which was divided time to determine the rate per site.
Clocking within the coding region
The use coding region was originally used with HVR because few had complete coding region sequence. There were suspicions that the HVR studies had missed major branches based on some earlier RFLP and coding region studies. The first study to compare genomic sequences (Ingman et al. 2000) for coalescence analysis. Coding region DNA has come under question because coding sequences are either under purifying selection to maintain structure and function, or under regional selection to evolve new capacities. Some newer studies propose using wobble positions and select HVR sites for MRCA and clade MRCA analysis. Some studies propose using these wobble positions and certain HVR sites, although deep analysis of mtDNA trees in theria
Theria
Theria is a subclass of mammals that give birth to live young without using a shelled egg, including both eutherians and metatherians .- Extent :...
ns suggest that some wobble sites are not neutrally evolving, assessing neutrality of HVR sites deep in ape evolution is thwarted by deletions and insertions in those sites, and long branch distances (e.g. HVR1 is variously deleted in gorilla gorilla).
While genomic mtDNA studies may have weaknesses in calibrating the molecular clock, without doubt, the genomic mtDNA greatly improved the molecular phylogenetic understanding. HVR studies completely missed the basal branch of the mtDNA tree, macrohaplogroup L0 (L0) which had been intermingled with the branches of macrohaplogroup L1 (L1). Mitochondrial Eve's sequence is typically represented as the top root node of the human mitochondrial phylogenetic tree. The first split in the tree is found between L0 and L1. Because the genomic DNA resolved the two deepest branches and HVR marks an improved method for estimating TMRCA over HVR alone.
Calculating population size
Population size estimates are one of the most important products of TMRCA determination. First, if one has a population size of X today, and Y say 10,000 years ago and Z 150,000 years ago, we can determine rates of growth in the population. Second, if Z is sufficiently large we might argue that Z was inclusive of all the similar morpho-metrically defined populations (i.e. fossil cousins) that existed at the time, but if Z is sufficiently small, one begin to look at the concept of speciation, the formation of a new species. In other words, the more that the boundaries of population size can be limited the more one is able to draw inferences about the population (its range, its location, its constituents).
Ploidy
Ploidy is the number of complete sets of chromosomes in a biological cell. In humans, the somatic cells that compose the body are diploid , but sex cells are haploid...
based on forward looking statistics and modeling (Kimura, 1956). However estimating population size based on diversity and parsimonious trees is a backward-looking analysis. The two perspectives have markedly different results. The forward looking conclusion that TMRCA is a probabilistic function of population structure supports the inverse conclusion that population structure can be predicted, probabilistically, based on TMRCA. If TMRCA is converted to generations (TMRCA/(average generation time) = generations (Tg) then the generations to MRCA should equal 2 times the population size. Therefore . A simple example of this if TMRCA = 200,000 years, population size was constant, and generation time was 20 years, then N = 200,000/(20*2) = 5000 individuals.
For mtDNA one can expect all individuals to converge on a single point in generational time of 1/2N where Ne♀ is the average number of effectively reproducing females in the population at any given time. The relationship of TMRCA probabilities and population size is nearly linear. The relative variance is quite large and also nearly-linear (see figure Ne versus TMRCA = 200,000 years).For mtDNA TMRCA of 200,000 years and generation times of 20 years, one expects a constant population size of 1500 and 15000 individuals >95% of the time. Extrinsic factors (described above) affecting the TMRCA (e.g. inaccurate rates, inaccurate generation times, etc) and intrinsic factors can affect the accuracy of the determination.
Effects of phylogenetic branching on the determination of population structure
Contrasting the forward-looking approach (above), the retrospective approach is heavily influenced by branching in several ways. The branching that creates accuracy in the TMRCA and, provided the rate determination is accurate, the points of branching within the trees increases the accuracy of size determination in population subsets. How this works, suppose we start at the present time, we see 1000s of branches, by analysis closest sister clades backwards. Each of those branches has a TMRCA and a variance. However for each interval backward one goes, the previous structure can be averaged and the standard variance decreases as a function of 1/(N^0.5). Therefore, if the tree has a great number of branches (as the mtDNA tree) the interpretation of TMRCA at given points becomes more a less a function of extrinsic variance, thus locking that portion of the tree in generations. Consequently there is more confidence about the when humans left Africa than about the time of the TMRCA.
