Molecular Clocks | Research & Encyclopedia Articles

Molecular Clocks

The molecular clock hypothesis, first advanced in 1965 by Linus Pauling (1901-1994) and Emile Zuckerkandl, suggests that the mutation driven changes (substitutions) in the amino acid sequences of proteins has a characteristic substitution rate that is related to time. The identification of such clocks would allow biologists to assign accurate dates to evolutionary history.

Upon comparing the amino acid sequences for hemoglobin molecules taken from different species, Pauling and Zuckerkandl noticed that the number of amino acid substitutions increased with the presumed evolutionary distance between species (i.e., how high up on the "evolutionary tree" a species appeared). One proposed mechanism that might account for such changes was an evolutionary clock in which the ticks of the clock are the number of amino acids substitutions that occur over time. Such molecular clocks are a predicted consequence of the neutral theory of molecular evolution (i.e., the theory that molecular evolution was primarily the result of genetic drift of neutral mutations rather than natural selection). Molecular clocks also allow scientists to determine the balance between the effects of natural selection, mutation, and genetic drift on evolutionary changes occurring in genes and proteins.

Evolution is defined as the process of biological change over time. These changes may be accomplished (mediated) by multiple, complex, and interdependent processes. Evidence bounds that species of organisms change, and that the rate of change depends upon the particular trait or characteristic under scrutiny. It is also known, however, that some characteristics are conservative and change slowly. Despite profound differences in appearance (morphological differences), the molecular structures fundamental to all life are essentially similar. The subtle changes of these fundamental molecules, in particular as measured by the substitution of nucleotides in nucleic acids (i.e., DNA and RNA) and amino acids in proteins, create the wide diversity of life on Earth.

An accurate molecular clock would make it possible to put a timepiece to evolutionary events. Instead of settling for relative relationships, a functional molecular clock could apply absolute dating to the development and divergence of life (phylogenetic history).

Scientists who study evolution continue to study the interactions of the mechanisms of evolutionary change. According to evolutionary theory stressing natural selection, most changes (mutations) have a selective advantage or disadvantage and neutral mutations are rare. According to the neutral evolutionary theory, however, most changes at the molecular level do not carry a selective advantage or disadvantage and are thus, selectively neutral. To account for differences in the genetic composition of the wide variety of life forms, this would mean that the rate of neutral mutations is high. Although neither selection based theory or neutral based theory excludes the other, the exact extent of the influence of each process on evolution is debated among biologists.

Because the molecular clock hypothesis is related to the neutral theory of evolution, first argued by Motoo Kimura. Accordingly, evidence for or against the molecular clock hypothesis is often used to argue for or against the neutral theory. According to neutral theory, molecules such as DNA, RNA and proteins with fewer active sites (functional constraints) evolve faster because the number of effectively neutral mutants is correspondingly higher. According to this argument, mutations that are deleterious are quickly lost and, while they occur, advantageous mutants are rare. By definition, neutral mutants have no effect on fitness. Supporting the neutral theory, Kimura observed that silent sites and pseudogenes evolved many times faster than coding sequences.

Complicating the accuracy, reliability, and applicability of molecular clocks, however, is the fact that not all DNA variation (e.g., silent mutations, synonymous codons, pseudogenes and non-coding DNA) translates into protein variation. Further, not all protein variation translates into differences that can be observed (phenotypic variation) and not all phenotypic variation ultimately makes a difference in fitness. Changes in phenotype may, in some circumstances, be due more to differences in gene regulation than in sequence alterations. Moreover, although advances in genetics research are rapid, researchers do not yet fully understand the exact relationship between changes in molecules (biochemical evolution) and changes in genes (genetic differentiation).

There is substantial evidence that different molecular clocks tick (undergo changes) at different rates. The rate itself may also change during a given span of time (episodic change). Some interpretations of data may also be hindered because of inaccurate assumptions about the pattern of evolution and of the extent of the genetic differences between species. Recent estimates, made in 2001, of the number of genes carried by humans, reduced prior estimates of the number of genes carried from 80,000 to about 30,000 (less than twice the number of genes found in the fruit fly (Drosophila melanogaster). Such data may lead to revision in current concepts regarding the evolutionary distance between species, and the interpretation of molecular clocks. It is also possible that the mechanisms of selection, mutation, and drift may have different effects at the levels of molecules or species.

Scientists continue to study molecular clocks in an attempt make the molecular clock hypothesis more useful and accurate. Although evolutionary theory is a well-established and well-supported cornerstone of modern science, there are a few critics who argue that the data regarding molecular clocks actually argues against some parts of evolutionary theory. Such arguments are most often the result of an incorrect understanding of evolutionary mechanisms. For example, some arguments fail distinguish between the functional and non-functional parts of proteins, or that parts of proteins may not have had the same function in the past as they do now. In fact, the critical or active portions of molecules or proteins are usually limited to a very limited portion of the molecule (site specific) and are but a fraction of both the total mass and volume of the protein. Another fundamental error involves arguments that rely on the existence of existing (extant) primitive organisms. There are no extant primitive organisms. For example, all eukaryotes have in common that a primitive common ancestor was derived from prokaryotic bacteria and that, therefore, all eukaryotes have evolved for the same amount of time. Accordingly, no eukaryote group or species (e.g., shark or man) is more primitive with regard to the amount of time they have been subjected to evolutionary mechanisms. Seemingly primitive characteristics are simply highly efficient and conserved characteristics that have changed little over time.

The molecular clock hypothesis, as well as the interpretation of data related to genetic change, has become a part of controversial interpretations regarding the exact nature of the relationships between species (e.g., the relationships between man, chimps and apes). Molecular clocks are also used to develop often controversial interpretations regarding the origin, geographic arrival time, and differentiation, of aboriginal peoples.

Until more is known about the mechanisms of genetic change, and of the differences between species, the ability to use molecular clocks to fix absolute dates to evolutionary events will remain limited.