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Molecular clocks: When timesare a-changin'

Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.
Trends in Genetics (Impact Factor: 9.92). 03/2006; 22(2):79-83. DOI: 10.1016/j.tig.2005.11.006
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ABSTRACT
The molecular clock has proved to be extremely valuable in placing timescales on evolutionary events that would otherwise be difficult to date. However, debate has arisen about the considerable disparities between molecular and palaeontological or archaeological dates, and about the remarkably high mutation rates inferred in pedigree studies. We argue that these debates can be largely resolved by reference to the "time dependency of molecular rates", a recent hypothesis positing that short-term mutation rates and long-term substitution rates are related by a monotonic decline from the former to the latter. Accordingly, the extrapolation of rates across different timescales will result in invalid date estimates. We examine the impact of this hypothesis with respect to various fields, including human evolution, animal domestication and conservation genetics. We conclude that many studies involving recent divergence events will need to be reconsidered.

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Available from: Greger Larson
Molecular clocks: when times
are a-changin’
Simon Y.W. Ho and Greger Larson
Department of Zoology, University of Oxford, Oxford, UK, OX1 3PS
The molecular clock has proved to be extremely valuable
in placing timescales on evolutionary events that would
otherwise be difficult to date. However, debate has
arisen about the considerable disparities between
molecular and palaeontological or archaeological
dates, and about the remarkably high mutation rates
inferred in pedigree studies. We argue that these
debates can be largely resolved by reference to the
‘time dependency of molecular rates’, a recent hypoth-
esis positing that short-term mutation rates and long-
term substitution rates are related by a monotonic
decline from the former to the latter. Accordingly, the
extrapolation of rates across different timescales will
result in invalid date estimates. We examine the impact
of this hypothesis with respect to various fields,
including human evolution, animal domestication and
conservation genetics. We conclude that many studies
involving recent divergence events will need to be
reconsidered.
The inconstant molecular clock
The molecular clock has become an indispensable tool
within evolutionary biology, enabling independent time-
scales to be placed on evolutionary events. Despite these
valuable contributions, date estimates derived from
molecular data have not been without controversy. In
particular, when molecular clocks have been employed to
estimate the timing of recent events already tentatively
dated on the basis of palaeontological, archaeological or
biogeographic sources, conflicting dates are frequently
obtained [1]. Some of the most significant discrepancies
have been evident in studies of human evolution and
animal domestication. Previous criticisms of divergence-
dating methodology have focused on faulty calibration
points [2] and the impact of rate heterogeneity among
lineages [3]. Although these points remain valid, many of
the disagreements are still unresolved. As we explain in
the following sections, we believe that the explanation lies
in another major methodological problem that has
recently come to light.
It has long been recognized that violations of the strict
molecular clock are commonplace [4]. More recently,
however, several studies have noted that molecular rates
observed on genealogical timescales [!1 million years
(My)] are an order of magnitude or more greater than
those measured over geological time (O1 My). In the avian
mitochondrial genome, for example, a mutation rate of
95% per My was estimated from the control region of
Ade
´
lie penguins [5], which is considerably greater than
the paradigmatic substitution rate of 1% per My observed
among various avian taxa [6–8], even after acknowledging
the accepted rate difference between non-coding and
protein-coding DNA. Elevated mutation rates (w30% per
My) have also been estimated from the control region of
recently diverged species within the Bison [9] and Bos
[10,11] genera. In the mitochondrial control region of
humans, Parsons et al. [12] estimated a mutation rate of
250% per My, whereas a meta-analysis [13] of data pooled
from eight pedigree studies yielded an overall rate
estimate of 95% per My. Both of these pedigree-based
estimates exceed those from phylogenetic studies [14,15]
by up to two orders of magnitude.
We argue that these debates actually stem from the
same phenomenon: the ‘time dependency of molecular
rates’, which has been described in several recent articles
[16–18]. The observed rate at which molecular clocks ‘tick’
is not entirely constant over time. Instead, there is a
measurable transition from an increased, short-term
mutation rate to a low, long-term substitution rate (see
Glossary), and this trend can be described mathematically
(Box 1). Failure to distinguish between the mutation rate
and the substitution rate, and to consider the relationship
between the two, is most likely to be the key factor
responsible for several prominent controversies in evol-
utionary biology. We examine some of these in the
following section and explain how these disputes can be
resolved by considering the time dependency of molecular
rates before discussing the implications for other studies.