Regional clusters and expansions
For regions with unique sets of alleles population sizes can also be estimated. A divide and conquer strategy can be used to estimate population structure going backwards through time. A few examples from the literature, it was found that by examining the graves of the pre-westernized indigenous Andaman Islanders
Andaman Islands
The Andaman Islands are a group of archipelagic islands in the Bay of Bengal, and are part of the Andaman and Nicobar Islands Union Territory of India. The Andaman Archipelago is an oceanic continuation of the Burmese Arakan Yoma range in the North and of the Indonesian Archipelago in the South...
that some peoples had deep mtDNA not found in other groups in surrounding regions, therefore isolation created a cluster, the cluster was estimated to be of age 65,000 years. In the Solomon Islands it was found that another isolated cluster had formed, of approximately 50,000 years in age. Both clusters represent branches of M or N lineages that are the cluster representing the mtDNA of most Exo-Africans (not of modern African origin). These clusters, by having multiple TMRCAs each statistically squeeze the time of exodus from Africa into SW Asia to a certain point, and also squeeze the female population sizes for the early settlers to a certain size. Going further backwards N and M, entered Eurasia at time point Tg. By examining both N and M we can argue their regional character (as ancient) and that archaeologically we can define time T as 100,000 (for simplicities sake), then to preserve the genetic structures population size on average is 100000/20*2 = 2500 individuals. Looking backward to 150,000 years ago that also preserved two branches LOd and LOk then that population had ~3750 females. As more of these regional branches are recognized and factored into the retrospective analysis the probability that all of these are at their low population limit decreases, and therefore the lower limits on size increase beyond the sum of cluster low limits. The branching structure however reaches a point within the human parsimonious tree that only one evident cluster remaines. At present this appears to be the time when L0k formed (~145,000 years ago) and beyond this earlier branching offers little evidence of population size.
Deep population structure
To maintain balance with population spread and advance, the upper limit of the population size within the early period the mean estimate of early size may need to be decreased. For example, the alleles that spread to other regions, M and N to Asia with large population size cannot be excluded, and if these appear only in Asians then only the exclusion of L0 and deeper L1 branchpoints can occur. Likewise if the core population of humans was in Tanzania and the population expanded LOd, LOk into southern Africa, it becomes more difficult to exclude L0d and L0k and since L1 is protected by M and N (population sizes in Eurasia) and L0 is protected by L0d and L0k (population sizes in South Africa) neither can be excluded easily. Thus inflection of branching (or lack thereof) within a parsimonious tree plotted against time and space offers more detail on retrospective population stucture. If these branches are protected after globalization and isolation then populations that caused quasi-fixation of the MRCA must have occurred more rapidly than evident, and thus implying a smaller population size, however there are minimum constraints on lower size as one goes backwards to the MRCA (see grey area in figure), and these constraints are also notable in studies of other loci.
Generic measures of structure
One of the most common measures implying structural changes are measures of selection. Selection in this context is not necessarily the same as positive selection in a competitive context. Fortuitous colonization of new territories by a small number of individuals can make unique alleles carried by those individuals appear selective to other individuals. If we apply this to humans, by creating a given in the argument that there was a place in Africa that was core to mtDNA of all humans and that there was at the geographic center of that core unique set of alleles. As the population expanded from the boundaries after the MRCA sequence had excluded all deeper branches then all the branches that expanded on the fringe would exhibit the appearance of positive selection relative to the allele that was unique to the central population. There are two measures of departure from Neutrality, the Tajima's D statistic and the D* and F* statistics of Fu and Li.
