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PubMed2006

A mitogenomic timescale for birds detects variable phylogenetic rates of molecular evolution and refutes the standard molecular clock.

Current understanding of the diversification of birds is hindered by their incomplete fossil record and uncertainty in phylogenetic relationships and phylogenetic rates of molecular evolution. Here we performed the first comprehensive analysis of mitogenomic data of 48 vertebrates, including 35 birds, to derive a Bayesian timescale for avian evolution and to estimate rates of DNA evolution. Our approach used multiple fossil time constraints scattered throughout the phylogenetic tree and accounts for uncertainties in time constraints, branch lengths, and heterogeneity of rates of DNA evolution. We estimated that the major vertebrate lineages originated in the Permian; the 95% credible intervals of our estimated ages of the origin of archosaurs (258 MYA), the amniote-amphibian split (356 MYA), and the archosaur-lizard divergence (278 MYA) bracket estimates from the fossil record. The origin of modern orders of birds was estimated to have occurred throughout the Cretaceous beginning about 139 MYA, arguing against a cataclysmic extinction of lineages at the Cretaceous/Tertiary boundary. We identified fossils that are useful as time constraints within vertebrates. Our timescale reveals that rates of molecular evolution vary across genes and among taxa through time, thereby refuting the widely used mitogenomic or cytochrome b molecular clock in birds. Moreover, the 5-Myr divergence time assumed between 2 genera of geese (Branta and Anser) to originally calibrate the standard mitochondrial clock rate of 0.01 substitutions per site per lineage per Myr (s/s/l/Myr) in birds was shown to be underestimated by about 9.5 Myr. Phylogenetic rates in birds vary between 0.0009 and 0.012 s/s/l/Myr, indicating that many phylogenetic splits among avian taxa also have been underestimated and need to be revised. We found no support for the hypothesis that the molecular clock in birds "ticks" according to a constant rate of substitution per unit of mass-specific metabolic energy rather than per unit of time, as recently suggested. Our analysis advances knowledge of rates of DNA evolution across birds and other vertebrates and will, therefore, aid comparative biology studies that seek to infer the origin and timing of major adaptive shifts in vertebrates.

Animals↗

PubMed2005

The molecular clock mediates leptin-regulated bone formation.

The hormone leptin is a regulator of bone remodeling, a homeostatic function maintaining bone mass constant. Mice lacking molecular-clock components (Per and Cry), or lacking Per genes in osteoblasts, display high bone mass, suggesting that bone remodeling may also be subject to circadian regulation. Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion. Thus, clock genes may mediate the leptin-dependent sympathetic regulation of bone formation. We show that expression of clock genes in osteoblasts is regulated by the sympathetic nervous system and leptin. Clock genes mediate the antiproliferative function of sympathetic signaling by inhibiting G1 cyclin expression. Partially antagonizing this inhibitory loop, leptin also upregulates AP-1 gene expression, which promotes cyclin D1 expression, osteoblast proliferation, and bone formation. Thus, leptin determines the extent of bone formation by modulating, via sympathetic signaling, osteoblast proliferation through two antagonistic pathways, one of which involves the molecular clock.

Animals↗

PubMed1987

Molecular clocks and evolutionary relationships: possible distortions due to horizontal gene flow.

This paper discusses recent evidence suggesting that genetic information from one species occasionally transfers to another remotely related species. Besides addressing the issue of whether or not the molecular data are consistent with a wide-spread influence of horizontal gene transfer, the paper shows that horizontal gene flow would not necessarily preclude a linear molecular clock or change the rate of molecular evolution (assuming the neutral allele theory). A pervasive influence of horizontal gene transfer is more than just consistent with the data of molecular evolution, it also provides a unique explanation for a number of possibly conflicting phylogenies and contradictory clocks. This phenomenon might explain why some protein clocks are linear while the superoxide dismutase clock is not, how the molecular data on the phylogeny of apes and Australian song birds are not necessarily in conflict with those based on morphology, and, finally, why the mycoplasmas have an accelerated molecular clock.

Animals↗

PubMed1986

Natural selection and the molecular clock.

This paper concludes that the statistical properties of protein evolution are compatible with a particular model of evolution by natural selection. The argument begins with a statistical description of the molecular clock based on a Poisson process with a randomly varying tick rate. If the time scale of the change of the tick rate of the molecular clock is assumed to be much less than the average time between substitutions, then it is shown that the substitution process must be episodic, with bursts of substitutions being separated by long periods of time with no substitutions. This analysis generalizes the recent work of Gillespie (1984a). The second part of the argument shows that a simple model of evolution by natural selection--one that incorporates a changing environment, the molecular landscape, and a simple form of epistasis--exhibits dynamics that are identical to those inferred from the statistical analysis. This leads to the conclusion that natural selection is a viable explanation for protein evolution. In addition, a correction formula for multiple substitutions is given that does not require that the substitution process be a Poisson process, and some comments on the inability of the neutral allele theory to account for the dynamics of the substitution process are presented.

