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Reliable estimates of the rate at which DNA accumulates mutations the substitution rate are crucial for our understanding of the evolution and past demography of virtually any species. In humans, there are considerable uncertainties around these rates, with substantial variation among recent published estimates. Substitution rates have traditionally been estimated by associating dated events to the root e. The recent availability of ancient mitochondrial DNA sequences allows for a more direct calibration by assigning the age of the sequenced samples to the tips within the human phylogenetic tree. But studies also vary greatly in the methodology employed and in the sequence panels analyzed, making it difficult to tease apart the causes for the differences between previous estimates.
Another likelier possibility is that mtDNA was transferred through hybridization between a proto-human and a protochimpanzee after the former had developed bipedalism. Unable to display preview. Download preview PDF. Skip to main content. Advertisement Hide. Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. This is a preview of subscription content, log in to check access.
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Mitochondrial dna dating method - Find single man in the US with mutual relations. Looking for love in all the wrong places? Now, try the right place. Register. By this method, scientists have calculated that the common ancestor of all this places the date of the common ancestor at around 6, years. We recalibrate the molecular clock of human mtDNA as years The molecular clock of mitochondrial DNA has been extensively used to date various genetic events . Such an approach was taken in a recent study .
Eisenberg JF The mammalian radiations: an analysis of trends in evolution, adaptation and behavior. Feldesman MR b Morphometric analysis of the distal humerus of some Cenozoic catarrhines: the late divergence hypothesis revisited. Gojobori T, Ishii K, Nei M Estimation of average number of nucleotide substitutions when the rate of substitution varies with nucleotides. Goodman M Immunochemistry of the primates and primate evolution.
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Kaimeisha, Tokyo Google Scholar. Our tip-based estimates of substitution rates are highly consistent with the values recently published by Brotherton et al. Consistently with the differences between tip- and node-based calibrations, we report here, our tip-based rate estimates are slower by a factor of 0. The answer to this question is unambiguous; the variance over individually calibrated substitution rates is 11 times smaller for tips than internal nodes.
The situation is strikingly different for node-based calibrations, where substitution rate estimates strongly depended on the demographic episode used for dating, with only four out of ten individually calibrated rates having overlapping HPDs. These results strongly suggest that tip calibration estimates are far more consistent than internal node-based ones.
However, tip-based calibration also point to slower mean substitution rates than those based on internal nodes. Thus, one important question we need to answer is whether tip-based calibrations are affected by some systematic bias that might lead to slow and homogeneous substitution rates. However, we feel confident that none of the sources of bias listed above is affecting our rate estimates. First, the sequences were generated by several laboratories, using different sequencing technologies and post processed considering different contamination assays.
The read depth of all the sequences included is high, thus minimizing the risk of incorrectly called SNPs. Our ancient sequence age randomization test clearly indicated that our data set contains a strong enough signal to accurately calibrate the reconstructed human mtDNA phylogeny. Moreover, confidence in our tip-based estimates is bolstered by the results from two recent independent analyses Brotherton et al. Taken together, all the available evidence suggests that tip-based calibration of human mtDNA are fairly immune to systematic biases and constitutes a strong case for them to be the most biologically relevant.
The superior performance of tip calibration over node calibration is not entirely surprising when we consider the various sources of uncertainties associated with both calibration strategies. The uncertainty associated with tip-dating simply mirrors the uncertainty in the estimated age of the sequences—in this case, the error of the C radiocarbon dating technology Bowman ; Molak et al. This is a well-characterized source of error which can and should be integrated into phylogenetic inference Drummond et al.
New 'Molecular Clock' Aids Dating Of Human Migration History
In contrast, the uncertainty around dated nodes is far more complex and multifactorial and is likely to lead to different degrees of reliability associated to each node. The age of the oldest evidence for human presence is unlikely to coincide exactly with the demographic expansion. Very generally, we would predict to see a delay in the appearance of traces of human presence after the expansion of AMHs into any new area Signor and Lipps However, we could also think of cases where the initial settlement which led to the archaeological evidence was followed by local population extinction and thus predates the age of the of the clade in the phylogenetic reconstruction; such a scenario has been suggested for the Qafzeh—Skhul early AMHs who are generally believed to have been part of an early, failed out-of-Africa exit Oppenheimer Second, even if a demographic event had been accurately dated, the age of the node in the phylogenetic tree might not coincide with it for a number of reasons Edwards and Beerli ; Ho and Phillips ; Balloux ; Firth et al.
For instance, the phylogenetic node of interest may correspond to the most recent common ancestor MRCA of the sampled sequences rather than the split of the population of interest. But even if the population was accurately sampled, we might still envision cases where the age of the coalescence does not coincide with the demographic event.