Early studies
In the 1970s, early molecular biologist noted that some aspects of mitochondrial DNA, curiously, had a faster rate of evolution than the protein sequences commonly used at the time, and this might be useful in determining rates of evolution between individuals and species. In 1980, W.M. Brown, looking at the relative variation between human and other species, recognizes there was a constriction in the human population 180,000 years ago. A year later Brown and Wilson were looking at RFLP
Restriction fragment length polymorphism
In molecular biology, the term restriction fragment length polymorphism, or RFLP, refers to a difference between two or more samples of homologous DNA molecules arising from differing locations of restriction sites, and to a related laboratory technique by which these segments can be distinguished...
fragments and determined the human population expanded more recently than other ape populations and noted that humans had the mtDNA diversity that was comparable to isolated subspecies of other apes. This study was followed by a more complete study by Cann et al. (1987) of RFLP fragments in larger numbers of Africans with early estimates of the TMRCA at 215 +/- 75 kya. Because these studies did not obtain SNP no rate estimate as described above could be made. Instead they used paleoanthropological evidence for human settlement in New Guinea, Australia and the New World allowing them to estimate the sequence divergence rate was 2 to 4% per million years(at the RFLP level). A hypothetical ancestor, type a, linked to all other extant sequences with a divergence rate of 0.57% would mean the TMRCA existed between 142,500 and 285,000 years ago. Another hypothetical ancestor c contained no known African ancestors and was between 90,000 and 180,000 years ago. Based on these and other early indirect studies Takahata estimated that the Ne, female was between 3,500 and 4,600 individuals.
DNA sequencing of PCR products
In 1989, Linda Vigilant of A.C. Wilson
Allan Wilson
Allan Charles Wilson was a pioneer in the use of molecular approaches to understand evolutionary change and reconstruct phylogenies. One of the great innovators of science, he revolutionised the study of human evolution...
's group used PCR to amplify a region of hypervariability called the D-loop from the single hairs of southern African hunter-gatherers (!kung-San are a click speaking tribe of Namibia and neighboring Botswana). Sequencing this region was advantageous because the larger density of mutations meant they need only to sequence a few hundred nucleotides to obtain enough sequence to reliably demonstrate the level of diversity of humans, in addition at the time it was believed that this rapid rate of evolution was due to the d-loop regions neutrality. Two years later they used the same technique and an estimated chimp/human last common ancestor (CHLCA) of 4 to 6 million years to produced human mtDNA-TMRCA between 166,000 and 249,000 years. With more recent paleoanthrpological studies in Africa this CHLCA appears unlikely, and the use of the more likely 6 to 10 million year CHLCA would place this ancestor between 249,000 and 415,000 years.
Despite the improvements in the technique the approach was troubled. First, within the D-loop, 'hypervariable' region there are sites which evolve extremely rapidly it was later noted that the sequence was not evolving completely neutral manner. Other problems included an indirect method for deriving the mutation rate between chimps and humans, a C/H LCA that more recent than currently postulated. This did not determine the 'Vigilant' TMRCA 'date range' was incorrect, but that the range was likely wider than indicated in the publication.
Between 1991 and 2000 a number of additional studies were conducted, including studies that compared RFLP with HVR and partial genomic sequences with HVR. It became increasingly clear that there were problems with the phylogenetics created with HVR sequences. Other than the hyper-hypervariable sites, there appear to have been problems over how the base of the mtDNA tree was defined.
Advances in sequencing made it possible to sequence large numbers of genomic mitochondrial DNA (mitogenome). In 2000, Max Ingman analyzed the genomic sequences and provided the first sequences of the 53 mitogenomes. The TMRCA for humans was of 171,500 ± 50,000 years were less than previous studies, but not significantly so. The studies presented with an 'exodus' time from Africa in non-Africans of 52,000 years +/- 27,500 years (Both TMRCA are based on the Chimp human LCA of 5 million years). From this it can be inferred that Mitochondrial Eve had at least two daughters who survived to have their own children. Today L0 is restricted to African populations, whereas L1 is the ancestral haplogroup of all non-Africans, as well as most Africans. Mitochondrial Eve's sequence can be approximated by comparing a sequence from L0 with a sequence from L1. By reconciling the mutations in L0 and L1. The mtDNA sequences of contemporary human populations will generally differ from Mitochondrial Eve's sequence by about 50 mutations.
Despite some agreement with this date in some anthropological circles, there was concern that this date was too recent. A growing body of evidence from the Levant (Skhul and Qafzeh
Qafzeh
The Jebel Qafzeh remains or Qafzeh-Skhul early modern humans were discovered at the paleoanthropological site Qafzeh near Mount Precipice south of Nazareth, Israel. Since 1933, 12 significant fossilised human skeletons have been found at the main rock shelter and nearby Skhul cave...
