Other than to determine evolutionary relationships, what are molecular clocks used for?
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For the past 40 years, evolutionary biologists have been investigating the possibility that some evolutionary changes occur in a clock-like fashion. Over the course of millions of years, mutations may build up in any given stretch of DNA at a reliable rate. For example,the gene that codes for the protein alpha-globin (a component of hemoglobin) experiences base changes at a rate of .56 changes per base pair per billion years1. If this rate is reliable, the gene could be used as a molecular clock. When a stretch of DNA does indeed behave like a molecular clock, it becomes a powerful tool for estimating the dates of lineage-splitting events. For example, imagine that a length of DNA found in two species differs by four bases (as shown below) and we know that this entire length of DNA changes at a rate of approximately one base per 25 million years. That means that the two DNA versions differ by 100 million years of evolution and that their common ancestor lived 50 million years ago. Since each lineage experienced its own evolution, the two species must have descended from a common ancestor that lived at least 50 million years ago. This general technique has been used to investigate several important issues, including the origin of modern humans, the date of the human/chimpanzee divergence, and the date of the Cambrian “explosion.” Using molecular clocks to estimate divergence dates depends on other methods of dating. In order to calculate the rate at which a stretch of DNA changes, biologists must use dates estimated from other relative and absolute dating techniques.
1This number is for changes that affect the structure of the protein. How do researchers figure out when the common ancestor of different organisms lived? How do they know the chronological order of evolutionary events? The molecular clock is a method that uses biomolecular data to estimate the amount of time needed for a certain amount of evolutionary change, and has helped researchers answer these questions as well as fill in gaps in the fossil record. In this article, we will discuss the origin of the molecular clock hypothesis, the definition of the molecular clock, some examples of how a molecular clock can be used in constructing phylogeny, and the limitations of using the molecular clock. Molecular clock conceptThe origin of the molecular clock hypothesisIn 1965, the proponents of the molecular clock hypothesis Zuckerkandl and Pauling observed that the constant accumulation of amino acid substitutions in hemoglobin was similar to the regular ‘ticks’ of a clock. From this observation, they thought that it was possible that a molecular evolutionary clock–which describes changes in amino acids over time since the divergence of species– also existed. The molecular clock hypothesis argues that DNA and protein sequences mutate at a constant rate over time among different organisms and that the number of genetic differences between organisms can give us an estimation of when they last shared a common ancestor. Mutation: changes in the sequence of genes. Molecular clock definitionToday, the molecular clock is a method used to estimate the amount of time needed for a certain amount of evolutionary change. This is done by analyzing biomolecular data, such as the number of changes or substitutions in nucleotide sequences of DNA and RNA, or the amino acid sequence of proteins. Substitution is a type of mutation where one nucleotide is replaced by another. Assuming that the nucleotide or amino acid sequences mutate at a constant rate, the number of substitutions over time is equivalent to the evolutionary rate. For this reason, the molecular clock is also known as the gene clock or the evolutionary clock. Example of a molecular clock diagramFigure 1 is an example of a molecular clock diagram. It shows how quickly CCDC92, a protein-coding gene, changes by graphing the number of amino acid substitutions per millions of years. As points of comparison, it also shows the rate of change in Fibrinogen (a protein with a higher mutation rate) and Cytochrome C (a protein with a lower rate of change). Figure 1. Molecular clock diagram showing the amino acid substitutions per millions of years to show the rate at which the gene CCDC92 changes. Source: Matdir, CC BY-SA 4.0, via Wikimedia Commons. How are DNA mutations used in molecular clocks?Mutations may be harmful, beneficial, or neutral. Harmful mutations have a negative impact on an organism's evolutionary fitness, or its ability to survive and reproduce. On the contrary, beneficial mutations have a positive impact on an organism's evolutionary fitness. Most mutations are neutral: they have no effect on an organism’s evolutionary fitness. Because neutral mutations have no effect on evolutionary fitness, their frequency in the succeeding generations of the population is determined by chance rather than natural selection. This means that all neutral mutations have an equal chance of undergoing substitution. As such, the substitution rate for neutral mutations is equal to the mutation rate. Neutral mutations are used for molecular clocks because they tend to accumulate at a constant rate over time. If a gene's specific amino acid sequence is necessary for survival, the majority of mutations will be harmful, with only a few neutral; such genes take a long time to change. On the other hand, if a gene's amino acid sequence is not as essential, fewer mutations will be harmful, and more will be neutral; such genes change at a faster rate. The molecular clock of a gene can be calibrated by corroborating the number of substitutions with dates from the fossil record that are known as diverging points. The process of calculating a molecular clock can be summed up as follows:
Let’s say the evolutionary rate of a species is 2 mutations every million years. If there are 10 mutations in the nucleotide or amino acid sequence being studied, then the sequences must have diverged 5 million years ago. Evolutionary rate: the number of evolutionary changes over a period of time. Fossil record: the documentation of the history of life on Earth based primarily on the sequence of fossils in sedimentary rock layers. Example of how molecular clocks are usedMolecular clocks can be used to determine when different species last shared a common ancestor and to put evolutionary events in chronological order, both of which are essential to the construction of phylogenetic trees. Phylogenetic trees are branching diagrams showing the evolutionary history and relationship of organisms or groups of organisms. Figure 2 is a phylogenetic tree that was reconstructed using the 16S rDNA of one member of each of the major clades belonging to the genus Rickettsia, which consists of bacteria that include disease-causing bacteria in lice, ticks, and mites. Notice that there is a scale at the top-left corner indicating the number of substitutions per site. This is because a molecular clock was used to infer the times of divergence, and the branches of the phylogenetic tree were scaled accordingly.
The phylogenetic tree shown in Figure 2 tells us that the common ancestor Pelagibacter, which are free-living bacteria, existed over 750 million years ago. Around 525 to 775 million years ago, there was a transition to living inside cells and, at around 425 to 525 million years ago, split into Holospora and a clade that primarily infests arthropods. The genus Rickettsia emerged approximately 150 million years ago. It is important to note that not all phylogenetic trees indicate the date of divergence of the organisms being studied; such is made possible by the use of a molecular clock. In addition to dating evolutionary changes, molecular clocks are also useful for studying species that do not fossilize well. For example, using molecular clock analyses, researchers found that animals and fungi last shared a common ancestor more than a billion years ago. This kind of information is difficult to obtain from the fossil record because the oldest fossils of fungi–which do not fossilize well because they are soft–can be dated only as far back as about 460 million years ago. Limitations of molecular clocksAs previously mentioned, molecular clocks work under the assumption that genetic changes (in DNA, RNA, or protein sequences) occur at a fixed rate. Limitations of molecular clocks include:
Evidence suggests that nearly half of the amino acid differences in Drosophila simulans and D. yakuba protein are not selectively neutral so they are affected by natural selection, leading to irregular mutation rates. However, the direction of natural selection can change several times over a long period, so it is possible for these differences to average out. In addition, estimates may be contested when molecular clocks are used to date evolutionary divergences that took place beyond what is documented by the fossil record. Molecular clocks have been used to estimate dates of evolutionary divergence that took place billions of years ago, but the fossil record extends back to only around 550 million years ago. These limitations can be resolved in some calibrating molecular clocks using data on the evolutionary rate of genes in various taxa. In other circumstances, it is helpful to use a large number of genes rather than just one or two. Natural selection or other circumstances may cause fluctuations in evolutionary rate, but by studying multiple genes, these fluctuations may be averaged out. As such, despite its limitations, molecular clocks can still be useful in determining evolutionary relationships when used carefully. Molecular Clock - Key takeaways
What are molecular clocks used for?Evolutionary biologists can use this information to deduce how species evolve, and to fix the date when two species diverged on the evolutionary timeline. "Unlike a wristwatch, which measures time from regular changes (ticks), a molecular clock measures time from random changes (mutations) in DNA," Hedges notes.
How molecular clocks are used to infer evolutionary relationships?The molecular clock posits a constant rate of genetic change among lineages, such that estimates of rates can be extrapolated across the Tree of Life to infer the timing of evolutionary divergence events. For this reason, the molecular clock has become a valuable component of phylogenetic analysis.
How scientists use a molecular clock to determine relationships between species?Molecular clocks are used to determine how closely two species are related by calculating the number of differences between the species' DNA sequences or amino acid sequences. These clocks are sometimes called gene clocks or evolutionary clocks.
Which molecule can be used as molecular clock in evolution?If the rate of evolution of a protein or gene were approximately the same in the evolutionary lineages leading to different species, proteins and DNA sequences would provide a molecular clock of evolution.
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