Animals↗

PubMed2004

Molecular clocks do not support the Cambrian explosion.

The fossil record has long supported the view that most animal phyla originated during a brief period approximately 520 MYA known as the Cambrian explosion. However, molecular data analyses over the past 3 decades have found deeper divergences among animals (approximately 800 to 1,200 MYA), with and without the assumption of a global molecular clock. Recently, two studies have instead reported time estimates apparently consistent with the fossil record. Here, we demonstrate that methodological problems in these studies cast doubt on the accuracy and interpretations of the results obtained. In the study by Peterson et al., young time estimates were obtained because fossil calibrations were used as maximum limits rather than as minimum limits, and not because invertebrate calibrations were used. In the study by Aris-Brosou and Yang, young time estimates were obtained because of problems with rate models and other methods specific to the study, and not because Bayesian methods were used. This also led to many anomalous findings in their study, including a primate-rodent divergence at 320 MYA. With these results aside, molecular clocks continue to support a long period of animal evolution before the Cambrian explosion of fossils.

Animals↗

PubMed2006

A survey of nuclear ribosomal internal transcribed spacer substitution rates across angiosperms: an approximate molecular clock with life history effects.

BACKGROUND: A full understanding of the patterns and processes of biological diversification requires the dating of evolutionary events, yet the fossil record is inadequate for most lineages under study. Alternatively, a molecular clock approach, in which DNA or amino acid substitution rates are calibrated with fossils or geological/climatic events, can provide indirect estimates of clade ages and diversification rates. The utility of this approach depends on the rate constancy of molecular evolution at a genetic locus across time and across lineages. Although the nuclear ribosomal internal transcribed spacer region (nrITS) is increasingly being used to infer clade ages in plants, little is known about the sources or magnitude of variation in its substitution rate. Here, we systematically review the literature to assess substitution rate variation in nrITS among angiosperms, and we evaluate possible correlates of the variation. RESULTS: We summarize 28 independently calibrated nrITS substitution rates ranging from 0.38 x 10(-9) to 8.34 x 10(-9) substitutions/site/yr. We find that herbaceous lineages have substitution rates almost twice as high as woody plants, on average. We do not find any among-lineage phylogenetic constraint to the rates, or any effect of the type of calibration used. Within life history categories, both the magnitude of the rates and the variance among rates tend to decrease with calibration age. CONCLUSION: Angiosperm nrITS substitution rates vary by approximately an order of magnitude, and some of this variation can be attributed to life history categories. We make cautious recommendations for the use of nrITS as an approximate plant molecular clock, including an outline of more appropriate phylogenetic methodology and caveats against over interpretation of results. We also suggest that for lineages with independent calibrations, much of the variation in nrITS substitution rates may come from uncertainty in calibration date estimates, highlighting the importance of accurate and/or multiple calibration dates.

Amino Acid Substitution↗

PubMedDate not supplied

The molecular clock runs more slowly in man than in apes and monkeys.

The molecular clock hypothesis postulates that the rate of molecular evolution is approximately constant over time. Although this hypothesis has been highly controversial in the past, it is now widely accepted. The assumption of rate constancy has often been taken as a basis for reconstructing the phylogenetic relationships among organisms or genes and for dating evolutionary events. Further, it has been taken as strong support for the neutral mutation hypothesis, which postulates that the majority of molecular changes in evolution are due to neutral or nearly neutral mutations. For these reasons, the validity of the rate constancy assumption is a vital issue in molecular evolution. Recent studies using DNA sequence data have raised serious doubts about the hypothesis. These studies provided support for the suggestion made from immunological distance and protein sequence data that a rate slowdown has occurred in hominoid evolution, and showed, in agreement with DNA hybridization studies, that rates of nucleotide substitution are significantly higher in rodents than in man. Here, rates of nucleotide substitution in rodents are estimated to be 4-10 times higher than those in higher primates and 2-4 times higher than those in artiodactyls. Further, this study provides strong evidence for the hominoid slowdown hypothesis and suggests a further rate-slowdown in hominoid evolution. Our results suggest that the variation in rate among mammals is primarily due to differences in generation time rather than changes in DNA repair mechanisms. We also propose a method for estimating the divergence times between species when the rate constancy assumption is violated.