), India, and China (LiuJiang) and Australia (Mungo Lake- LM3) that humans had migrated from Africa well before 52 kya.
Considering the C/H LCA calibration of the molecular clock, a higher-set confidence range (6.5 my C/H LCA) places the upper limit of confidence at 139,000 years ago. Of particular concern, however, is the recent finding that the oldest individuals at Skhul cave (Israel) are 100,000 to 135,000 years and the high end of Ingman's exoafrican TMRCA is 107,000. However, Tattersall and Schwartz (2008) recognize that some examples of late archaic homo sapiens may be better placed in other taxa as the Levant may not have been an early site of human occupation out of Africa. Rightmire (2009) associates archaic humans from Jebel Irhoud
Jebel Irhoud
Jebel Irhoud is an archaeological cave site located near Sidi Moktar, about 100 km west of Marrakesh, Morocco. Since circa 1991 7 significant hominid fossils have been discovered, and are currently dated to circa 160,000 years ago. The fossils include portions of two adult skulls , a child’s...
(Morroco 160,000) in a Mousterian tool context with the early Skhul fossils and if this dating is correct (real date not less than the estimate) then it distances both Jebel Irhoud and the oldest Skhul fossils from the geographic limits of the constrict population. Because of the sample size this study failed to see evidence of selection or population size growth; however, coalescence theory predicts that under neutral models, current population size in Africa is far too great to explain coalescence as recent as 171,500 years ago without some selection.
Consequently, Gonder et al. (2006) group undertook mitogenomic sequencing in areas of Africa were previous studies indicated deep diversity. This new study found new lineages of African mtDNA and more importantly narrowed the region within Africa in which humans ancestors likely arose. This new study indicated that the TMRCA likely occurred between 160,000 to 226,000 years ago (but dates between 130,000 and 280,000 cannot be ruled out, the Chimp-Human mtDNA MRCA time was anchored at 6.5 million years). This improved study however is not without criticism, the authors pointed out that by one measure selection is acting on all mtDNA (except in the proposed core region, Tanzania) and another measure found non-neutrality in the evolution of all mtDNA. Since this study a number of papers have been published that try to explain the appearance of excessive numbers of coding region mutations relative to expectations, one hypothesis is that these are the result of 'purifying selection' that occurred as people migrated. Another hypothesis is that these occurred as a consequence of selective pressure. A subsequent study has stated the following concerning the age estimates We used the rate of 5138 years per coding region single nucleotide polymorphism to translate the age estimate in mutations into ages in years. It is worth noting that age estimates in years should be cautiously interpreted because the actual mutation rate in years per mutation remains an open debate in the literature.
The Khoisan population was closely examined in 2008, adding many more sequences. Behar et al.(2008) determined that other than the L0d and LOk mitogenomes in Khoisan, other genomes in the Khoisan appear to be the result of recent admixture, consequently they estimated that Khoisans separated from the core interbreeding population after both the L0d and L0k clades had formed, about 144,000 years ago +/-11,000 years. In as much as their evidence suggested very low geneflow between non-Khoisan females and Khoisan females for 10,000s of years it was no longer possible for a population constriction to fix mtDNA in both groups, the period of constrained population size had effectively ended.
Implications
The background for the interpretation of the mtDNA TMRCA are the numerous studies showing human-like fossils and bone remnants in Africa and Eurasia. These studies progress in concert with modern molecular genetics, with sequencing of ancient bone remnants becoming more common-place, particularly for Neandertals. Prior to the sequencing of the first Neandertal mtDNA, the TMRCA and PMRCA for modern humans set ancient humans apart from Neandertals. The current sequence of a number of Neanderthal mtDNA has reaffirmed that in the genus homo's recent past the female lineages of Neandertals and Humans existed in non-crossbreeding populations. Thus the implication of recent African origins 20 years ago set off one of the biggest battles in paleoanthropology, setting major players, such as Milford Wolpoff against molecular paleontologist such as AC Wilson.
However, despite the compatibility of TMRCAs/PMRCAs from Neandertals and Humans with a multiple species model, other genetic studies ambiguously supported this theory. Y chromosomal studies produced a TMRCA, at less than 50,000 years, this estimate occurred after humans had expanded. Studies of other loci presented with a wide variety of fixation times, from 0 to 2 million years. Others studies did not adequately sample in Africa and presented ambiguous PMRCA or PMRCA on other continents. Francisco Ayala tried to discredit the coalescent population size by arguing that the HLA-DRB1 locus had a TMRCA of 10s of millions of years.
