History of molecular evolution
Encyclopedia
The history of molecular evolution starts in the early 20th century with "comparative biochemistry", but the field of molecular evolution
came into its own in the 1960s and 1970s, following the rise of molecular biology
. The advent of protein sequencing
allowed molecular biologists to create phylogenies based on sequence comparison, and to use the differences between homologous sequences as a molecular clock
to estimate the time since the last common ancestor. In the late 1960s, the neutral theory of molecular evolution
provided a theoretical basis for the molecular clock, though both the clock and the neutral theory were controversial, since most evolutionary biologists held strongly to panselectionism, with natural selection
as the only important cause of evolutionary change. After the 1970s, nucleic acid sequencing allowed molecular evolution to reach beyond proteins to highly conserved ribosomal RNA
sequences, the foundation of a reconceptualization of the early history of life.
in the 1950s and 1960s, a small number of biologists had explored the possibilities of using biochemical differences between species to study evolution
. Ernest Baldwin
worked extensively on comparative biochemistry beginning in the 1930s, and Marcel Florkin
pioneered techniques for constructing phylogenies based on molecular and biochemical characters in the 1940s. However, it was not until the 1950s that biologists developed techniques for producing biochemical data for the quantitative study of molecular evolution
.
The first molecular systematics research was based on immunological assay
s and protein "fingerprinting" methods. Alan Boyden—building on immunological methods of G. H. F. Nuttall—developed new techniques beginning in 1954, and in the early 1960s Curtis Williams
and Morris Goodman
used immunological comparisons to study primate
phylogeny. Others, such as Linus Pauling
and his students, applied newly developed combinations of electrophoresis
and paper chromatography
to proteins subject to partial digestion by digestive enzymes to create unique two-dimensional patterns, allowing fine-grained comparisons of homologous proteins.
Beginning in the 1950s, a few naturalists also experimented with molecular approaches—notably Ernst Mayr
and Charles Sibley
. While Mayr quickly soured on paper chromatography, Sibley successfully applied electrophoresis to egg-white proteins to sort out problems in bird taxonomy, soon supplemented that with DNA hybridization techniques—the beginning of a long career built on molecular systematics.
While such early biochemical techniques found grudging acceptance in the evolutionary biology community, for the most part they did not impact the main theoretical problems of evolution and population genetics. This would change as molecular biology shed more light on the physical and chemical nature of genes.
, the increase in fitness observed when inbred lines are outcrossed. In 1950, James F. Crow
offered two different explanations (later dubbed the classical and balance positions) based the paradox first articulated by J. B. S. Haldane
in 1937: the effect of deleterious mutations on the average fitness of a population depends only on the rate of mutations (not the degree of harm caused by each mutation) because more-harmful mutations are eliminated more quickly by natural selection, while less-harmful mutations remain in the population longer. H. J. Muller dubbed this "genetic load
".
Muller, motivated by his concern about the effects of radiation on human populations, argued that heterosis is primarily the result of deleterious homozygous recessive alleles, the effects of which are masked when separate lines are crossed—this was the dominance hypothesis, part of what Dobzhansky labeled the classical position. Thus, ionizing radiation and the resulting mutations produce considerable genetic load even if death or disease does not occur in the exposed generation, and in the absence of mutation natural selection will gradually increase the level of homozygosity. Bruce Wallace, working with J. C. King, used the overdominance hypothesis to develop the balance position, which left a larger place for overdominance
(where the heterozygous state of a gene is more fit than the homozygous states). In that case, heterosis is simply the result of the increased expression of heterozygote advantage
. If overdominant loci are common, then a high level of heterozygosity would result from natural selection, and mutation-induced radiation may in fact facilitate an increase in fitness due to overdominance. (This was also the view of Dobzhansky.)
Debate continued through 1950s, gradually becoming a central focus of population genetics. A 1958 study of Drosophila by Wallace suggested that radiation-induced mutations increased the viability of previously homozygous flies, providing evidence for heterozygote advantage and the balance position; Wallace estimated that 50% of loci in natural Drosophila populations were heterozygous. Motoo Kimura
's subsequent mathematical analyses reinforced what Crow had suggested in 1950: that even if overdominant loci are rare, they could be responsible for a disproportionate amount of genetic variability. Accordingly, Kimura and his mentor Crow came down on the side of the classical position. Further collaboration between Crow and Kimura led to the infinite alleles model
, which could be used to calculate the number of different alleles expected in a population, based on population size, mutation rate, and whether the mutant alleles were neutral, overdominant, or deleterious. Thus, the infinite alleles model offered a potential way to decide between the classical and balance positions, if accurate values for the level of heterozygosity could be found.
By the mid-1960s, the techniques of biochemistry and molecular biology—in particular protein electrophoresis
—provided a way to measure the level of heterozygosity in natural populations: a possible means to resolve the classical/balance controversy. In 1963, Jack L. Hubby published an electrophoresis study of protein variation in Drosophila; soon after, Hubby began collaborating with Richard Lewontin
to apply Hubby's method to the classical/balance controversy by measuring the proportion of heterozygous loci in natural populations. Their two landmark papers, published in 1966, established a significant level of heterozygosity for Drosophila (12%, on average). However, these findings proved difficult to interpret. Most population geneticists (including Hubby and Lewontin) rejected the possibility of widespread neutral mutations; explanations that did not involve selection were anathema to mainstream evolutionary biology. Hubby and Lewontin also ruled out heterozygote advantage as the main cause because of the segregation load it would entail, though critics argued that the findings actually fit well with overdominance hypothesis.