Such a mismatch could arise if the founding population was already polymorphic for the marker under study, so that the estimated coalescence event is older than the population split i. A similar situation could arise when multiple waves of colonists contributed to a demographic expansion.
Conversely, the population might have experienced a reduction in size later on, so that the TMRCA could coincide with this subsequent population bottleneck. We could think of additional scenarios and the situation would become even more complex if we considered a possible effect of natural selection. To summarize, node calibration can be affected by many sources of error, and it is thus nearly impossible to model the age uncertainty around nodes satisfyingly.
There is an extensive debate in the literature on the existence and significance of time-dependent rates of molecular evolution Ho, Shapiro, et al. This acceleration in substitution rates in recent generations has previously been described and discussed in several species Ho, Shapiro, et al.
It is generally ascribed to the time needed for natural selection to weed out slightly deleterious mutations from the population Endicott et al. We observed a subtle but significant negative linear correlation between the age of the ancient sequence used for calibration and the substitution rate estimated supplementary appendix S13Supplementary Material onlinewhich is consistent with this prediction.
There has also been a vigorous debate in the literature regarding the extent to which positive selection and local adaptation may have shaped the current distribution of human mitochondrial, with a particular focus on the possible role of climate Mishmar et al.
The fact that a relaxed clock fits our data best would be in line with the idea that rate variation in human mtDNA is subject to positive selection. Alternatively, this variation in evolutionary rates could stem from purifying selection on mtDNA being more effective in some human populations than others due to differences is population size and past demography. However, the effect we detect is extremely subtle and only statistically significant thanks to the large data set.
We also failed to find any ecological or demographic factor that could explain variation in inter-individual rate variation satisfactorily results not shown. Using both anatomically modern and archaic ancient mtDNA sequences to calibrate the tree, we obtain a rate of 0. The rates changed little when we ignored the external calibration tips archaic humans. This result points to external calibration tips having limited influence on rate estimates, as previously discussed by Krause, Fu, et al.
Using tip calibration, we also estimated the coalescence dates of various nodes of interests in the tree. We obtained a value of 4. This estimation may appear too young when compared with the dates that are generally derived from the fossil record.
We estimated a split time between Homo neanderthalensis and H. Considering the widely held view that H. The Boxgrove tibia from Sussex, Englandattributed to H. This estimation rather places a conservative upper bound of 93 ka for the time of the last major gene exchange between non-African and sub-Saharan African populations.
As pointed out by Fu, Mittnik, et al. Finally, our results also allowed us to check whether the coalescence dates of some major haplogroups associated with human migrations table 2 are consistent with the archaeological evidence supplementary appendix S However, in the case of the Canary Islands, Remote Oceania, New Zealand, and the Americas, the estimated coalescence times were systematically older than the archaeological evidence.
Potential explanations for such discrepancies include ancestral polymorphism in the founding population or complex demographic histories involving multiples waves of colonists. N ote. In conclusion, our results demonstrate that the recent availability of ancient high-quality mtDNA genomes offers a powerful tool to robustly date past evolutionary events of our own species. Using the age of ancient sequences leads to far more reproducible inferences and allows circumventing the large number of assumptions behind node and root calibration, which in turn should lead to an improvement of the estimation of human mitochondrial substitution rates.
It should be possible to obtain increasingly narrow and precise substitution rate estimates by including additional ancient genomes in the analyses, as they will become available.
In this context, ancient isolates from geographic regions which are not represented yet, such as Africa and Australia, would be particularly helpful, as these would allow fine calibration of further clades in the human mitochondrial genome. From a more general point of view, the growing availability of ancient sequences due to sequencing technology improvements should allow reliable tip-calibrated phylogenetic rate and divergence time estimates to be obtained in many species for which internal nodes split times information are presently not available.
Our data set composed of cAMH and 30 ancient human complete mitochondrial genomes, consisting of both new and publicly available sequences. A total of new samples were obtained from two different sources.
First, samples were selected by randomly choosing two individuals from each of the 51 populations of the HGDP-CEPH human genome diversity cell line panel Cann et al. Second, we randomly selected two individuals from each of the 21 Native American and one Siberian populations that had previously been genotyped at autosomal microsatellites Wang et al.
Details on the molecular and data processing are given in supplementary appendix S1Supplementary Material online. A total of public cAMH sequences were selected from GenBank to complete the geographic coverage and the haplogroup spectrum of the cAMH sequences generated in this project supplementary appendix S2Supplementary Material online.