Glossary
Mutation rate: the instantaneous rate at which nucleotide changes occur in the
genome. Lethal or near-lethal mutations are often ignored in calculations of the
mutation rate.
Pedigree rate: an estimate of the mutation rate, assessed by calculating the
number of nucleotide changes observed over a known number of reproductive
events (based on a known genealogy of individuals and a given or assumed
generation time).
Substitution rate: the rate at which mutations are fixed in the population.
Because most nucleotide changes (mutations) that appear within a population
are eventually eliminated (by purifying or background selection or by drift),
there will be fewer observed changes per unit of time. As a result, the
substitution rate will always be slower than the mutation rate (except under
perfectly neutral conditions).
Phylogenetic rate: an estimate of the substitution rate, calculated by comparing
molecular sequence data obtained from different species.
Corresponding author: Larson, G. (greger.larson@zoo.ox.ac.uk).
Available online 13 December 2005
Opinion TRENDS in Genetics Vol.22 No.2 February 2006
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Page 1
Human migration and origins
Many of the current hypotheses concerning human
migration events are based on molecular date estimates.
Most of these date estimates rely on two main assump-
tions: (i) that the human–chimpanzee divergence occurred
between four and six million years ago (Mya); and (ii) that
the substitution rate inferred from this calibration has
remained the same throughout the comparatively recent
generation of human genetic diversity. We believe that
this second assumption does not hold and that the
application of an inappropriately low rate leads to an
overestimation of molecular dates.
One prominent example in which this occurs is in
studies of the peopling of the Americas, which archae-
ological evidence places at w10–12 thousand years ago
(kya) with the appearance of the Clovis culture [19].
However, when Ward et al. [20] applied the human–
chimpanzee substitution rate to Amerindian sequences,
they found that the tribal lineages diverged from each
other w60 kya. On the basis of this evidence, they rejected
the notion of a founder effect in the peopling of the
Americas. In a similar study, Horai et al. [21] eliminated
the possibility of post-migration genetic differentiation
and concluded that Native Americans must have entered
the New World in several waves.
It is clear that the extrapolation of phylogenetic rates
onto population-level data is a recurrent error, but the
opposite scenario (the extrapolation of pedigree rates to
deeper timescales) also occurs. To place a timescale on the
unique divergence between African and non-African
humans, Armour et al. [22] applied a relatively rapid
pedigree rate to the data and concluded that this event
occurred only 15 kya. This date falls well short of the
archaeologically defined first appearance of humans in
both Europe (40 kya [23]) and Israel (90 kya [24]). The
scenarios described here represent only the tip of the
iceberg. The timing of many other events in human
evolution, such as the origin of HIV and other viruses, the
divergence between humans and Neanderthals and the
dispersals of other hominids, might also require revision.
One of the most familiar debates in human evolution is
the age of the most recent female ancestor of all existing
human mitochondrial lineages, commonly referred to as
‘mitochondrial Eve’. Molecular analyses using a human–
chimpanzee calibration have placed her age at 150–
250 kya [25–27] (Table 1), whereas using a rate derived
from pedigree studies yields a date estimate that is
patently too recent (e.g. 6 kya [1,28]). In this particular
example, the dates estimated on the basis of an
intraspecific calibration [29] are probably closest to the
truth. The provisional date estimates proposed by Ho et al.
[17], which were obtained using a method that accommo-
dates the time dependency of molecular rates, also
demonstrate that the actual age of mitochondrial Eve
most probably lies between the estimates based on the
pedigree (mutation) and phylogenetic (substitution) rates
(Box 1).