Variance of neutral fixation times
One early oversight of many early studies is that the fixation of alleles (the object of coalescent theory study) is not a discrete mathematical function, it is a probabilistic function, and it is highly dependent on the ploidy being studied.
Comparison to the X-linked and Autosomal TMRCAs
Takahata (1999) was the first molecular anthropologist to point out that conclusions drawn from single locus studies suffer from the large randomness of the fixation process. Schaffner (2004) has cleared up this issue by demonstrating the 3 sets of fixation ranges, haploid, X-linked and diploid where TMCRAs for different loci are expected to fall. Takahata (1993) estimated the effective human population size at 11,000 individuals, and Schaffner working on an improved set of X-linked markers from low recombination regions of the X-chromosome identified an effective size of approximately 12,000 individuals. PDHA1 falls on the edge of fixation times for X-linked chromosome. For autosomes, the MX1 locus and the HLA loci appear to preserve past diversity in the human population. With few exceptions however X-linked and autosomes appear to coalesce under a common populationsize, these exceptions, most of the quasi-neutral loci studied so far fall within the expected distributions of TMRCAs that can be anticipated by the 2N rule.
Comparison to the Y chromosomal TMRCA
Just as mitochondria are inherited matrilineally, Y-chromosomes are inherited patrilineally. Y chromosomal TMRCA, the time of the Y-chromosomal Adam
Y-chromosomal Adam
In human genetics, Y-chromosomal Adam is the patrilineal human most recent common ancestor from whom all Y chromosomes in living men are descended...
, lie in the 42 to 110ky range, which is a little less than half the TMRCA of mtDNA. Importantly, the genetic evidence suggests that the most recent patriarch of all humanity is much more recent than the most recent matriarch, suggesting that 'Adam' and 'Eve' were not alive at the same time. While 'Eve' is believed to be alive 140,000 years ago, 'Adam' lived only 60,000 years ago. According to Wilder et al. (2004), the lower TMRCA of Y is due to an effective population size of males 1/2 that of females over most of human evolution. However, even with a reduced effective population size, given humans expanded out of Africa >60,000 years ago, the effective population of males would have to have been a small fraction of that of females to neutrally explain the recent fixation (see graph on right). A recent study of X-chromosome suggests that different rates of male sperm production between humans and chimps has altered the molecular clock in sex chromosomes.
Population size oscillation
The term bottleneck has been used to describe the population structure that created mtDNA Eve. The appearance of a bottleneck was a consequence of the appearance of a 'big bang' of HVR branching about the time humans first left Africa. From that point back to the TMRCA was less than 100,000 years and the population size estimate was below 5000 effective females. Looking backwards in time this is what might be called a retrograde bottleneck, however it is an artifact of fixation process, since the last quasi-fixation event (the event which initiated with mtDNA Eve and extended to the extant population) conceals the population size from all points earlier than that mutation (see figure Retrograde look at bottlenecks). The work done on Neanderthal sequencing (Green 2007) has identified little evidence of Neanderthal contribution to humans, moreover it describes an effective size of the population when humans and Neanderthals split was about 3000 individuals. Taken in the light of Schaffner's and Takahata's effective populations sizes, 3000 <>e, female <>e, male < 4000 does not appear to represent a magnitude shift downward from the average size. Taking a null hypothesis, prior to and after the mtDNA MRCA population sizes appear to reflect long-term small population structure up until 70,000~150,000 years ago, not a brief constricting bottleneck, but a long period of constrained size followed by an expansion.
Statistics does not require an alternative, bottleneck, hypothesis prior to the expansion, however, a bottleneck may have existed. If the population size were at 11,000 to 12,000 individuals, the Ne for mtDNA and Y in particular, is below the expected median TMRCAs (See image Above and on the left). The difference between X-linked/Autosome TMRCA and mtDNA/Y TMRCA is the former covers and averages events that occur over a 1+ million year time frames whereas the haploid TMRCA reflect more recent time frames. Y chromosome and mtDNA may be more representative of population structure immediately prior to expansion. The ability to mesh mtDNA coalescence and Y coalescence depend on a better understanding of male to female ratios in the late stone age and agreement TMRCA of Y chromosome, which is currently the subject of much critique. If these two loci could be treated together, they would likely fall significantly below the X-linked and Autosomal population sizes.