A chimpanzee sequence accession number HM was used as outgroup. This resulted in a 16,bp aligned sequences matrix in which each nucleotide has been annotated by matching to the Cambridge reference annotation file using an in-house R script R Core Team It is well documented that substantial chemical modifications of nucleotide bases can be introduced postmortem as a result of DNA damage Paabo ; Sawyer et al.
This feature has been used to distinguish between ancient damaged sequences and putative modern contaminants Green et al.
Here, we took advantage of the random nature of DNA damage to test for sequence quality in the ancient samples. Moreover, given that deamination errors are expected to happen at random, the probability of observing the same error in multiple sequences is low. The optimal partitioning scheme and the best-fit nucleotide substitution model for each partition of the mtDNA molecule was estimated using the software PartitionFinder Lanfear et al.
We defined the following seven groups of nucleotides: 1 HVS1, 2 HVS2, 3, 4, 5 protein coding positions at 1st, 2nd, and 3rd codon, 6 tRNAs, 7 rRNAs and used PartitionFinder to analyze every scheme that includes those seven groups in any possible combination. We also used the same algorithm to independently select the best model of nucleotide evolution to apply to the whole molecule. In all analyses on the partitioned data, substitution and clock models were unlinked, whereas tree topology was assumed to be the same between schemes.
We also performed separate phylogenetic inferences on the whole-mtDNA molecule. We compared constant size, logistic growth, and exponential growth models.
The new method refines the mtDNA calculation by taking into account the process of natural selection - which researchers realised was. We report a method for dating ancient human samples that uses the Keywords: molecular clock, generation interval, ancient DNA, A revised timescale for human evolution based on ancient mitochondrial genomes. A generalized leastsquares method was applied in fitting a model to mtDNA sequence Although there is some uncertainty in the clock, this dating may pose a.
We specified a model where the probability that any transition sites of the alignment remained undamaged is assumed to decay exponentially with sample age. Model choice was based on the Bayes factors calculated from the marginal likelihoods, the latter being computed using both the PS and SS methods as recently recommended by Baele et al.
The human mitochondrial molecular clock is the rate at which mutations have been . Pedigree methods estimate the mutation rate by comparing the mtDNA sequences of a . Methods/parameters for estimating date of mitochondrial Eve.
Substitution models were based on the best fit from Partition Finder, and rate variation among sites both including and excluding invariant sites was modeled with a discrete gamma distribution with four rate categories. An independent constant population size model was applied to the Neanderthal clade as recommended by Briggs et al. For each analysis, we ran four independent chains in which samples were drawn every 5, MCMC steps from a total of 50, steps, after a discarded burn-in of 5, steps.
Parameter estimation was based on the samples combined from the different chains. The best supported tree was estimated from the combined samples using the maximum clade credibility method implemented in TreeAnnotator."Mitochondrial DNA variation in Human Origins and Disease"
We compared the effect of different tree calibration strategies on the estimation of substitution rates and divergence times. Priors were placed on tips, internal nodes, and root age. Tip age was specified using reliable dates available for all high-quality ancient complete human mtDNA sequences available at the time.
Uncertainty around the dating was modeled in BEAST using a normal prior with standard deviation equal to the standard error of the radiocarbon date supplementary appendix S3Supplementary Material online. We first used date-randomization tests to determine whether the temporal and genetic information contained in the ancient sequences were sufficient for a thorough estimation of substitution rates.
From the total data set composed of sequencesages of the sequences were randomly shuffled ten times, and date-randomized data sets were reanalyzed with BEAST. Point-calibrated tips analyses i. To prevent the chain from becoming stuck on unrealistic inflated values, flat priors uniform distributions were applied for all other internal nodes and root ages 0. Tip dating analyses were performed while considering aAMHs intraspecific calibration and archaic humans extra-specific calibration either separately or simultaneously.
Finally, to test whether the inferred substitution rates are dependent on a single-dated aAMH sequence, we performed BEAST analyses using each ancient mtDNA sequence independently as separate tip calibrations. Internal node calibration was conducted by specifying priors on the ages of some specific nodes in the tree.
Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced.
Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12, and 45, y ago and show an excellent correlation of the genetic and 14 C dates.
By considering the slope of the correlation between the genetic dates, which are in units of generations, and the 14 C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26—30 y.
Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier. Ancient DNA analyses have transformed research into human evolutionary history, making it possible to directly observe genetic variation patterns that existed in the past, instead of having to infer them retrospectively 1.
To interpret findings from an ancient specimen, it is important to have an accurate estimate of its age. The current gold standard is radiocarbon dating, which is applicable for estimating dates for samples up to 50, y old 2.