After developing the fundamentals of protein sequencing with insulin
between 1951 and 1955, Frederick Sanger
and his colleagues had published a limited interspecies comparison of the insulin sequence in 1956. Francis Crick
, Charles Sibley
and others recognized the potential for using biological sequences to construct phylogenies, though few such sequences were yet available. By the early 1960s, techniques for protein sequencing
had advanced to the point that direct comparison of homologous amino acid sequences was feasible. In 1961, Emanuel Margoliash
and his collaborators completed the sequence for horse cytochrome c
(a longer and more widely distributed protein than insulin), followed in short order by a number of other species.
In 1962, Linus Pauling
and Emile Zuckerkandl
proposed using the number of differences between homologous protein sequences to estimate the time since divergence
, an idea Zuckerkandl had conceived around 1960 or 1961. This began with Pauling's long-time research focus, hemoglobin
, which was being sequenced by Walter Schroeder; the sequences not only supported the accepted vertebrate phylogeny, but also the hypothesis (first proposed in 1957) that the different globin chains within a single organism could also be traced to a common ancestral protein. Between 1962 and 1965, Pauling and Zuckerkandl refined and elaborated this idea, which they dubbed the molecular clock
, and Emil L. Smith
and Emanuel Margoliash expanded the analysis to cytochrome c. Early molecular clock calculations agreed fairly well with established divergence times based on paleontological evidence. However, the essential idea of the molecular clock—that individual proteins evolve at a regular rate independent of a species' morphological
evolution—was extremely provocative (as Pauling and Zuckerkandl intended it to be).
, Theodosius Dobzhansky
and G. G. Simpson, three of the founders of the modern evolutionary synthesis
of the 1930s and 1940s—were extremely skeptical of molecular approaches, especially when it came to the connection (or lack thereof) to natural selection
. Molecular evolution in general—and the molecular clock in particular—offered little basis for exploring evolutionary causation. According to the molecular clock hypothesis, proteins evolved essentially independently of the environmentally determined forces of selection; this was sharply at odds with the panselectionism prevalent at the time. Moreover, Pauling, Zuckerkandl, and other molecular biologists were increasingly bold in asserting the significance of "informational macromolecules" (DNA, RNA and proteins) for all biological processes, including evolution. The struggle between evolutionary biologists and molecular biologists—with each group holding up their discipline as the center of biology as a whole—was later dubbed the "molecular wars" by Edward O. Wilson, who experienced firsthand the domination of his biology department by young molecular biologists in the late 1950s and the 1960s.
In 1961, Mayr began arguing for a clear distinction between functional biology (which considered proximate causes
and asked "how" questions) and evolutionary biology (which considered ultimate causes and asked "why" questions) He argued that both disciplines and individual scientists could be classified on either the functional or evolutionary side, and that the two approaches to biology were complementary. Mayr, Dobzhansky, Simpson and others used this distinction to argue for the continued relevance of organismal biology, which was rapidly losing ground to molecular biology and related disciplines in the competition for funding and university support. It was in that context that Dobzhansky first published his famous statement, "nothing in biology makes sense except in the light of evolution
", in a 1964 paper affirming the importance of organismal biology in the face of the molecular threat; Dobzhansky characterized the molecular disciplines as "Cartesian
" (reductionist) and organismal disciplines as "Darwinian".
Mayr and Simpson attended many of the early conferences where molecular evolution was discussed, critiquing what they saw as the overly simplistic approaches of the molecular clock. The molecular clock, based on uniform rates of genetic change driven by random mutations and drift, seemed incompatible with the varying rates of evolution and environmentally-driven adaptive processes (such as adaptive radiation
) that were among the key developments of the evolutionary synthesis. At the 1962 Wenner-Gren conference, the 1964 Colloquium on the Evolution of Blood Proteins in Bruges
, Belgium
, and the 1964 Conference on Evolving Genes and Proteins at Rutgers University
, they engaged directly with the molecular biologists and biochemists, hoping to maintain the central place of Darwinian explanations in evolution as its study spread to new fields.
, spurred by George C. Williams
's Adaptation and Natural Selection
(1966). Debate over units of selection, particularly the controversy over group selection
, led to increased focus on individual genes (rather than whole organisms or populations) as the theoretical basis for evolution. However, the increased focus on genes did not mean a focus on molecular evolution; in fact, the adaptationism
promoted by Williams and other evolutionary theories further marginalized the apparently non-adaptive changes studied by molecular evolutionists.
. Based on the available molecular clock studies (of hemoglobin from a wide variety of mammals, cytochrome c from mammals and birds, and triosephosphate dehydrogenase from rabbits and cows), Kimura (assisted by Tomoko Ohta
) calculated an average rate of DNA substitution of one base pair
change per 300 base pairs (encoding 100 amino acids) per 28 million years. For mammal genomes, this indicated a substitution rate of one every 1.8 years, which would produce an unsustainably high substitution load
unless the preponderance of substitutions was selectively neutral. Kimura argued that neutral mutations occur very frequently, a conclusion compatible with the results of the electrophoretic studies of protein heterozygosity. Kimura also applied his earlier mathematical work on genetic drift to explain how neutral mutations could come to fixation
, even in the absence of natural selection; he soon convinced James F. Crow of the potential power of neutral alleles and genetic drift as well.
Kimura's theory—described only briefly in a letter to Nature—was followed shortly after with a more substantial analysis by Jack L. King and Thomas H. Jukes
—who titled their first paper on the subject "non-Darwinian evolution
". Though King and Jukes produced much lower estimates of substitution rates and the resulting genetic load in the case of non-neutral changes, they agreed that neutral mutations driven by genetic drift were both real and significant. The fairly constant rates of evolution observed for individual proteins was not easily explained without invoking neutral substitutions (though G. G. Simpson and Emil Smith had tried). Jukes and King also found a strong correlation between the frequency of amino acids and the number of different codons encoding each amino acid. This pointed to substitutions in protein sequences as being largely the product of random genetic drift.
