by Frank Ryan
It was hardly a criticism of Darwin that he could not explain how hereditary change might come about—next to nothing was known about it in his day. He speculated that hereditary variation arose from a kind of “blending” of the pedigrees of the two parents. The first two chapters of The Origin are devoted to explaining how blending worked, both in animals and domesticated crops. But over time, Darwin himself became less and less convinced that blending was a sufficient explanation. In the words of the leading American Darwinian, the late Ernst Mayr: “The origin of this variation puzzled him all of his life.” Today we know that what Darwin implied by “variation” suggests some mechanism or mechanisms that give rise to hereditary genetic, or genomic, change. The rediscovery of Mendel's laws of heredity produced a breakthrough in the understanding of how heredity actually operated: specific characters, or traits, were inherited as discrete genetic units—what we now call “genes.” In 1900, a Dutch botanist, Hugo de Vries, took this an important step further when he had the inspiration that heredity could be altered if mistakes were made during the copying of these genes. The obvious opportunity was during reproduction—here a mistake in copying a gene would give rise to what de Vries called a “mutation.”
In the 1920s and 1930s, the reality of mutations was confirmed by the laboratory experiments of evolutionary biologists such as Thomas Hunt Morgan, Barbara McClintock, and Hermann J. Muller. Mutation was no longer a theoretical possibility but a fact and, very likely, a common enough fact to be mathematically predictable. A number of investigating scientists throughout the world began to piece together a mathematically based synthesis of how natural selection would be enabled through such “germ-line mutations” of genes. These included pioneering geneticists such as Ronald Aylmer Fisher and John Burdon Sanderson Haldane in Britain, Sewall Wright and Theodosius Dobzhansky in the United States, and Sergei Sergeevich Chetverikov in the Soviet Union.
In time, geneticists found that most of the mutations in DNA sequences during the formation of the human ova and sperm had little or no effect on the function of proteins and thus seemed unlikely to contribute to evolution or to disease. Those that did give rise to change in proteins, or regulatory function, mostly did so for the worse. They were the causes of inherited diseases. But a small minority of mutations altered the heredity of the offspring in ways that might potentially improve the chances of survival. For example, there is growing evidence that a small number of mutations in a gene known as Prx1 may have contributed to the elongation of the forelimb skeleton that enabled the evolution of the membranous wings of bats.
From a medical perspective, mutations of DNA can also arise during the cell division that is a normal part of the replenishment processes in the many tissues and organs during life. These so-called “somatic mutations” are important in the causation of various types of cancers, from the leukemias and lymphomas of blood and lymphatic tissues to cancers of breast, skin, kidney, and bowel, and so on. The reality is a little more complex. The genomes of the eukaryotic life-forms—those with nucleated cells, including animals and plants—have mechanisms for correcting these copying errors as they arise, but these mechanisms can sometimes fail or be overwhelmed.
Medical geneticists can now list thousands of germ-line mutations that give rise to a range of inherited problems affecting the internal chemistry of the affected offspring. Many of these “errors of metabolism” arise from a mutation affecting a single gene, but some can result from mutations affecting clusters of genes, aberrant sections of chromosomes, or the loss or gain of a whole chromosome. In an earlier chapter we witnessed the recessive mutation affecting beta-globin that causes sickle cell disease. At this stage we might hop aboard our magical train to visit the genome of an individual who has had the misfortune to inherit a dominant mutation and take a look in a little more detail at how this mutation has come about.
Each of our 46 human chromosomes is, in our model, a separate railway line. Trains can only run from start to finish—they cannot switch lines, since each chromosome is a separate linear structure. On this occasion we choose to travel on Line 4—human chromosome 4. We chug along until we come to a stretch of track that is signposted “Huntingtin.” If we alight here and examine the adjacent track carefully, we observe the typical gene structure we saw in an earlier trip. Here is the section of DNA, with its nucleotide sleepers, that announces itself as the Huntingtin gene “promoter.” This sequence, which is usually adjacent to the start of the gene, is the genetic switch that turns the gene off and on. From here we stroll further eastward, moving “sense-wise” along the track, till we arrive at the first exon of the gene. As we stroll a little further along the exon track, we come across something very odd; we see that a triplet of nucleotide sequences, cytosine-adenine-guanine—CAG—appears to be repeating itself over and over in successive sleepers.
“Go ahead,” I suggest. “Count the number of repeats.”
You are surprised to discover that there are 45 CAG repeats, one after another, in the first exon of the gene, Huntingtin.
“This mutation is the cause of the illness called Huntington's disease, which causes cerebral deterioration during adult life.”
“You mean there should be no repeats?”
“It's a little more complex. Curiously, we all have many repeats of the CAG sequence in the first exon of the gene, Huntingtin. It's the actual number that determines whether or not we inherit the condition. If we have between 6 and 34 repeats, we do not inherit the disease. The more repeats above this number, the more likely we are to inherit the condition. Above 40 repeats means disease in nearly every case. And the higher the number, the younger the onset of symptoms.”
“So what we find here is bad news for this unfortunate individual?”