By measuring the ratio of 14 C to 12 C in the sample and assuming that the starting ratio of carbon isotopes is the same everywhere in the biosphere, the age of the sample is inferred. A complication is that carbon isotope ratios vary among carbon reservoirs e. Thus, 14 C dates must be converted to calendar years using calibration curves based on other sources, including annual tree rings dendrochronology or uranium-series dating of coral 2.
Such calibrations, however, may not fully capture the variation in atmospheric carbon. In addition, contamination of a sample by modern carbon, introduced during burial or by handling afterwards, can make a sample seem younger than it actually is 2.
The problem is particularly acute for samples that antedate 30, y ago because they retain very little original 14 C. Here, we describe a genetic approach for dating ancient samples, applicable in cases where DNA sequence data are available, as is becoming increasingly common 1.
This method relies on the insight that an ancient genome has experienced fewer generations of evolution compared with the genomes of its living i. Because recombination occurs at an approximately constant rate per generation, the accumulated number of recombination events provides a molecular clock for the time elapsed or, in the case of an ancient sample, the number of missing generations since it ceased to evolve.
Branch shortening has been used in studies of population history, for inferring mutation rates, and for establishing time scales for phylogenic trees in humans and other species 45.
It was first applied for dating ancient samples on a genome-wide scale by Meyer et al. Specifically, the authors compared the divergence between the Denisova and extant humans and calibrated the branch shortening relative to human—chimpanzee HC divergence time. The use of ape divergence time for calibration, however, relies on estimates of mutation rate that are uncertain 7.
In particular, recent pedigree studies have yielded a yearly mutation rate that is approximately twofold lower than the one obtained from phylogenetic methods 7.
In addition, comparison with HC divergence relies on branch-shortening estimates that are small relative to the total divergence of millions of years, so that even very low error rates in allele detection can bias estimates.
These issues lead to substantial uncertainty in estimated age of the ancient samples, making this approach impractical for dating specimens that are tens of thousands of years old, a time period that encompasses the vast majority of ancient human samples sequenced to date. Given the challenges associated with the use of the mutation clock, here we explore the possibility of using a molecular clock based on the accumulation of crossover events the recombination clockwhich is measured with high precision in humans 8.
In addition, instead of using a distant outgroup, such as chimpanzees, we rely on a more recent shared event that has affected both extant and ancient modern humans and is therefore a more reliable fixed point on which to base the dating. The idea of our method is to estimate the date of Neanderthal gene flow separately for the extant and ancient genomes.
The difference in the dates thus provides an estimate of the amount of missing evolution: that is, the age of the ancient sample. An illustration of the idea is shown in SI AppendixFig.
An assumption in our approach is that the Neanderthal admixture into the ancestors of modern humans occurred approximately at the same time and that the same interbreeding events contributed to the ancestry of all of the non-African samples being compared. Deviations from this model could lead to incorrect age estimates. Our method is not applicable for dating genomes that do not have substantial Neanderthal ancestry, such as sub-Saharan African genomes. To date the Neanderthal admixture event, we used the insight that gene flow between genetically distinct populations, such as Neanderthals and modern humans, introduces blocks of archaic ancestry into the modern human background that break down at an approximately constant rate per generation as crossovers occur 13 — Thus, by jointly modeling the decay of Neanderthal ancestry and recombination rates across the genome, we can estimate the date of Neanderthal gene flow, measured in units of generations.
Similar ideas have been used to estimate the time of admixture events between contemporary human populations 14 — 16as well as between Eurasians and Neanderthals 9 An important feature of our method is that it is expected to give more precise results for samples that are older because these samples are closer in time to the Neanderthal introgression event, thus it is easier to accurately estimate the time of the admixture event for them.
Thus, unlike 14 C dating, the genetic approach becomes more reliable with age and, in that regard, complements 14 C dating.
Although a number of approaches exist for dating admixture when multiple genomes are available from the target 91415none are applicable to single diploid genomes as required here for ancient specimens. Thus, we took advantage of our recent method introduced in Fu et al.
The HGDP-CEPH mtDNA sequences are part of a wider sequencing the PS and SS methods as recently recommended by Baele et al. Uncertainty around the dating was modeled in BEAST using a. Fossil evidence has been frequently used to estimate a date for the MRCA of two Attempts at calculating the human mitochondrial DNA (mtDNA) Using a previously published contamination estimation method , four. Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. Hasegawa M, Kishino H, Yano T. A new statistical method for estimating.
Assuming that the gene flow occurred instantaneously and by fitting a single exponential to the decay pattern, we estimate the average date of the Neanderthal gene flow in the target genome. Our simulations find that the estimated ages of Neanderthal gene flow are accurate when the admixture occurred between and 1, generations ago.