King and Jukes' paper, especially with the provocative title, was seen as a direct challenge to mainstream neo-Darwinism, and it brought molecular evolution and the neutral theory to the center of evolutionary biology. It provided a mechanism for the molecular clock and a theoretical basis for exploring deeper issues of molecular evolution, such as the relationship between rate of evolution and functional importance. The rise of the neutral theory marked synthesis of evolutionary biology and molecular biology—though an incomplete one.
With their work on firmer theoretical footing, in 1971 Emile Zuckerkandl and other molecular evolutionists founded the Journal of Molecular Evolution
.
From the 1970s through the early 1980s, both selectionists and neutralists could explain the observed high levels of heterozygosity in natural populations, by assuming different values for unknown parameters. Early in the debate, Kimura's student Tomoko Ohta
focused on the interaction between natural selection and genetic drift, which was significant for mutations that were not strictly neutral, but nearly so. In such cases, selection would compete with drift: most slightly deleterious mutations would be eliminated by natural selection or chance; some would move to fixation through drift. The behavior of this type of mutation, described by an equation that combined the mathematics of the neutral theory with classical models, became the basis of Ohta's nearly neutral theory of molecular evolution
.
In 1973, Ohta published a short letter in Nature suggesting that a wide variety of molecular evidence supported the theory that most mutation events at the molecular level are slightly deleterious rather than strictly neutral. Molecular evolutionists were finding that while rates of protein evolution (consistent with the molecular clock
) were fairly independent of generation time, rates of noncoding DNA
divergence were inversely proportional to generation time. Noting that population size is generally inversely proportional to generation time, Tomoko Ohta proposed that most amino acid substitutions are slightly deleterious while noncoding DNA substitutions are more neutral. In this case, the faster rate of neutral evolution in proteins expected in small populations (due to genetic drift) is offset by longer generation times (and vice versa), but in large populations with short generation times, noncoding DNA evolves faster while protein evolution is retarded by selection (which is more significant than drift for large populations).
Between then and the early 1990s, many studies of molecular evolution used a "shift model" in which the negative effect on the fitness of a population due to deleterious mutations shifts back to an original value when a mutation reaches fixation. In the early 1990s, Ohta developed a "fixed model" that included both beneficial and deleterious mutations, so that no artificial "shift" of overall population fitness was necessary. According to Ohta, however, the nearly neutral theory largely fell out of favor in the late 1980s, because the mathematically simpler neutral theory for the widespread molecular systematics research that flourished after the advent of rapid DNA sequencing
. As more detailed systematics studies started to compare the evolution of genome regions subject to strong selection versus weaker selection in the 1990s, the nearly neutral theory and the interaction between selection and drift have once again become an important focus of research.
, a molecular biologist whose earlier work was on the genetic code and its origin, began using small subunit ribosomal RNA
to reclassify bacteria by genetic (rather than morphological) similarity. Work proceeded slowly at first, but accelerated as new sequencing methods were developed in the 1970s and 1980s. By 1977, Woese and George Fox
announced that some bacteria, such as methanogen
s, lacked the rRNA units that Woese's phylogenetic studies were based on; they argued that these organisms were actually distinct enough from conventional bacteria and the so-called higher organisms to form their own kingdom, which they called archaebacteria. Though controversial at first (and challenged again in the late 1990s), Woese's work became the basis of the modern three-domain system
of Archaea
, Bacteria
, and Eukarya (replacing the five-domain system that had emerged in the 1960s).
Work on microbial phylogeny also brought molecular evolution closer to cell biology
and origin of life research. The differences between archaea pointed to the importance of RNA in the early history of life. In his work with the genetic code, Woese had suggested RNA-based life had preceded the current forms of DNA-based life, as had several others before him—an idea that Walter Gilbert
would later call the "RNA world". In many cases, genomics research in the 1990s produced phylogenies contradicting the rRNA-based results, leading to the recognition of widespread lateral gene transfer across distinct taxa. Combined with the probable endosymbiotic origin of organelle
-filled eukarya, this pointed to a far more complex picture of the origin and early history of life, one which might not be describable in the traditional terms of common ancestry.
Molecular evolution
Molecular evolution is in part a process of evolution at the scale of DNA, RNA, and proteins. Molecular evolution emerged as a scientific field in the 1960s as researchers from molecular biology, evolutionary biology and population genetics sought to understand recent discoveries on the structure...
came into its own in the 1960s and 1970s, following the rise of molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
. The advent of protein sequencing
Protein sequencing
Protein sequencing is a technique to determine the amino acid sequence of a protein, as well as which conformation the protein adopts and the extent to which it is complexed with any non-peptide molecules...
allowed molecular biologists to create phylogenies based on sequence comparison, and to use the differences between homologous sequences as a molecular clock
Molecular clock
The molecular clock is a technique in molecular evolution that uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...
to estimate the time since the last common ancestor. In the late 1960s, the neutral theory of molecular evolution
Neutral theory of molecular evolution
The neutral theory of molecular evolution states that the vast majority of evolutionary changes at the molecular level are caused by random drift of selectively neutral mutants . The theory was introduced by Motoo Kimura in the late 1960s and early 1970s...
provided a theoretical basis for the molecular clock, though both the clock and the neutral theory were controversial, since most evolutionary biologists held strongly to panselectionism, with natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
as the only important cause of evolutionary change. After the 1970s, nucleic acid sequencing allowed molecular evolution to reach beyond proteins to highly conserved ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
sequences, the foundation of a reconceptualization of the early history of life.
