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Molecular Clock

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Molecular Clock

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 concept

The origin of the molecular clock hypothesis

In 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 definition

Today, 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 diagram

Figure 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).

Molecular clock, diagram showing the amino acid substitutions per millions of years to show the rate at which the gene CCDC92 changes, StudySmarter

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:

  1. Estimate the number of substitutions in the nucleotide or amino acid sequences.

  2. Using the fossil record, determine the date when the organisms being studied last shared a common ancestor.

  3. Estimate the number of substitutions in the nucleotide or amino acid sequences per unit of time. This will be our evolutionary rate.

  4. Using the evolutionary rate, calculate the time of divergence for the new sequences.

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 used

Molecular 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.


Molecular Clock, phylogenetic tree shows the evolutionary relationship and date of divergence of the major clades of order Rickettsia, StudySmarterFigure 2. This phylogenetic tree shows the evolutionary relationship and date of divergence of the major clades of order Rickettsia. Source: Weinert L, Werren J, Aebi A, Stone G, Jiggins F, CC BY 2.0, via Wikimedia Commons.

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 clocks

As 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:

  • DNA, RNA, or protein sequences may change at irregular bursts instead of at a constant rate.

  • Some DNA, RNA, or protein sequences may appear to change at a smooth average rate but actually have some deviations from that average rate.

  • As a result of natural selection, some genetic changes are favored over others.

  • The same DNA, RNA, or protein sequence substitutions may be occurring at different rates in different organisms.

  • Some DNA, RNA, or protein sequences evolve faster than others.

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

  • The molecular clock hypothesis states that the divergence of species can be estimated using the constant accumulation of amino acid substitutions in a protein sequence which is similar to the regular ‘ticks’ of a clock.
  • The molecular clock is a method used to estimate the amount of time needed for a certain amount of evolutionary change using biomolecular data such as nucleotide sequences in DNA and RNA or amino acid sequences in protein.
  • The molecular clock is useful in: determining when different species last shared a common ancestor, putting evolutionary events in chronological order, and studying the evolutionary history of organisms that do not easily fossilize.
  • A key assumption in using a molecular clock is that the nucleotide or amino acid sequences mutate at a constant rate.

Frequently Asked Questions about Molecular Clock

The molecular clock is a method used to estimate the amount of time needed for a certain amount of evolutionary change.

A molecular clock works 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. 


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

 The process of calculating a molecular clock can be summed up as follows:


  1. Estimate the number of substitutions in the nucleotide or amino acid sequences.
  2. Using the fossil record, determine the date when the organisms being studied last shared a common ancestor.
  3. Estimate the number of substitutions in the nucleotide or amino acid sequences per unit of time. This will be our evolutionary rate. 
  4. Using the evolutionary rate, calculate the time of divergence for the new sequences.

The number of substitutions in nucleotide sequences of DNA can be used in molecular clocks. DNA mutations may be harmful, beneficial, or neutral. Neutral mutations–which have no effect on an organism’s ability to survive and reproduce–are used for molecular clocks because these accumulate at a consistent rate over time.

Neutral mutations–which have no effect on an organism’s ability to survive and reproduce–are used for molecular clocks because these accumulate at a consistent rate over time.

Final Molecular Clock Quiz

Question

What is the molecular clock hypothesis?

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Answer

Proponents Zuckerkandl and Pauling hypothesized that the divergence of species can be estimated using the constant accumulation of amino acid substitutions in a protein sequence which is similar to the regular ‘ticks’ of a clock.

Show question

Question

What is a molecular clock?

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Answer

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. 

Show question

Question

What is a key assumption in using a molecular clock?

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Answer

A key assumption is that the nucleotide or amino acid sequences mutate at a constant rate.

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Question

What are neutral mutations?

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Answer

Neutral mutations are changes in genetic sequences that do not affect an organism’s ability to survive and reproduce.

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Question

Why are neutral mutations used in molecular clocks?

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Answer

Neutral mutations are used for molecular clocks because these accumulate at a consistent rate over time.  

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Question

What is the definition of evolutionary rate?

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Answer

Evolutionary rate is the number of evolutionary changes over a period of time.

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Question

How are molecular clocks useful in determining phylogeny?

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Answer

Molecular clocks can be used to determine when different species last shared a common ancestor and to put evolutionary events in chronological order.

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Question

How are molecular clocks used when there is insufficient fossil evidence?

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Answer

Molecular clocks are useful for analyzing the evolutionary history of species that do not fossilize well.  

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Question

What kind of mutations are used in molecular clocks?

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Answer

Neutral mutations

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Question

What kind of data is used in producing molecular clocks?

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Answer

Biomolecular evidence such as nucleotide or amino acid sequences are used in molecular clocks.

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Question

Assuming that the nucleotide or amino acid sequences mutate at a constant rate, what is the number of substitutions over time is equivalent to?

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Answer

Evolutionary rate

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Question

If the evolutionary rate of a species is 2 mutations every million years, and there are 10 mutations in the nucleotide or amino acid sequence being studied, when did the sequences diverge?

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Answer

The sequences diverged 5 million years ago.

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Question

How can a molecular clock be used in creating a phylogenetic tree?

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Answer

A molecular clock can be used in scaling the length of the branches of a phylogenetic tree so that the times of divergence are more accurately depicted.

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Question

How does natural selection limit the use of a molecular clock?

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Answer

Due to natural selection, some genetic changes are favored over others, making mutation rates irregular.

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Question

What biomolecular evidence is typically used in molecular clocks?

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Answer

Nucleotide sequences in DNA and RNA, as well as amino acid sequences in proteins

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Question

How is the divergence of species similar to the ticks of a clock?

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Answer

The divergence of species can be estimated using the constant accumulation of amino acid substitutions in a protein sequence, which is similar to the regular ‘ticks’ of a clock.

Show question

Question

How is the molecular clock of a gene calibrated?

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Answer

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.  

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