Domestication
Studies of the timing of domestication have persistently
generated the greatest inconsistencies between
Box 1. Time dependency of molecular rates
During the past decade, a remarkable disparity has been discovered
between molecular rates estimated from pedigrees (mutation rate)
and from phylogenetic studies (substitution rate) [13,28]. Instead of a
simple dichotomy between fast (recent) rates and slower (older)
rates, however, there exists a measurable transition between the two
[16–18]. The relationship can be described by a vertically translated
exponential decay curve, with the y-axis intercept representing the
instantaneous rate of non-lethal mutations and the asymptote
representing the substitution rate (Figure I). The critical region of
the curve lies between 0 and 1–2 My. Thus, any date estimates that
fall within this region need to be corrected for the rapid decline in the
molecular rate.
The exact causes of the time dependency of molecular rates are
not entirely clear, but it is most likely to be a combination of (i)
purifying selection against deleterious and slightly deleterious
mutations; and (ii) saturation at mutational ‘hotspots’. Many of the
polymorphisms within species do not persist over long time frames
because they are removed by purifying (background) selection or by
chance (drift). These polymorphisms, however, contribute to the
elevated rate estimates made from population-level sequence data,
leading to an apparent increase in molecular rates towards the
present. Errors in calibration points and in molecular sequence data
can also contribute to this trend [17].
Importantly, the decrease in molecular rate (as the timescale
increases) does not require the invocation of a novel mechanism of
‘rate acceleration’ towards the present. It is merely an observed
decrease in molecular rate, the end result of mutation on the one
side and purifying selection and saturation on the other. Finally,
although the rate curve has only been generated using data from
primates and birds, there is no compelling reason to suspect that the
same phenomenon does not hold across other large endotherms.
However, the exact shape of the curve (and hence, the age at which
the observed rate begins to asymptote along the substitution rate) is
dependent on the taxon in question.
TRENDS in Genetics
Mutation rate
Substitution rate
Observed rate
Time before present
Faster
1–2 My Older
Figure I. A molecular rate curve showing the transition between the
instantaneous mutation rate and the long-term substitution rate, passing
through a critical region at w1-2 My.
Table 1. Estimates of the age of ‘mitochondrial Eve’ using
various calibration points
Calibration Date estimate (ka) Refs
Phylogenetic 166–249 [48]
(human-chimpanzee) 120–150 [25]
170 [27]
Pedigree rate 6.5 [1]
Intraspecific 133 [29]
76 [17]
Opinion TRENDS in Genetics Vol.22 No.2 February 200680
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Page 2
archaeological and molecular date estimates. To discrimi-
nate between wild and domestic animals, and thus
establish when and where domestication began, archae-
ozoologists have generally relied on the morphological
differentiation brought on by the domestication process.
This reliance on phenotypic change biases archaeologi-
cally based dates towards the later stages of domesti-
cation. Because molecular differentiation would have
begun as soon as domestic populations were no longer
interbreeding with their wild counterparts, the estimates
using molecular clocks were expected to pre-date those
inferred from archaeological remains. The surprising
results revealed that, for virtually every major domestic
mammal, molecular date estimates exceeded the accepted
archaeological dates by tens or even hundreds of
thousands of years (Table 2).
The simplest explanation for this discrepancy is that
the molecular dates reflect the splits among multiple wild
lineages, all (or most) of which were subsequently
domesticated (e.g. Ref. [30]). Most of the studies cited in
Table 2 at least acknowledged this possibility, but even
those that controlled for this by calculating the age of a
single clade containing only domestic animals still
produced molecular estimates that significantly contra-
dicted the archaeological record [31,32].
A second general explanation for the vast disparities
between molecular and fossil-based date estimates is the
problem associated with calibration points. Although this
issue applies to all divergence date analyses, it is
particularly relevant for domestication studies, given the
relatively short time frame of domestication and the large
uncertainty surrounding splits between wild progenitors
and their sister species. In coyotes and wolves, for
example, Kurten [33] places the split at 1.5–4.5 Mya
based on the fossil record. Even employing the most recent
extreme of the fossil-based ranges (thus producing the
fastest rate) for any of the domestic animals in Table 2,
however, does not resolve the discrepancy between the
molecular and archaeological estimates.
