Time-dependent rates of molecular evolution

For over half a century, it has been known that the rate of morphological evolution appears to vary with the time frame of measurement. Rates of microevolutionary change, measured between successive generations, were found to be far higher than rates of macroevolutionary change inferred from the fossil record. More recently, it has been suggested that rates of molecular evolution are also time dependent, with the estimated rate depending on the timescale of measurement. This followed surprising observations that estimates of mutation rates, obtained in studies of pedigrees and laboratory mutation-accumulation lines, exceeded long-term substitution rates by an order of magnitude or more. Although a range of studies have provided evidence for such a pattern, the hypothesis remains relatively contentious. Furthermore, there is ongoing discussion about the factors that can cause molecular rate estimates to be dependent on time. Here we present an overview of our current understanding of time-dependent rates. We provide a summary of the evidence for time-dependent rates in animals, bacteria and viruses. We review the various biological and methodological factors that can cause rates to be time dependent, including the effects of natural selection, calibration errors, model misspecification and other artefacts. We also describe the challenges in calibrating estimates of molecular rates, particularly on the intermediate timescales that are critical for an accurate characterization of time-dependent rates. This has important consequences for the use of molecular-clock methods to estimate timescales of recent evolutionary events.

Review ["Telling the Evolutionary Time : Molecular Clocks and the Fossil Record" edited by Philip C. J. Donoghue and M. Paul Smith]

Determining the temporal scale of biological evolution has traditionally been the preserve of paleontology, with the timing of species originations and major diversifications all being read from the fossil record. However, the ages of the earliest (correctly identified) records will underestimate actual origins due to the incomplete nature of the fossil record and the necessity for lineages to have evolved sufficiently divergent morphologies in order to be distinguished. The possibility of inferring divergence times more accurately has been promoted by the idea that the accumulation of genetic change between modern lineages can be used as a molecular clock (Zuckerkandl and Pauling, 1965). In practice, though, molecular dates have often been so old as to be incongruent even with liberal readings of the fossil record. Prominent examples include inferred diversifications of metazoan phyla hundreds of millions of years before their Cambrian fossil record appearances (e.g., Nei et al., 2001) and a basal split between modern birds (Neoaves) that is almost double the age of their earliest recognizable fossils (e.g., Cooper and Penny, 1997).

Time dependency of molecular rate estimates and systematic overestimation of recent divergence times

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (<1–2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222–705 ka), Neandertals (108 ka; 70–156 ka), and modern humans (76 ka; 47–110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.

Evidence for time dependency of molecular rate estimates

Long-term changes in the genetic composition of a population occur by the fixation of new mutations, a process known as substitution. The rate at which mutations arise in a population and the rate at which they are fixed are expected to be equal under neutral conditions (Kimura, 1968). Between the appearance of a new mutation and its eventual fate of fixation or loss, there will be a period in which it exists as a transient polymorphism in the population (Kimura and Ohta, 1971). If the majority of mutations are deleterious (and nonlethal), the fixation probabilities of these transient polymorphisms are reduced and the mutation rate will exceed the substitution rate (Kimura, 1983). Consequently, different apparent rates may be observed on different time scales of the molecular evolutionary process (Penny, 2005; Penny and Holmes, 2001). The substitution rate of the mitochondrial protein-coding genes of birds and mammals has been traditionally recognized to be about 0.01 substitutions/site/million years (Myr) (Brown et al., 1979; Ho, 2007; Irwin et al., 1991; Shields and Wilson, 1987), with the noncoding D-loop evolving several times more quickly (e.g., Pesole et al., 1992; Quinn, 1992). Over the past decade, there has been mounting evidence that instantaneous mutation rates substantially exceed substitution rates, in a range of organisms (e.g., Denver et al., 2000; Howell et al., 2003; Lambert et al., 2002; Mao et al., 2006; Mumm et al., 1997; Parsons et al., 1997; Santos et al., 2005). The immediate reaction to the first of these findings was that the polymorphisms generated by the elevated mutation rate are short-lived, perhaps extending back only a few hundred years (Gibbons, 1998; Macaulay et al., 1997). That is, purifying selection was thought to remove these polymorphisms very rapidly.

Branch-length estimation bias misleads molecular dating for a vertebrate mitochondrial phylogeny

Despite recent methodological advances in inferring the time-scale of biological evolution from molecular data, the fundamental question of whether our substitution models are sufficiently well specified to accurately estimate branch-lengths has received little attention. I examine this implicit assumption of all molecular dating methods, on a vertebrate mitochondrial protein-coding dataset. Comparison with analyses in which the data are RY-coded (AG → R; CT → Y) suggests that even rates-across-sites maximum likelihood greatly under-compensates for multiple substitutions among the standard (ACGT) NT-coded data, which has been subject to greater phylogenetic signal erosion. Accordingly, the fossil record indicates that branch-lengths inferred from the NT-coded data translate into divergence time overestimates when calibrated from deeper in the tree. Intriguingly, RY-coding led to the opposite result. The underlying NT and RY substitution model misspecifications likely relate respectively to “hidden” rate heterogeneity and changes in substitution processes across the tree, for which I provide simulated examples. Given the magnitude of the inferred molecular dating errors, branch-length estimation biases may partly explain current conflicts with some palaeontological dating estimates.

Proteomics Approaches in the Identification of Molecular Signatures of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are undifferentiated, multi-potent stem cells with the ability to renew. They can differentiate into many types of terminal cells, such as osteoblasts, chondrocytes, adipocytes, myocytes, and neurons. These cells have been applied in tissue engineering as the main cell type to regenerate new tissues. However, a number of issues remain concerning the use of MSCs, such as cell surface markers, the determining factors responsible for their differentiation to terminal cells, and the mechanisms whereby growth factors stimulate MSCs. In this chapter, we will discuss how proteomic techniques have contributed to our current knowledge and how they can be used to address issues currently facing MSC research. The application of proteomics has led to the identification of a special pattern of cell surface protein expression of MSCs. The technique has also contributed to the study of a regulatory network of MSC differentiation to terminal differentiated cells, including osteocytes, chondrocytes, adipocytes, neurons, cardiomyocytes, hepatocytes, and pancreatic islet cells. It has also helped elucidate mechanisms for growth factor–stimulated differentiation of MSCs. Proteomics can, however, not reveal the accurate role of a special pathway and must therefore be combined with other approaches for this purpose. A new generation of proteomic techniques have recently been developed, which will enable a more comprehensive study of MSCs. Keywords

Molecular phylogeny supports the paraphyletic nature of the genus Trogoderma (Coleoptera: Dermestidae) collected in the Australasian ecozone

To date, a molecular phylogenetic approach has not been used to investigate the evolutionary structure of Trogoderma and closely related genera. Using two mitochondrial genes, Cytochrome Oxidase I and Cytochrome B, and the nuclear gene, 18S, the reported polyphyletic positioning of Trogoderma was examined. Paraphyly in Trogoderma was observed, with one Australian Trogoderma species reconciled as sister to all Dermestidae and the Anthrenocerus genus deeply nested within the Australian Trogoderma clade. In addition, time to most recent common ancestor for a number of Dermestidae was calculated. Based on these estimations, the Dermestidae origin exceeded 175 million years, placing the origins of this family in Pangaea.