Early history
Before the rise of molecular biologyMolecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
in the 1950s and 1960s, a small number of biologists had explored the possibilities of using biochemical differences between species to study evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
. Ernest Baldwin
Ernest Baldwin
Ernest Hubert Francis Baldwin was an English biochemist, textbook author and pioneer in the field of comparative biochemistry....
worked extensively on comparative biochemistry beginning in the 1930s, and Marcel Florkin
Marcel Florkin
Marcel Florkin was a Belgian biochemist. Florkin was graduated as a Doctor in Medicine and became a professor of biochemistry at the University of Liège....
pioneered techniques for constructing phylogenies based on molecular and biochemical characters in the 1940s. However, it was not until the 1950s that biologists developed techniques for producing biochemical data for the quantitative study of molecular evolution
Molecular evolution
Molecular evolution is in part a process of evolution at the scale of DNA, RNA, and proteins. Molecular evolution emerged as a scientific field in the 1960s as researchers from molecular biology, evolutionary biology and population genetics sought to understand recent discoveries on the structure...
.
The first molecular systematics research was based on immunological assay
Assay
An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...
s and protein "fingerprinting" methods. Alan Boyden—building on immunological methods of G. H. F. Nuttall—developed new techniques beginning in 1954, and in the early 1960s Curtis Williams
Curtis Williams
Curtis Williams is an American television actor who is best known for his role as Nicholas Peterson on the sitcom The Parent 'Hood...
and Morris Goodman
Morris Goodman
Morris Goodman was an American scientist known for his work in molecular evolution and molecular systematics...
used immunological comparisons to study primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
phylogeny. Others, such as Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
and his students, applied newly developed combinations of electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
and paper chromatography
Paper chromatography
Paper chromatography is an analytical chemistry technique for separating and identifying mixtures that are or can be colored, especially pigments. This can also be used in secondary or primary colors in ink experiments. This method has been largely replaced by thin layer chromatography, however it...
to proteins subject to partial digestion by digestive enzymes to create unique two-dimensional patterns, allowing fine-grained comparisons of homologous proteins.
Beginning in the 1950s, a few naturalists also experimented with molecular approaches—notably Ernst Mayr
Ernst Mayr
Ernst Walter Mayr was one of the 20th century's leading evolutionary biologists. He was also a renowned taxonomist, tropical explorer, ornithologist, historian of science, and naturalist...
and Charles Sibley
Charles Sibley
Charles Gald Sibley was an American ornithologist and molecular biologist. He had an immense influence on the scientific classification of birds, and the work that Sibley initiated has substantially altered our understanding of the evolutionary history of modern birds.Sibley's taxonomy has been a...
. While Mayr quickly soured on paper chromatography, Sibley successfully applied electrophoresis to egg-white proteins to sort out problems in bird taxonomy, soon supplemented that with DNA hybridization techniques—the beginning of a long career built on molecular systematics.
While such early biochemical techniques found grudging acceptance in the evolutionary biology community, for the most part they did not impact the main theoretical problems of evolution and population genetics. This would change as molecular biology shed more light on the physical and chemical nature of genes.
Genetic load, the classical/balance controversy, and the measurement of heterozygosity
At the time that molecular biology was coming into its own in the 1950s, there was a long-running debate—the classical/balance controversy—over the causes of heterosisHeterosis
Heterosis, or hybrid vigor, or outbreeding enhancement, is the improved or increased function of any biological quality in a hybrid offspring. The adjective derived from heterosis is heterotic....
, the increase in fitness observed when inbred lines are outcrossed. In 1950, James F. Crow
James F. Crow
James F. Crow is Professor Emeritus of Genetics at the University of Wisconsin–Madison.Some of his most significant peer-reviewed contributions were coauthored with Motoo Kimura. His major contribution to the field, however, is arguably his teaching...
offered two different explanations (later dubbed the classical and balance positions) based the paradox first articulated by J. B. S. Haldane
J. B. S. Haldane
John Burdon Sanderson Haldane FRS , known as Jack , was a British-born geneticist and evolutionary biologist. A staunch Marxist, he was critical of Britain's role in the Suez Crisis, and chose to leave Oxford and moved to India and became an Indian citizen...
in 1937: the effect of deleterious mutations on the average fitness of a population depends only on the rate of mutations (not the degree of harm caused by each mutation) because more-harmful mutations are eliminated more quickly by natural selection, while less-harmful mutations remain in the population longer. H. J. Muller dubbed this "genetic load
Genetic load
In population genetics, genetic load or genetic burden is a measure of the cost of lost alleles due to selection or mutation...
".
Muller, motivated by his concern about the effects of radiation on human populations, argued that heterosis is primarily the result of deleterious homozygous recessive alleles, the effects of which are masked when separate lines are crossed—this was the dominance hypothesis, part of what Dobzhansky labeled the classical position. Thus, ionizing radiation and the resulting mutations produce considerable genetic load even if death or disease does not occur in the exposed generation, and in the absence of mutation natural selection will gradually increase the level of homozygosity. Bruce Wallace, working with J. C. King, used the overdominance hypothesis to develop the balance position, which left a larger place for overdominance
Overdominance
Overdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents. Overdominance can also be described as heterozygote advantage, wherein heterozygous individuals have a higher fitness than homozygous individuals.An...
(where the heterozygous state of a gene is more fit than the homozygous states). In that case, heterosis is simply the result of the increased expression of heterozygote advantage
Heterozygote advantage
A heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. The specific case of heterozygote advantage is due to a single locus known as overdominance...
. If overdominant loci are common, then a high level of heterozygosity would result from natural selection, and mutation-induced radiation may in fact facilitate an increase in fitness due to overdominance. (This was also the view of Dobzhansky.)