Animals↗

PubMed1997

Prostaglandin D synthase (beta-trace protein): a molecular clock to trace the origin of REM sleep?

In 1965, Zuckerkandl and Pauling proposed a novel concept that some important molecules termed semantides, which carry the information of the genes or a transcript thereof, can be used as molecular clocks to trace evolutionary history. According to this concept, enzymes are designated as tertiary semantides, following genes (primary semantides) and the mRNA (secondary semantides). Based on this idea, I propose that prostaglandin D synthase (which has been demonstrated recently as identical to the beta-trace protein present in the cerebrospinal fluid of mammals) may serve as a molecular clock to trace the origin and evolution of rapid eye movement sleep in the vertebrates.

Animals↗

PubMed1999

The molecular clock of HIV-1 unveiled through analysis of a known transmission history.

Detailed knowledge about the rate and mode of the genetic variation is vital for understanding how HIV-1 induces disease and develops resistance as well as for studies on the molecular epidemiology and origin of the virus. To unveil the molecular clock of HIV-1 we analyzed a unique set of viruses from a known transmission history with separation times between samples of up to 25 years. The env V3 and p17gag regions of the genome were sequenced, and genetic distances were estimated by using the true tree and a nucleotide substitution model based on a general reversible Markov process with a gamma distribution to account for differences in substitution rates among sites. Linear regression analysis showed that separation times were significantly correlated with synonymous as well as nonsynonymous nucleotide distances in both V3 and p17, giving strong support for the existence of a molecular clock. The estimated rate of nucleotide substitution was 6.7 +/- 2.1 x 10(-3) substitutions/site per year in V3 and 2.7 +/- 0.5 x 10(-3) in p17. Importantly, the regression analyses showed that there was a significant genetic distance at zero divergence times. This pretransmission interval exists because the ramifications in the phylogenetic trees do not correspond to time of transmission, but rather to the coalescence time of the most recent common ancestor of the viruses carried by the transmitter and the recipient. Simulation experiments showed that neither the V3 nor the p17 clocks were overdispersed, which indicates that the introduction of nucleotide substitutions can be described adequately by a simple stochastic Poisson process.

Disease Transmission, Infectious↗

PubMed2002

A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades.

The prevalence of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is considerably lower in the U.S. than in Japan. To elucidate this difference, we determined the time origin of the HCV epidemic in each country by using molecularly clocked long-term serial samples obtained from HCV carriers of genotypes 1a and 1b. The molecular clock estimated that HCV genotype 1 first appeared in Japan in around 1882, whereas emergence in the U.S. was delayed until around 1910. In addition, by statistical analysis using coalescent theory, the major spread time for HCV infection in Japan occurred in the 1930s, whereas widespread dissemination of HCV in the U.S. occurred in the 1960s. These estimates of viral spread time are consistent with epidemiologic observations and predict that the burden of HCC in the U.S. will increase in the next two to three decades, possibly to equal that currently experienced in Japan.

Adult↗

PubMed1997

Clusters of identical new mutations can account for the "overdispersed" molecular clock.

Germ-cell mutations may occur during meiosis, giving rise to independent mutant gametes in a Poisson process, or before meiosis, giving rise to multiple copies of identical mutant gametes at a much higher probability than the Poisson expectation. We report that the occurrence of these early premeiotic clusters of new identical mutant alleles increases the variance-to-mean ratio of mutation rate (R(u) > 1). This leads to an expected variance-to-mean ratio (R(t)) of the molecular clock that is always greater than one and may cover the observed range of R(t) values. Hence, the molecular clock may not be over-dispersed based on this new mutational model that includes clusters. To get a better estimation of R(u) and R(t), one needs measurements of the intrageneration variation of reproductive success (Nt/Ne(i)), population dynamics (ki), and the proportion of new mutations that occur in clusters (rc), especially those formed before germ-cell differentiation.

Animals↗

PubMed2000

Phylogenetics of Perissodactyla and tests of the molecular clock.