Moreover, the TMRCA calculations above frequently assume there have been no structural changes in Africa, even though the population size of Africa currently is several magnitudes higher than the predicted effective size by mitogenomic, Y , X-lined or autosomal DNA. Some models assumed much of the growth occurred recently, however inflection of lineage growth is evident in the mtDNA trees at approximately 100 to 150 thousand years ago. This becomes more so evident if the population assumption of Gonder. et al. (2007), that all lineages are under selection except a few in Tanzania, then the growth in human population size between 140 and 60kya may have effectively ended a constriction that could reasonably have excluded deep branches within the human mtDNA population. If so, this requires much lower population sizes to achieve fixation within a bottleneck, sizes 1/2 to 1/3 the effective sizes postulated by Shaffner and Takahata, might best fit the observations. The mtDNA TMRCA distribution is marginally within the statistical limits for haploid fixation even considering high effective number of females (See graph: Most probable number of effective females based on TMRCA). The Y-chromosomal TMRCA, however, is not (see left most part of above graph). Others have postulated that by some form of selection (hegemony, cultural, or genetic), the Y chromosome swept the population, and, if so, this would negate a joint treatment . The problem with this hypothesis however is that; if the TMRCA for Y occurred after mtDNA entered greater Africa or Eurasia as a consequence of expansion, then Y could have expanded from anywhere (Central Africa, North Africa, Eurasia). However, Y diversity is greatest in Southern Africa, within the two earliest demographic branches observed with mtDNA in Behar et al. 2009 suggesting the earliest branch in Y should be about 150,000 mtDNA years in age. This points to disagreement between calibrations/interpretation of the Y-chromosomal molecular clock and mtDNA molecular clock.
Geographic constraints of ancient humans
The principal philosophical battle between strict Out of Africa and Multiregional Evolution hypotheses revolves around the placement of humans at times during human evolution the singly interpretable result of mtDNA coalescence determined the battleground that would follow its presentation.
The strict Out of Africa model places humans in SSA or even more strictly, ~10,000 interbreeding individuals in a defined domain in sub-Saharan Africa. With this model, because all humans are in this domain as other hominids continue to evolve Eurasia and parts of Africa evolution occurred independently at some point when homo sapiens beings effectively became a new species of the archaic homo sapiens. As part of this model specific events happen, population remains in a contained region, and at some point expands, expands out of Africa, expands to most parts of Africa, and since other hominids are no longer apparent, probably took part in a global-'competitive' displacement.
The strict multiregional hypothesis on-the-other-hand has humans spread broadly across Africa, Eurasia, parts of Oceania. Humans interbreed overtime across long ranges, but modern humans primarily represent evolution in-situ. As part of this model the ice age ends allowing people to travel, agriculture increase population size, but people have largely evolved in place. Massive migrations and displacement would not explain genetic makeup.
If we assume that there were humans in NE China, central China, southern China, Sumatra, Flores Island, Europe, the Levant, North Africa and Subsaharan Africa, and assuming there were no other humans other (e.g. Narmada India) then effective sizes per known regions was about 103 effective females. In an area like sub-Saharan Africa this would mean that the density of humans would be on the order of individuals per 1000s of square miles.
The Out of Africa hypothesis asserts that human populations originated in a contained region and fits better the predicted population sizes, the more recent information on mtDNA found in Tanzania, and the evidence for an early branch that separated L0d and L0k from other L0 and L1 is suggestive of the power small migrations have on isolating peoples, this further argues for a contained geographic region in origin of modern humans. This constraint compresses population density by 2 magnitudes over the multiregional model and is comparable to densities of stone age peoples. Largely other genetic data support mtDNA, and thus multiregionalism has faded from the forefront of human evolution hypothesis and has been replaced by mostly Out of Africa hypothesis.