The most likely explanation for the discrepancy
between the dates is that substitution rates derived from
phylogenetic divergences have been incorrectly used to
date splits among conspecific populations. The projection
of a rate estimated using palaeontologically derived splits
between outgroup and wild progenitor taxa (all of which
are O1 My) onto sequences obtained from populations of
modern domestic animals have consistently produced
artificially deep time estimates for the domestication of
many animals, including dogs [31], donkeys [34] and
sheep [35]. Other domestication studies (e.g. pigs [36] and
sheep [37]) that imported general substitution rates
derived from mammalian taxa might have also over-
estimated the timing of the coalescence of domesticated
lineages. In turn, these practices might necessitate the
postulation of either many independent domestication
events or numerous domesticated wild lineages [30].
It remains possible that the earliest phases of domes-
tication began tens of thousands of years ago and that the
phenotypic changes associated with the process are a
relatively recent phenomenon. What is more likely,
however, is that the highly controversial discrepancies
are largely the spurious product of invalid extrapolations
of molecular rates.
Implications for other fields
The inappropriate application of substitution rates to
intraspecific evolutionary questions has also occurred in
numerous other fields of biology. Because this method-
ology results in an overestimation of the time required to
attain a given level of genetic diversity, the time
dependency of molecular rates has a substantial impact
on conservation genetics. A study on humpback whales,
for example, calculated a molecular rate on the basis of
calibration points at 6–25 My. This rate was used to
conclude that existing populations of humpback whales
underwent ancient divergences [38]. Menotti-Raymond
and O’Brien [39] applied a felid substitution rate to
cheetah mitochondrial sequences, estimating that a
genetic bottleneck occurred at 28–36 kya. More recently,
Eizirik et al. [40] used an almost identical approach to date
the coalescence of modern jaguar lineages. In both of these
felid studies, and in others based on the same method-
ology, the dates were probably overestimated, which has
significant consequences for conservation strategies.
Studies tying evolutionary events to climatic changes
in the Pleistocene period are also susceptible to the misuse
of long-term substitution rates in the analysis of popu-
lation-level data. For example, the classic 1% per My
avian mitochondrial substitution rate was applied to pairs
of songbird subspecies (e.g. Myrtle and Audubon’s
warblers) to reject the ‘late Pleistocene origins’ hypothesis,
which associates the origins of North American songbirds
with Pleistocene glacial events [41].Correlationsof
megafaunal-extinction events with either climate change
or human activity are highly dependent on accurate
estimates of divergence dates, implying that these are
particularly sensitive to inappropriately applied substi-
tution rates. By employing a felid substitution rate in the
analysis of puma sequences, Culver et al. [42] inferred the
coincidence of recolonisation of North America by pumas
and a widespread megafaunal-extinction event.
Population genetics and demographics are directly
affected by the time dependency of molecular rates because
simplifying assumptions about rates must be made in order
to separate them from the effects of population size. A
recent study [43] on the size of the American founding
population extrapolated the human–chimpanzee mutation
rate, resulting in an estimated effective size of 80
Table 2. Disparity between archaeologically derived dates and
molecular dates for domestication among a variety of animals
Animal Archaeological
estimates
(ka)
Molecular
date
estimates
(ka)
a
Refs
Pig (Sus domesticus) 9 58–500 [36,49,50]
Sheep (Ovis aries) 12 84–750 [35,37,49]
Dog (Canis familiaris) 12–14 18–135 [31,51,52]
Cow (Bos taurus and
B. indicus)
8 10.1–37.6 [10,49]
Donkey (Equus asinus) 5.5 303–910 [34,49]
Horse (Equus caballus) 6 320–630 [32,49]
a
These dates represent the most literal interpretation of molecular clock analyses. A
more in-depth discussion is presented in the main text.
Opinion TRENDS in Genetics Vol.22 No.2 February 2006 81
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Page 3
individuals. If a more appropriate, intraspecific human
mutation rate had been used, the effective population size
would have been even lower, given the reciprocal relation-
ship between population size and mutation rate (for a given
value of the population mutation rate parameter, q, which
is proportional to the product of the mutation rate and the
effective population size).