Two mitochondrial genes, the protein-coding cytochrome c oxidase subunit II (COII) gene and a portion of the 12S rRNA gene, were used for phylogenetic investigation of the mammalian order Perissodactyla. The primary objective of the study was to utilize the extensive fossil record of perissodactyls for calibrating molecular clocks and comparing estimates of divergence times using both genes and two fossil calibration points. Secondary objectives included clarification of previously unresolved relationships within Tapiridae and comparison of the results of separate and combined analyses of two genes. Analyses included several perissodactyl lineages representing all three families (Tapiridae, Equidae, and Rhinocerotidae), most extant genera, all four species of tapirs, two to four species of rhinoceros, and two species of Equus. The application of a relatively recent fossil calibration point and a relatively ancient calibration point produced greatly different estimates of evolutionary rates and divergence times for both genes, even though a relative rates test did not find significant rate differences among taxa. A likelihood-ratio test, however, rejected a molecular clock for both genes. Neither calibration point produced estimates of divergence times consistent with paleontological evidence over a range of perissodactyl radiations. The combined analysis of both genes produces a well-resolved phylogeny with Perissodactyla that conforms to traditional views of interfamilial relationships and supports monophyly of neotropical tapirs. Combining the data sets increases support for most nodes but decreases the support for a neotropical tapir clade because the COII and 12S rRNA data sets are in conflict for tapir relationships.

Animals↗

PubMed1994

The superoxide dismutase molecular clock revisited.

The Cu,Zn superoxide dismutase (SOD) was examined earlier and found to behave in a very unclock-like manner despite (accepted point mutation, or PAM) corrections for multiple replacements per site. Depending upon the time span involved, rates could differ 5-fold. We have sought to determine whether the data might be clock-like if a covarion model were used. We first determined that the number of concomitantly variable codons (covarions) in SOD is 28. With that value fixed we found that the observations for SOD could fit reasonably well a molecular clock if, given 28 covarions, (i) there are approximately six replacements every 10 million years, (ii) the total number of codons is 162, (iii) the number of codons that are permanently invariable across the range of taxa from fungi to mammals is 44, and (iv) the persistence of variability is quite low (0.01). Thus, the inconsistent number of amino acid differences between various pairs of descendent sequences could well be the result of a fairly accurate molecular clock. The general conclusion has two sides: (i) the inference that a given gene is a bad clock may sometimes arise through a failure to take all the relevant biology into account and (ii) one should examine the possibility that different subsets of amino acids are evolving at different rates, because otherwise the assumption of a clock may yield erroneous estimates of divergence times on the basis of the observed number of amino acid differences.

Animals↗

PubMed2002

Fossil calibration of molecular clocks and the divergence times of geminate species pairs separated by the isthmus of panama.

Calibration of nucleotide sequence divergence rates provides an important method by which to test many hypotheses of evolution. In the absence of an adequate fossil record, geological events, rather than the first appearances of sister taxa in the geological record, are often used to calibrate molecular clocks. The formation of the Isthmus of Panama, which isolated the tropical western Atlantic and eastern Pacific oceans, is one such event that is frequently used to infer rates of nucleotide sequence divergence. Isthmian calibrations assume that morphologically similar "geminate" species living now on either side of the isthmus were isolated geographically by the latest stages of seaway closure 3.1-3.5 MYA. Here, I have applied calibration dates from the fossil record to cytochrome c oxidase-1 (CO1) and nuclear histone-3 (H3) divergences among six pairs of geminates in the Arcidae to test this hypothesis. Analysis of CO1 first and third positions yield geminate divergences that predate final seaway closure, and on the basis of CO1 first positions, times for all six geminates are significantly greater than 3.5 Myr. H3 sequences produce much more recent geminate divergences, some that are younger than 3.1 Myr. But H3-derived estimates for all arcid geminates are not significantly different from both 0 and 15 Myr. According to CO1, one of the two most divergent pairs, Arca mutabilis and A. imbricata, split more than 30 MYA. This date is compatible with the fossil record, which indicates that these species were morphologically distinct at least 16-21 MYA. Across all CO1 nucleotide sites, divergence rates for arcids are slower than the rates reported for other taxa on the basis of isthmian calibrations, with the exception of rates determined from the least divergent species pair in larger surveys of multiple transisthmian pairs. Rate differences between arcids and some taxa may be real, but these data suggest that divergence rates can be greatly overestimated when dates corresponding to final closure of the Central American Seaway are used to calibrate the molecular clocks of marine organisms.

Animals↗

PubMed2005

Taxon sampling effects in molecular clock dating: an example from the African Restionaceae.