Debate continued through 1950s, gradually becoming a central focus of population genetics. A 1958 study of Drosophila by Wallace suggested that radiation-induced mutations increased the viability of previously homozygous flies, providing evidence for heterozygote advantage and the balance position; Wallace estimated that 50% of loci in natural Drosophila populations were heterozygous. Motoo Kimura
Motoo Kimura
was a Japanese biologist best known for introducing the neutral theory of molecular evolution in 1968. He became one of the most influential theoretical population geneticists. He is remembered in genetics for his innovative use of diffusion equations to calculate the probability of fixation of...
's subsequent mathematical analyses reinforced what Crow had suggested in 1950: that even if overdominant loci are rare, they could be responsible for a disproportionate amount of genetic variability. Accordingly, Kimura and his mentor Crow came down on the side of the classical position. Further collaboration between Crow and Kimura led to the infinite alleles model
Infinite alleles model
The infinite alleles model is a mathematical model for calculating genetic mutations. The Japanese geneticist Motoo Kimura and American geneticist James F. Crow introduced the infinite alleles model, an attempt to determine for a finite diploid population what proportion of loci would be...
, which could be used to calculate the number of different alleles expected in a population, based on population size, mutation rate, and whether the mutant alleles were neutral, overdominant, or deleterious. Thus, the infinite alleles model offered a potential way to decide between the classical and balance positions, if accurate values for the level of heterozygosity could be found.
By the mid-1960s, the techniques of biochemistry and molecular biology—in particular protein electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
—provided a way to measure the level of heterozygosity in natural populations: a possible means to resolve the classical/balance controversy. In 1963, Jack L. Hubby published an electrophoresis study of protein variation in Drosophila; soon after, Hubby began collaborating with Richard Lewontin
Richard Lewontin
Richard Charles "Dick" Lewontin is an American evolutionary biologist, geneticist and social commentator. A leader in developing the mathematical basis of population genetics and evolutionary theory, he pioneered the notion of using techniques from molecular biology such as gel electrophoresis to...
to apply Hubby's method to the classical/balance controversy by measuring the proportion of heterozygous loci in natural populations. Their two landmark papers, published in 1966, established a significant level of heterozygosity for Drosophila (12%, on average). However, these findings proved difficult to interpret. Most population geneticists (including Hubby and Lewontin) rejected the possibility of widespread neutral mutations; explanations that did not involve selection were anathema to mainstream evolutionary biology. Hubby and Lewontin also ruled out heterozygote advantage as the main cause because of the segregation load it would entail, though critics argued that the findings actually fit well with overdominance hypothesis.
Protein sequences and the molecular clock
While evolutionary biologists were tentatively branching out into molecular biology, molecular biologists were rapidly turning their attention toward evolution.After developing the fundamentals of protein sequencing with insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
between 1951 and 1955, Frederick Sanger
Frederick Sanger
Frederick Sanger, OM, CH, CBE, FRS is an English biochemist and a two-time Nobel laureate in chemistry, the only person to have been so. In 1958 he was awarded a Nobel prize in chemistry "for his work on the structure of proteins, especially that of insulin"...
and his colleagues had published a limited interspecies comparison of the insulin sequence in 1956. Francis Crick
Francis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...
, Charles Sibley
Charles Sibley
Charles Gald Sibley was an American ornithologist and molecular biologist. He had an immense influence on the scientific classification of birds, and the work that Sibley initiated has substantially altered our understanding of the evolutionary history of modern birds.Sibley's taxonomy has been a...
and others recognized the potential for using biological sequences to construct phylogenies, though few such sequences were yet available. By the early 1960s, techniques for protein sequencing
Protein sequencing
Protein sequencing is a technique to determine the amino acid sequence of a protein, as well as which conformation the protein adopts and the extent to which it is complexed with any non-peptide molecules...
had advanced to the point that direct comparison of homologous amino acid sequences was feasible. In 1961, Emanuel Margoliash
Emanuel Margoliash
Emanuel Margoliash was a biochemist who spent much of his career studying the protein cytochrome c. He is best known for his work on molecular evolution; with Walter Fitch, he devised Fitch-Margoliash method for constructing evolutionary trees based on protein sequences.He was a member of the...
and his collaborators completed the sequence for horse cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
(a longer and more widely distributed protein than insulin), followed in short order by a number of other species.
In 1962, Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
and Emile Zuckerkandl
Emile Zuckerkandl
Emile Zuckerkandl is an Austrian-American biologist considered one of the founders of the field of molecular evolution. He is best known for introducing, with Linus Pauling, the concept of the molecular clock, which set the stage for the neutral theory of molecular evolution.- Life and work...
proposed using the number of differences between homologous protein sequences to estimate the time since divergence
Genetic divergence
Genetic divergence is the process in which two or more populations of an ancestral species accumulate independent genetic changes through time, often after the populations have become reproductively isolated for some period of time...
, an idea Zuckerkandl had conceived around 1960 or 1961. This began with Pauling's long-time research focus, hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, which was being sequenced by Walter Schroeder; the sequences not only supported the accepted vertebrate phylogeny, but also the hypothesis (first proposed in 1957) that the different globin chains within a single organism could also be traced to a common ancestral protein. Between 1962 and 1965, Pauling and Zuckerkandl refined and elaborated this idea, which they dubbed the molecular clock
Molecular clock
The molecular clock is a technique in molecular evolution that uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...