It is possible to list many studies from other fields, such
as biogeography [44], in which molecular rates have been
inappropriately extrapolated across the population-
species boundary. However, the diverse catalogue of
examples presented here already provides a cogent
indication that the problem is widespread.
Dating recent events
It is clear that the direct application of a strict molecular
clock across the population-species boundary (in either
direction) is unjustifiable, and that the time dependency of
molecular rates complicates the process of molecular date
estimation. To estimate the timing of recent events in a
valid manner, it is paramount to use a method that
distinguishes mutation rates from substitution rates.
Several different options are apparent, including but not
limited to the following:
(i) Use calibration points that are as close as possible
to the date being estimated (e.g. intraspecific
calibration points for population-level studies
[29,45]). Given the time dependency of molecular
rates, failure to do so will result in a greater
discrepancy between the true rate and the rate that
is used in the analysis. This approach could be
somewhat circular, however, because it is necessary
to have a reasonable idea of what the true date
might be to select a suitable calibration;
(ii) If reliable ancient DNA data are available, use
radiocarbon-dated sequences [9,46] to decrease the
amount of extrapolation required to estimate the
age of the root of the tree, as in (i);
(iii) Estimate dates in a relaxed clock framework that
permits molecular rates to vary among branches
[47], enabling terminal branches to have faster
rates (this only works if there is reasonably dense
taxon sampling);
(iv) Use an accurately estimated molecular rate curve
(Box 1) to derive the rate needed for the timescale in
question [17].
Although the last of these methods represents the most
straightforward approach, it is not an altogether realistic
option owing to the extreme difficulty in obtaining
accurate rate curves and because individually generated
rate curves cannot (and should not) be generalized across
unrelated taxa.
Concluding remarks
In the midst of widespread confusion and criticism
concerning molecular date estimates of recent evolutionary
events, we believe that many outstanding inconsistencies
can be explained by the time dependency of molecular rates.
Although it would not be reasonable to expect that molecular
date estimates should always be identical to those from
other sources (considering not only the biased and incom-
plete nature of the fossil and archaeological records, but also
the difference between gene trees and species trees), we
should expect that increasingly realistic genetic models will
reduce the discrepancy.
The examples provided in this article highlight the
difficulty of producing accurate date estimates but suggest
that meaningful dates can be obtained from molecular
data if the analysis is done correctly. However, the time
dependency of rates also provides a strong warning
against extrapolating molecular rates across the popu-
lation-species boundary, unless the transition is well
understood and has been quantified. Unfortunately,
many current hypotheses about human evolution, domes-
tication, conservation genetics and human demographic
history rest on date estimates that have been improperly
calculated. Clearly, many previous studies dealing with
recent timescales will need to be re-evaluated.
Acknowledgements
We thank P. Holland, B. Shapiro, A. Rambaut, and three anonymous
reviewers for valuable comments on this article, and A. Cooper, A. J.
Drummond, D. Penny and R. Barnett for advice. We also thank the
Leverhulme Trust, the Arts and Humanities Research Board, the
Commonwealth Scholarship Commission and Linacre College, Oxford,
for financial support.
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Opinion TRENDS in Genetics Vol.22 No.2 February 2006 83
www.sciencedirect.com
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    • "Systemic bias in molecular age estimates has been demonstrated in numerous studies (Ho and Jermiin 2004, Jansa et al. 2006, Norris et al. 2015). Deep branches may be underestimated relative to more recent branches (Ho and Larson 2006), especially in situations where fast-evolving genes have become saturated (Hugall et al. 2007, Dornburg et al. 2014). If such systemic bias is present, it may affect both chipmunks and Holarctic ground squirrels equally, but the bias would be corrected only for the Holarctic ground squirrels, thanks to the presence of a calibrating fossil. "
    [Show abstract] [Hide abstract] ABSTRACT: The chipmunks are a Holarctic group of ground squirrels currently allocated to the genus Tamias within the tribe Marmotini (Rodentia: Sciuridae). Cranial, post-cranial, and genital morphology, cytogenetics, and genetics each separate them into three distinctive and monophyletic lineages now treated as subgenera. These groups are found in eastern North America, western North America, and Asia, respectively. However, available genetic data (mainly from mitochondrial cytochrome b) demonstrate that the chipmunk lineages diverged early in the evolution of the Marmotini, well before various widely accepted genera of marmotine ground squirrels. Comparisons of genetic distances also indicate that the chipmunk lineages are as or more distinctive from one another as are most ground squirrel genera. Chipmunk fossils were present in the late Oligocene of North America and shortly afterwards in Asia, prior to the main radiation of Holarctic ground squirrels. Because they are coordinate in morphological, genetic, and chronologic terms with ground squirrel genera, the three chipmunk lineages should be recognized as three distinct genera, namely, Tamias Illiger, 1811, Eutamias Trouessart, 1880, and Neotamias A. H. Howell, 1929. Each is unambiguously diagnosable on the basis of cranial, post-cranial, and external morphology.