Three commonly used molecular dating methods for correction of variable rates (non-parametric rate smoothing, penalized likelihood, and Bayesian rate correction) as well as the assumption of a global molecular clock were tested for sensitivity to taxon sampling. The test dataset of 6854 basepairs for 300 terminals includes a nearly complete sample of the Restio-clade of the African Restionaceae (272 of the 288 species), as well as 26 outgroup species. Of this, nested subsets of 35, 51, 80, 120, 150, and the full 300 species were used. Molecular dating experiments with these datasets showed that all methods are sensitive to undersampling, but that this effect is more severe in analyses that use more extreme rate smoothing. Additionally, the undersampling effect is positively related to distance from the calibration node. The combined effect of undersampling and distance from the calibration node resulted in up to threefold differences in the age estimation of nodes from the same dataset with the same calibration point. We suggest that the most suitable methods are penalized likelihood and Bayesian when a global clock assumption has been rejected, as these methods are more successful at finding optimal levels of smoothing to correct for rate heterogeneity, and are less sensitive to undersampling.

Africa↗

PubMed2005

Relaxed molecular clock provides evidence for long-distance dispersal of Nothofagus (southern beech).

Nothofagus (southern beech), with an 80-million-year-old fossil record, has become iconic as a plant genus whose ancient Gondwanan relationships reach back into the Cretaceous era. Closely associated with Wegener's theory of "Kontinentaldrift", Nothofagus has been regarded as the "key genus in plant biogeography". This paradigm has the New Zealand species as passengers on a Moa's Ark that rafted away from other landmasses following the breakup of Gondwana. An alternative explanation for the current transoceanic distribution of species seems almost inconceivable given that Nothofagus seeds are generally thought to be poorly suited for dispersal across large distances or oceans. Here we test the Moa's Ark hypothesis using relaxed molecular clock methods in the analysis of a 7.2-kb fragment of the chloroplast genome. Our analyses provide the first unequivocal molecular clock evidence that, whilst some Nothofagus transoceanic distributions are consistent with vicariance, trans-Tasman Sea distributions can only be explained by long-distance dispersal. Thus, our analyses support the interpretation of an absence of Lophozonia and Fuscospora pollen types in the New Zealand Cretaceous fossil record as evidence for Tertiary dispersals of Nothofagus to New Zealand. Our findings contradict those from recent cladistic analyses of biogeographic data that have concluded transoceanic Nothofagus distributions can only be explained by vicariance events and subsequent extinction. They indicate that the biogeographic history of Nothofagus is more complex than envisaged under opposing polarised views expressed in the ongoing controversy over the relevance of dispersal and vicariance for explaining plant biodiversity. They provide motivation and justification for developing more complex hypotheses that seek to explain the origins of Southern Hemisphere biota.

Chronobiology Phenomena↗

PubMed2000

Estimation of primate speciation dates using local molecular clocks.

Protein-coding genes of the mitochondrial genomes from 31 mammalian species were analyzed to estimate the speciation dates within primates and also between rats and mice. Three calibration points were used based on paleontological data: one at 20-25 MYA for the hominoid/cercopithecoid divergence, one at 53-57 MYA for the cetacean/artiodactyl divergence, and the third at 110-130 MYA for the metatherian/eutherian divergence. Both the nucleotide and the amino acid sequences were analyzed, producing conflicting results. The global molecular clock was clearly violated for both the nucleotide and the amino acid data. Models of local clocks were implemented using maximum likelihood, allowing different evolutionary rates for some lineages while assuming rate constancy in others. Surprisingly, the highly divergent third codon positions appeared to contain phylogenetic information and produced more sensible estimates of primate divergence dates than did the amino acid sequences. Estimated dates varied considerably depending on the data type, the calibration point, and the substitution model but differed little among the four tree topologies used. We conclude that the calibration derived from the primate fossil record is too recent to be reliable; we also point out a number of problems in date estimation when the molecular clock does not hold. Despite these obstacles, we derived estimates of primate divergence dates that were well supported by the data and were generally consistent with the paleontological record. Estimation of the mouse-rat divergence date, however, was problematic.

Animals↗

PubMed1996

Complete families of linear invariants for some stochastic models of sequence evolution, with and without the molecular clock assumption.

For various models of sequence evolution, the set of linear functions of the frequencies of the nucleotide patterns forms a vector space, the invariant space. Here we distinguish between the model of nucleotide substitution, and the phylogenetic tree T describing the paths on which these changes occur. We describe a procedure to construct a basis of the invariant space for those models that are extensions of models incorporating Kimura's three substitution model of nucleotide change, including both the Jukes-Cantor and Cavender-Farris models. The dimension of the invariant space is determined, for those models where it is independent of the tree topology, as a function of the number of sequences. These are calculated where the nucleotide distribution at the root is unspecified, and both with, and without, the assumption of the molecular clock hypothesis. The invariants have a number of potential applications, including tree identification, and testing the fit of models (which could include the molecular clock) to sequence data.

Biological Evolution↗