, and Emil L. Smith
Emil L. Smith
Emil L. Smith was an American biochemist who studied protein structure and function as well as biochemical evolution....
and Emanuel Margoliash expanded the analysis to cytochrome c. Early molecular clock calculations agreed fairly well with established divergence times based on paleontological evidence. However, the essential idea of the molecular clock—that individual proteins evolve at a regular rate independent of a species' morphological
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
evolution—was extremely provocative (as Pauling and Zuckerkandl intended it to be).
The "molecular wars"
From the early 1960s, molecular biology was increasingly seen as a threat to the traditional core of evolutionary biology. Established evolutionary biologists—particularly Ernst MayrErnst Mayr
Ernst Walter Mayr was one of the 20th century's leading evolutionary biologists. He was also a renowned taxonomist, tropical explorer, ornithologist, historian of science, and naturalist...
, Theodosius Dobzhansky
Theodosius Dobzhansky
Theodosius Grygorovych Dobzhansky ForMemRS was a prominent geneticist and evolutionary biologist, and a central figure in the field of evolutionary biology for his work in shaping the unifying modern evolutionary synthesis...
and G. G. Simpson, three of the founders of the modern evolutionary synthesis
Modern evolutionary synthesis
The modern evolutionary synthesis is a union of ideas from several biological specialties which provides a widely accepted account of evolution...
of the 1930s and 1940s—were extremely skeptical of molecular approaches, especially when it came to the connection (or lack thereof) to natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
. Molecular evolution in general—and the molecular clock in particular—offered little basis for exploring evolutionary causation. According to the molecular clock hypothesis, proteins evolved essentially independently of the environmentally determined forces of selection; this was sharply at odds with the panselectionism prevalent at the time. Moreover, Pauling, Zuckerkandl, and other molecular biologists were increasingly bold in asserting the significance of "informational macromolecules" (DNA, RNA and proteins) for all biological processes, including evolution. The struggle between evolutionary biologists and molecular biologists—with each group holding up their discipline as the center of biology as a whole—was later dubbed the "molecular wars" by Edward O. Wilson, who experienced firsthand the domination of his biology department by young molecular biologists in the late 1950s and the 1960s.
In 1961, Mayr began arguing for a clear distinction between functional biology (which considered proximate causes
Proximate causation
In philosophy a proximate cause is an event which is closest to, or immediately responsible for causing, some observed result. This exists in contrast to a higher-level ultimate cause which is usually thought of as the "real" reason something occurred.* Example: Why did the ship sink?** Proximate...
and asked "how" questions) and evolutionary biology (which considered ultimate causes and asked "why" questions) He argued that both disciplines and individual scientists could be classified on either the functional or evolutionary side, and that the two approaches to biology were complementary. Mayr, Dobzhansky, Simpson and others used this distinction to argue for the continued relevance of organismal biology, which was rapidly losing ground to molecular biology and related disciplines in the competition for funding and university support. It was in that context that Dobzhansky first published his famous statement, "nothing in biology makes sense except in the light of evolution
Nothing in Biology Makes Sense Except in the Light of Evolution
"Nothing in Biology Makes Sense Except in the Light of Evolution" is a 1973 essay by the evolutionary biologist and Russian Orthodox Christian Theodosius Dobzhansky, criticising anti-evolution creationism and espousing theistic evolution...
", in a 1964 paper affirming the importance of organismal biology in the face of the molecular threat; Dobzhansky characterized the molecular disciplines as "Cartesian
Cartesianism
Cartesian means of or relating to the French philosopher and mathematician René Descartes—from his name—Rene Des-Cartes. It may refer to:*Cartesian anxiety*Cartesian circle*Cartesian dualism...
" (reductionist) and organismal disciplines as "Darwinian".
Mayr and Simpson attended many of the early conferences where molecular evolution was discussed, critiquing what they saw as the overly simplistic approaches of the molecular clock. The molecular clock, based on uniform rates of genetic change driven by random mutations and drift, seemed incompatible with the varying rates of evolution and environmentally-driven adaptive processes (such as adaptive radiation
Adaptive radiation
In evolutionary biology, adaptive radiation is the evolution of ecological and phenotypic diversity within a rapidly multiplying lineage. Starting with a recent single ancestor, this process results in the speciation and phenotypic adaptation of an array of species exhibiting different...
) that were among the key developments of the evolutionary synthesis. At the 1962 Wenner-Gren conference, the 1964 Colloquium on the Evolution of Blood Proteins in Bruges
Bruges
Bruges is the capital and largest city of the province of West Flanders in the Flemish Region of Belgium. It is located in the northwest of the country....
, Belgium
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
, and the 1964 Conference on Evolving Genes and Proteins at Rutgers University
Rutgers University
Rutgers, The State University of New Jersey , is the largest institution for higher education in New Jersey, United States. It was originally chartered as Queen's College in 1766. It is the eighth-oldest college in the United States and one of the nine Colonial colleges founded before the American...
, they engaged directly with the molecular biologists and biochemists, hoping to maintain the central place of Darwinian explanations in evolution as its study spread to new fields.
Gene-centered view of evolution
Though not directly related to molecular evolution, the mid-1960s also saw the rise of the gene-centered view of evolutionGene-centered view of evolution
The gene-centered view of evolution, gene selection theory or selfish gene theory holds that evolution occurs through the differential survival of competing genes, increasing the frequency of those alleles whose phenotypic effects successfully promote their own propagation, with gene defined as...
, spurred by George C. Williams
George C. Williams
Professor George Christopher Williams was an American evolutionary biologist.Williams was a professor emeritus of biology at the State University of New York at Stony Brook. He was best known for his vigorous critique of group selection. The work of Williams in this area, along with W. D...
's Adaptation and Natural Selection
Adaptation and Natural Selection
Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought is a 1966 book by the American evolutionary biologist George C. Williams...