Homo sapiens
Archaic Homo sapiens
Archaic Homo sapiens is a loosely defined term used to describe a number of varieties of Homo, as opposed to anatomically modern humans , in the period beginning 500,000 years ago....
is assumed to have speciated from Homo heidelbergensis
Homo heidelbergensis
Homo heidelbergensis is an extinct species of the genus Homo which may be the direct ancestor of both Homo neanderthalensis in Europe and Homo sapiens. The best evidence found for these hominin date between 600,000 and 400,000 years ago. H...
in the period of 200–160 kya. The fact that Mitochondrial Eve happens to be dated to precisely this period has been taken as evidence of a population bottleneck
Population bottleneck
A population bottleneck is an evolutionary event in which a significant percentage of a population or species is killed or otherwise prevented from reproducing....
(e.g. Toba catastrophe theory
Toba catastrophe theory
The Toba catastrophe theory holds that 70,000 to 75,000 years ago, a supervolcanic event at Lake Toba, on Sumatra , possibly the largest explosive volcanic eruption within the last twenty-five million years plunged the Earth, which was already in an ice-age, into an even colder spell...
) giving rise to the human species. There are, however, many ways such family trees can be constructed. A tree can be constructed based on any gene, not just the mitochondrial DNA. When different such trees including the mtDNA tree are compared, no population bottleneck is found because different trees show different coalescent
Coalescent theory
In genetics, coalescent theory is a retrospective model of population genetics. It employs a sample of individuals from a population to trace all alleles of a gene shared by all members of the population to a single ancestral copy, known as the most recent common ancestor...
points. The inconsistencies between coalescent points indicate that there had been numerous gene interchanges between population groups around the world, even after the first exodus out of Africa. This idea forms the basis of Alan Templeton
Alan Templeton
Alan Templeton is an American geneticist and statistician from Washington University in St. Louis, known for his theories regarding the lack of genetic differences between humans of different races. According to Templeton's research, perceived differences in races are more related to cultural...
's 'Out of Africa Again and Again' theory.
The Mitochondrial DNA provides another support for the Out of Africa hypothesis in the form of gene diversity. One finding not subject to interpretation is that the greatest diversity of mitochondrial DNA sequences exists among Africans. This diversity is believed to have accumulated because humans have been living longer in Africa than anywhere. Family trees (or "phylogenies
Phylogenetics
In biology, phylogenetics is the study of evolutionary relatedness among various groups of organisms , which is discovered through molecular sequencing data and morphological data matrices...
") constructed on the basis of mitochondrial DNA comparisons show that the living humans whose mitochondrial lineages branched earliest from the tree (L0
Haplogroup L0 (mtDNA)
In human mitochondrial genetics, Haplogroup L0 is a human mitochondrial DNA haplogroup.-Origin:L0 is one of two branches from the of the most recent common ancestor, MRCA, for the shared human maternal lineage. This ancestor is estimated to have lived in Southern Africa or East Africa...
) are prevalent among the San and the Mbuti
Mbuti
Mbuti or Bambuti are one of several indigenous pygmy groups in the Congo region of Africa. Their language belongs to the Central Sudanic subgroup of the Nilo-Saharan phylum.-Overview:...
people. The subsequent branches of L1
Haplogroup L1 (mtDNA)
In human mitochondrial genetics, Haplogroup L1 is a human mitochondrial DNA haplogroup.-Origin:Haplogroup L1 is believed to have first appeared in East Africa approximately 150,000 to 170,000 years ago. Haplogroup L1 is a daughter of Mitochondrial Eve like haplogroup L0...
, L2
Haplogroup L2 (mtDNA)
In human mitochondrial genetics, Haplogroup L2 is a human mitochondrial DNA haplogroup.-Origin:Haplogroup L2* originated in East Africa. Either L2* or its subclades are present in approximately one third of recent African people. It is believed to have evolved between 87,000 to 107,000 years...
and L3
Haplogroup L3 (mtDNA)
In human mitochondrial genetics, Haplogroup L3 is a human mitochondrial DNA haplogroup.-Distribution:It is most common in East Africa, in contrast to others parts of Africa where the haplogroups L1 and L2 represent two thirds of mtDNAs....
are also largely confined to Africa, while only the macrogroups M
Haplogroup M (mtDNA)
In human mitochondrial genetics, Haplogroup M is a human mitochondrial DNA haplogroup. An enormous haplogroup spanning all the continents, the macro-haplogroup M, like its sibling N, is a descendant of haplogroup L3....
and N
Haplogroup N (mtDNA)
In human mitochondrial genetics, Haplogroup N is a human mitochondrial DNA haplogroup. An enormous haplogroup spanning many continents, the macro-haplogroup N, like its sibling M, is a descendant of haplogroup L3....