    Full-text · Article · Apr 2016 · Mammalia
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    • "Specifically, a relationship between rate estimates and calibration times has been found to span many orders of magnitude of time depth. This relationship is best described by a power law (Duch^ ene et al. 2014; Aiewsakun & Katzourakis 2015b; Molak & Ho 2015 ), rather than by a translated exponential function as previously believed (Ho et al. 2005; Ho & Larson 2006). Although quantifying the time-dependent biases in rate estimates has not directly enabled resolution of its specific causes, the temporal span of the trend suggests that there are likely to be multiple drivers (Molak & Ho 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: We are writing in response to a recent critique by Emerson & Hickerson (2015), who challenge the evidence of a time-dependent bias in molecular rate estimates. This bias takes the form of a negative relationship between inferred evolutionary rates and the ages of the calibrations on which these estimates are based. Here, we present a summary of the evidence obtained from a broad range of taxa that supports a time-dependent bias in rate estimates, with a consideration of the potential causes of these observed trends. We also describe recent progress in improving the reliability of evolutionary rate estimation and respond to the concerns raised by Emerson & Hickerson (2015) about the validity of rates estimated from time-structured sequence data. In doing so, we hope to dispel some misconceptions and to highlight several research directions that will improve our understanding of time-dependent biases in rate estimates.
    Full-text · Article · Dec 2015
    • "However, these time estimates should be considered only as suggestions. Mutation rates may differ among species, and molecular rates observed on genealogical time scales (<10 6 y) are at least an order of magnitude greater than those measured over geological time scales (>10 6 y) (Ho and Larson 2006 ). This pattern has been observed in various species and for different mitochondrial genes (e.g., Audzijonyte and Väinölä 2006, Ho et al. 2007, Millar et al. 2008 ). "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of our study was to analyze the origin of the Icelandic population of the Holarctic caddisfly Apatania zonella, a species with a highly skewed sex ratio. Biological diversity in Iceland, as in the Arctic, has been shaped by the glacial periods of the Pleistocene, but Iceland’s geographic isolation contributes to its low diversity. Many species at high latitudes in the northern hemisphere have diverged in allopatric areas during glacial periods and expanded their distribution following the retreat of the glaciers. Genetic patterns of various species reflect these climate changes. Recent work on freshwater insects has shown patterns that differ from those of many vertebrate and terrestrial species. To analyze the origin of the Icelandic population we assessed sequence variation of the mitochondrial cytochrome c oxidase subunit I (COI) gene in specimens from Iceland and throughout its distribution range. We included sequences from different species for a further comparison. We also assessed sequence variation in 3 nuclear introns for a subset of the sample. We partitioned variation at the molecular level among and within groups and reconstructed and dated phylogenetic trees based on Bayesian and maximum likelihood methods. The molecular variation was highly structured at the large geographical scale and within Iceland. The analysis defined 2 major lineages, Nearctic and Palaearctic, which diverged during the last ice age. Both lineages have colonized Iceland, resulting in a high diversity in the Icelandic population. High diversity is also observed in Alaska, and the Alaskan mitochondrial DNA haplotypes are situated close to the center of the genealogical network. The phylogeny of the genus Apatania is not fully resolved, and several species of Apatania cluster within the genealogy of Apatania zonella.
    No preview · Article · Dec 2015 · Freshwater science
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