(1966). Debate over units of selection, particularly the controversy over group selection
Group selection
In evolutionary biology, group selection refers to the idea that alleles can become fixed or spread in a population because of the benefits they bestow on groups, regardless of the alleles' effect on the fitness of individuals within that group....
, led to increased focus on individual genes (rather than whole organisms or populations) as the theoretical basis for evolution. However, the increased focus on genes did not mean a focus on molecular evolution; in fact, the adaptationism
Adaptationism
Adaptationism is a set of methods in the evolutionary sciences for distinguishing the products of adaptation from traits that arise through other processes. It is employed in fields such as ethology and evolutionary psychology that are concerned with identifying adaptations...
promoted by Williams and other evolutionary theories further marginalized the apparently non-adaptive changes studied by molecular evolutionists.
The neutral theory of molecular evolution
The intellectual threat of molecular evolution became more explicit in 1968, when Motoo Kimura introduced the neutral theory of molecular evolutionNeutral theory of molecular evolution
The neutral theory of molecular evolution states that the vast majority of evolutionary changes at the molecular level are caused by random drift of selectively neutral mutants . The theory was introduced by Motoo Kimura in the late 1960s and early 1970s...
. Based on the available molecular clock studies (of hemoglobin from a wide variety of mammals, cytochrome c from mammals and birds, and triosephosphate dehydrogenase from rabbits and cows), Kimura (assisted by Tomoko Ohta
Tomoko Ohta
is a Japanese scientist working on molecular evolution. In 1956, she graduated from the University of Tokyo. After working on the neutral theory of evolution with her mentor, Motoo Kimura, she became convinced of the importance of the mutations that were nearly neutral. She developed the slightly...
) calculated an average rate of DNA substitution of one base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
change per 300 base pairs (encoding 100 amino acids) per 28 million years. For mammal genomes, this indicated a substitution rate of one every 1.8 years, which would produce an unsustainably high substitution load
Haldane's dilemma
Haldane's Dilemma refers to a limit on the speed of beneficial evolution, first calculated by J. B. S. Haldane in 1957, and clarified further by later commentators. Creationists, and proponents of intelligent design in particular, claim it remains unresolved. Contrary to creationist claims,...
unless the preponderance of substitutions was selectively neutral. Kimura argued that neutral mutations occur very frequently, a conclusion compatible with the results of the electrophoretic studies of protein heterozygosity. Kimura also applied his earlier mathematical work on genetic drift to explain how neutral mutations could come to fixation
Fixation (population genetics)
In population genetics, fixation is the change in a gene pool from a situation where there exist at least two variants of a particular gene to a situation where only one of the alleles remains...
, even in the absence of natural selection; he soon convinced James F. Crow of the potential power of neutral alleles and genetic drift as well.
Kimura's theory—described only briefly in a letter to Nature—was followed shortly after with a more substantial analysis by Jack L. King and Thomas H. Jukes
Thomas H. Jukes
Thomas Hughes Jukes was a British-American biologist known for his work in nutrition, molecular evolution, and for his public engagement with controversial scientific issues, including DDT, vitamin C and creationism...
—who titled their first paper on the subject "non-Darwinian evolution
Non-Darwinian Evolution
"Non-Darwinian Evolution" is a 1969 scientific paper co-authored by Jack Lester King and Thomas H. Jukes that is credited, along with Motoo Kimura's 1968 paper "Evolutionary Rate at the Molecular Level", with proposing what became known as the neutral theory of molecular evolution...
". Though King and Jukes produced much lower estimates of substitution rates and the resulting genetic load in the case of non-neutral changes, they agreed that neutral mutations driven by genetic drift were both real and significant. The fairly constant rates of evolution observed for individual proteins was not easily explained without invoking neutral substitutions (though G. G. Simpson and Emil Smith had tried). Jukes and King also found a strong correlation between the frequency of amino acids and the number of different codons encoding each amino acid. This pointed to substitutions in protein sequences as being largely the product of random genetic drift.
King and Jukes' paper, especially with the provocative title, was seen as a direct challenge to mainstream neo-Darwinism, and it brought molecular evolution and the neutral theory to the center of evolutionary biology. It provided a mechanism for the molecular clock and a theoretical basis for exploring deeper issues of molecular evolution, such as the relationship between rate of evolution and functional importance. The rise of the neutral theory marked synthesis of evolutionary biology and molecular biology—though an incomplete one.
With their work on firmer theoretical footing, in 1971 Emile Zuckerkandl and other molecular evolutionists founded the Journal of Molecular Evolution
Journal of Molecular Evolution
The Journal of Molecular Evolution is a peer-reviewed scientific journal that covers molecular evolution. The journal is published by Springer and was established in 1971. The founding editor is Emile Zuckerkandl, who remained editor in chief until the late 1990s...
.
The neutralist-selectionist debate and near-neutrality
The critical responses to the neutral theory that soon appeared marked the beginning of the neutralist-selectionist debate. In short, selectionists viewed natural selection as the primary or only cause of evolution, even at the molecular level, while neutralists held that neutral mutations were widespread and that genetic drift was a crucial factor in the evolution of proteins. Kimura became the most prominent defender of the neutral theory—which would be his main focus for the rest of his career. With Ohta, he refocused his arguments on the rate at which drift could fix new mutations in finite populations, the significance of constant protein evolution rates, and the functional constraints on protein evolution that biochemists and molecular biologists had described. Though Kimura had initially developed the neutral theory partly as an outgrowth of the classical position within the classical/balance controversy (predicting high genetic load as a consequence of non-neutral mutations), he gradually deemphasized his original argument that segregational load would be impossibly high without neutral mutations (which many selectionists, and even fellow neutralists King and Jukes, rejected).From the 1970s through the early 1980s, both selectionists and neutralists could explain the observed high levels of heterozygosity in natural populations, by assuming different values for unknown parameters. Early in the debate, Kimura's student Tomoko Ohta
Tomoko Ohta
is a Japanese scientist working on molecular evolution. In 1956, she graduated from the University of Tokyo. After working on the neutral theory of evolution with her mentor, Motoo Kimura, she became convinced of the importance of the mutations that were nearly neutral. She developed the slightly...