, descended from L3, participated in the ancient migration(s) out of Africa.
The Mitochondrial MRCA and the most recent common ancestor of all humans
Mitochondrial Eve is the most recent common matrilineal
Matrilineality
Matrilineality is a system in which lineage is traced through the mother and maternal ancestors. In this article matrilineality also is a societal system in which one belongs to one's matriline or mother's lineage, which can involve the matrilineal inheritance of property and/or titles.A...
ancestor, not the MRCA
Most recent common ancestor
In genetics, the most recent common ancestor of any set of organisms is the most recent individual from which all organisms in the group are directly descended...
. Since the mtDNA are 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 only valid when discussing mitochondrial DNA. Ironically mtDNA are not human, they are organelles that live within our cells, so it is better to say these are human-mitochondrial Most Recent Common Ancestor. Despite the recent fixation of the mtDNA genome in humans, other genes have evolved that were broadly selective in the human population, these genes have swept through the human population, two such genes have been identified on the X-chromosome.
Other studies have indicated the overwhelming majority of humans have a recent common ancestor within the last 5000 years (albeit between any two individuals it may not be the same ancestor), however the genetic relationship between well diverged individuals may not reflect the theoretical relationship, as geographic and cultural barriers may slow geneflow. Gene flow is not fluid in humans, genes are passed in units called chromosomes, which undergo limited number of recombination on each unit per generation, therefore a common ancestor genealogically may not indicate the passage of DNA from that ancestor to the two divergent individuals. Whereas since mtDNA does not undergo this dilution via recombination, we can argue that the majority of mtDNA sequence (that which has not undergone mutation) from mtDNA ~16000 nts came from a single individual >150,000 years ago. A more recent common ancestor for all Males is the much larger Y chromosome (however it codes for very few genes).
Mitochondrial Eve was not the only woman alive in her time
Allan Wilson
Allan Wilson
Allan Charles Wilson was a pioneer in the use of molecular approaches to understand evolutionary change and reconstruct phylogenies. One of the great innovators of science, he revolutionised the study of human evolution...
's naming Mitochondrial Eve after Eve
Adam and Eve
Adam and Eve were, according to the Book of Genesis of the Bible, the first man and woman created by God...
of the Genesis creation account
Creation according to Genesis
Creation according to Genesis is the account of the creation of the world and of the first man and woman as found in the first two chapters of the Book of Genesis of the Hebrew Bible....
has led to some misunderstandings among the general public. A common misconception is that Mitochondrial Eve was the only living human female of her time.
Indeed, not only were many women alive at the same time as Mitochondrial Eve but many of them have living descendants through their sons. While the mtDNA of these women is gone, their Nuclear genes are present in today's population.
What distinguishes Mitochondrial Eve (and her matrilineal ancestors) from all her female contemporaries is that she has a purely matrilineal line of descent to all humans alive today, whereas all her female contemporaries with descendants alive today have at least one male in every line of descent. Because mitochondrial DNA is only passed through matrilineal descent, all humans alive today have mitochondrial DNA that is traceable back to Mitochondrial Eve.
Furthermore, it can be shown that every female contemporary of Mitochondrial Eve either has no living descendant today or is an ancestor to all living people. Starting with 'the' MRCA at around 3,000 years ago, one can trace all ancestors of the MRCA backward in time. At every ancestral generation, more and more ancestors (via both paternal and maternal lines) of MRCA are found. These ancestors are by definition also common ancestors of all living people. Eventually, there will be a point in the past where all humans can be divided into two groups: those who left no descendants today and those who are common ancestors of all living humans today. This point in time is termed the identical ancestors point and is estimated to be between 5,000 and 15,000 years ago. Since Mitochondrial Eve is estimated to have lived more than a hundred thousand years before the identical ancestors point, every woman contemporary to her is either not an ancestor of any living people, or a common ancestor of all living people.