However, for samples older than 2, generations, our method underestimates the true ages. To avoid complications due to the bias, we restricted our application of the single-sample statistic to ancient genomes where the expected date of Neanderthal gene flow is less than 1, generations. This method measures the extent of admixture linkage disequilibrium LD by computing the covariance for each pair of ascertained single nucleotide polymorphisms SNPs and thus requires data from more than one diploid genome making it inapplicable when only a single ancient genome is available.
For extant genomes, we verified that the application of this statistic removes the bias observed in ref. To test the utility of our method for estimating the age of ancient genomes and not just dating Neanderthal gene flowwe simulated data for both extant and ancient Europeans sampled between and 1, generations ago and set the date of the shared Neanderthal gene flow to 2, generations ago 9.
Our simulations show that the estimated ages of ancient genomes are accurate and that, as expected, the dates are more precise for older samples SI AppendixNote S2c. Thus far, we have assumed that admixture occurred instantaneously as a single pulse of gene flow. However, in real populations, admixture could occur as multiple pulses or continuously over an extended period. To explore how this scenario affects our results, we performed simulations based on a similar setup as before, with the modification that the admixture occurred continuously for a period of either 10 or generations, starting at 2, generations ago.
Fitting a single exponential to the ancestry covariance patterns, we found that the estimated dates of admixture were intermediate between the start and end of the period of gene flow.
The magnitude of the effect was similar for both ancient and extant samples and thus there is no reason to think that this complication would bias the date estimates SI AppendixNote S2d. Our simulations relied on the accurate modeling of the recombination rate across the genome. The S map, which focuses on the part of the landscape of recombination in African Americans that is shared with Europeans, is one of the most accurate genetic maps for Europeans currently available 8.
Mitochondrial dna dating method
Despite the high resolution, even the best available genetic maps are not perfectly accurate at the short distances [tens of kilobases kb ] that are relevant for some of our analysis. Notably, Sankararaman et al. The effect of this level of map uncertainty is likely to be minimal for ancient samples, in which the ancestry covariance extends to large distances greater than hundreds of kb. In contrast, for extant samples where the blocks are an order of magnitude smaller, the resulting bias can be substantial, as shown in ref.
Thus, we applied the map correction separately for ancient and extant samples to obtain corrected dates of Neanderthal gene flow in generations t n in generations.
To convert the dates of gene flow from generations to years t n in years while accounting for uncertainty in the generation interval, we assumed a uniform prior probability distribution on the generation interval between 25 and 33 y 21 — The mean generation interval in ancient humans is not known and is likely to have some cultural variability but 2124 showed that, at least in modern humans over a wide variety of cultures and degrees of economic development, the mean age of reproduction falls within this range.
The difference in the dates of gene flow in ancient and extant genomes translates to an estimate of branch shortening or the age of the ancient genome t c. To illustrate the utility of our method, we applied our approach to ancient genomes that have radiocarbon dates of at least 10, y. This threshold was chosen so that the expected date of Neanderthal admixture in the ancient genome is less than 1, generations thus not affected by the bias seen in simulations and that the difference between the dates of admixture in extant and ancient samples is significant beyond statistical error.
This date is within the previously published estimate of 37,—86, yBP most likely range of 47,—65, yBP based on a different ascertainment scheme and genetic map correction 9. The broader confidence interval in ref. Our simulations indicate that the use of the population-sample statistic and ascertainment 0 should not provide biased dates under demographic scenarios that are applicable to Europeans, and thus we believe that the additional bias correction is too aggressive SI AppendixNote S2.
If our assumptions are valid, dates in the range of 40,—54, y ago are important because they suggest that the main Neanderthal interbreeding with modern humans may have occurred in the context of the Upper Paleolithic expansion of modern humans, rather than at earlier times We applied our method to estimate the age of five ancient samples. Below and in SI AppendixTable S1we discuss the dating results for each sample using the S map and ascertainment 0.
The Clovis genome from North America sequenced to an average coverage of After accounting for uncertainty, this estimate is consistent with its radiocarbon date Fig. Estimated age of ancient genomes. For Oase1 Lower Rightwe show single exponential fit up to the genetic distance of 65 cM and bin size of 0. We do not show CEU because the analysis was based on a different bin size and maximum distance. The Kostenki14 K14 genome from European Russia sequenced to an average coverage of 2.
However, the details of method used in ref. Because the coverage for this sample is high enough, we were able to make reliable heterozygous calls and thus we used diploid genotypes for the inference.