focused on the interaction between natural selection and genetic drift, which was significant for mutations that were not strictly neutral, but nearly so. In such cases, selection would compete with drift: most slightly deleterious mutations would be eliminated by natural selection or chance; some would move to fixation through drift. The behavior of this type of mutation, described by an equation that combined the mathematics of the neutral theory with classical models, became the basis of Ohta's nearly neutral theory of molecular evolution
Nearly neutral theory of molecular evolution
The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for slightly advantageous or deleterious mutations at the molecular level...
.
In 1973, Ohta published a short letter in Nature suggesting that a wide variety of molecular evidence supported the theory that most mutation events at the molecular level are slightly deleterious rather than strictly neutral. Molecular evolutionists were finding that while rates of protein evolution (consistent with the molecular clock
Molecular clock
The molecular clock is a technique in molecular evolution that uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...
) were fairly independent of generation time, rates of noncoding DNA
Noncoding DNA
In genetics, noncoding DNA describes components of an organism's DNA sequences that do not encode for protein sequences. In many eukaryotes, a large percentage of an organism's total genome size is noncoding DNA, although the amount of noncoding DNA, and the proportion of coding versus noncoding...
divergence were inversely proportional to generation time. Noting that population size is generally inversely proportional to generation time, Tomoko Ohta proposed that most amino acid substitutions are slightly deleterious while noncoding DNA substitutions are more neutral. In this case, the faster rate of neutral evolution in proteins expected in small populations (due to genetic drift) is offset by longer generation times (and vice versa), but in large populations with short generation times, noncoding DNA evolves faster while protein evolution is retarded by selection (which is more significant than drift for large populations).
Between then and the early 1990s, many studies of molecular evolution used a "shift model" in which the negative effect on the fitness of a population due to deleterious mutations shifts back to an original value when a mutation reaches fixation. In the early 1990s, Ohta developed a "fixed model" that included both beneficial and deleterious mutations, so that no artificial "shift" of overall population fitness was necessary. According to Ohta, however, the nearly neutral theory largely fell out of favor in the late 1980s, because the mathematically simpler neutral theory for the widespread molecular systematics research that flourished after the advent of rapid DNA sequencing
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
. As more detailed systematics studies started to compare the evolution of genome regions subject to strong selection versus weaker selection in the 1990s, the nearly neutral theory and the interaction between selection and drift have once again become an important focus of research.
Microbial phylogeny
While early work in molecular evolution focused on readily sequenced proteins and relatively recent evolutionary history, by the late 1960s some molecular biologists were pushing further toward the base of the tree of life by studying highly conserved nucleic acid sequences. Carl WoeseCarl Woese
Carl Richard Woese is an American microbiologist and physicist. Woese is famous for defining the Archaea in 1977 by phylogenetic taxonomy of 16S ribosomal RNA, a technique pioneered by Woese and which is now standard practice. He was also the originator of the RNA world hypothesis in 1977,...
, a molecular biologist whose earlier work was on the genetic code and its origin, began using small subunit ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
to reclassify bacteria by genetic (rather than morphological) similarity. Work proceeded slowly at first, but accelerated as new sequencing methods were developed in the 1970s and 1980s. By 1977, Woese and George Fox
George Fox
George Fox was an English Dissenter and a founder of the Religious Society of Friends, commonly known as the Quakers or Friends.The son of a Leicestershire weaver, Fox lived in a time of great social upheaval and war...
announced that some bacteria, such as methanogen
Methanogen
Methanogens are microorganisms that produce methane as a metabolic byproduct in anoxic conditions. They are classified as archaea, a group quite distinct from bacteria...
s, lacked the rRNA units that Woese's phylogenetic studies were based on; they argued that these organisms were actually distinct enough from conventional bacteria and the so-called higher organisms to form their own kingdom, which they called archaebacteria. Though controversial at first (and challenged again in the late 1990s), Woese's work became the basis of the modern three-domain system
Three-domain system
The three-domain system is a biological classification introduced by Carl Woese in 1977 that divides cellular life forms into archaea, bacteria, and eukaryote domains. In particular, it emphasizes the separation of prokaryotes into two groups, originally called Eubacteria and Archaebacteria...
of Archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
, Bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, and Eukarya (replacing the five-domain system that had emerged in the 1960s).
Work on microbial phylogeny also brought molecular evolution closer to cell biology
Cell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
and origin of life research. The differences between archaea pointed to the importance of RNA in the early history of life. In his work with the genetic code, Woese had suggested RNA-based life had preceded the current forms of DNA-based life, as had several others before him—an idea that Walter Gilbert
Walter Gilbert
Walter Gilbert is an American physicist, biochemist, molecular biology pioneer, and Nobel laureate.-Biography:Gilbert was born in Boston, Massachusetts, on March 21, 1932...
would later call the "RNA world". In many cases, genomics research in the 1990s produced phylogenies contradicting the rRNA-based results, leading to the recognition of widespread lateral gene transfer across distinct taxa. Combined with the probable endosymbiotic origin of organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
-filled eukarya, this pointed to a far more complex picture of the origin and early history of life, one which might not be describable in the traditional terms of common ancestry.
External links
- Perspectives on Molecular Evolution - maintained by historian of science Michael R. Dietrich