“I'm afraid it is. All humans have two versions of chromosome 4, one inherited from our mother and one from our father. If we were to go and visit the other version of the gene on the matching chromosome, we'd discover that it was normal.”
“In other words, Huntington's disease is, what…a dominantly inherited mutation?”
“That's right. It also means that if medical science could find a way of switching off this damaged gene, the remaining normal gene would take over and the condition would, hopefully, be cured.”
At first people only thought of mutations as affecting these types of protein-coding genes. But as geneticists came to understand the importance of genes that coded for regulatory genetic sequences, including genes that coded for proteins that were intrinsically involved in gene regulation, they realized that a mutation that affected a regulatory sequence, for example a sequence that affected embryological development, could also affect the physical and mental development of the offspring. We shall look at this in more detail in later chapters. At this point, I merely wish to explain that the same patterns of mutation will sometimes change the hereditary nature of an individual in a beneficial way—a way that enhances the individual's chances of survival. And since this is hereditary, that beneficial mutation will be passed down to the individual's offspring and future generations. This doesn't just apply to humans; it applies to all animals, plants, fungi—indeed to every living organism. This is integral to the way in which evolution operates.
For almost a century, evolutionary geneticists have been recording how mutations in protein-coding and regulatory regions have contributed to the diversity of life on Earth, from the evolution of whales and dolphins from original land-living creatures to the origins of flight in insects and birds. They have also found some evidence for the evolution of genes that may have contributed to the expansion in size, and complexity, of the human brain. But mutations didn't have to be as dramatic as this. A small change that affected, say, the duration of effectiveness of a digestive enzyme such as lactase in humans, is capable of telling us a great deal about our own migratory history. As we shall discover in later chapters, evolutionary genetics appears to be entering a golden age, where the genomes of long-dead ancestors, includi
ng supposedly extinct humans, are being resurrected and subjected to intensive study. Soon we shall be in a position to determine with clinical accuracy why people of European origins found a way to digest cow's and goat's milk throughout life while those from Asian ancestry did not. We are already capable of determining through resurrected genomes when and how Europeans developed blue eyes and fair, or red, hair, in the same way that we can determine, through the genomic examination of fossil bones, how dark-skinned our ancestors were—or through analysis of teeth, how fast they matured during childhood and what diet they consumed.
The inspiration, and subsequent study, of mutation has provided evolutionary biology with a treasure trove of information on how life evolved and diversified on Earth. But the fact that the mutations occur randomly—and this random accumulation of mutations is easily measured—is only part of it. Random mutation on its own would not be enough to create biodiversity. The key to understanding is that natural selection is operating on the variation being presented by the random mutations. And the operation of natural selection is not random; it chooses those mutations that favor survival, and through survival, reproduction.
Mutation plus selection was soon recognized to be a very important mechanism in evolution. It has played a major role in the evolution of the human genome. It also has a seductive mathematical attraction: since mutations are thought to arise at a fairly regular rate—giving rise to what we shall subsequently encounter as the so-called molecular clock—mutation plus selection lent itself to calculus-based mathematical extrapolations that were increasingly seen as the major, if not the exclusive, mechanism of evolutionary change. This came to be viewed as the central mechanism of modern Darwinism, also called neo-Darwinism. Today, many school and college teachers still teach that this is the main, if not the only, source of the hereditary change, but we now know that mutation is not the only mechanism of creating hereditary change. On the contrary, mutation is one of a number of different naturally occurring mechanisms that are capable of changing the heredity of living organisms.
For close to a century, biologists and molecular geneticists have been gathering information on three other mechanisms that also generate the hereditary change necessary for evolution to take place. These include epigenetic inheritance systems, genetic symbiosis and hybridization, which, together with mutation, I have gathered under the convenient umbrella designation of “genomic creativity.” I chose my words carefully when I coined the phrase in a paper published in the Biological Journal of the Linnean Society because I wanted to emphasize that these four mechanisms are creative in themselves. And I used the word “genomic” rather than “genetic” because the very definition of epigenetic systems defines them as non-genetic. Each of the three other mechanisms is very different from mutation, and their genetic and genomic implications are also quite different. Following publication of the same ideas in my book Virolution, Gordon N. Dutton, emeritus professor at Glasgow Caledonian University, suggested I use the easily remembered acronym MESH for these four distinct mechanisms: mutation, epigenetics, symbiosis, and hybridization. Thank you, Professor Dutton, henceforth I shall. As we originally saw with mutation, all four mechanisms work hand in glove with Darwin's concept of natural selection.
Had there not been a lack of communication between my teachers and colleagues at Berkeley…and my quantitative friends at the Bacteria and Virus Laboratories, I might not have found myself groping with the problems whose possible solution is presented in this book.
LYNN MARGULIS
The study of nature has amply confirmed Darwin's insight—the land, air, and oceans are replete with examples of the struggle for survival. Competition for resources, the need for camouflage, the armor of protection, the massing of numbers, such as we see in the great herds of herbivores, shoals of fish, and the magnificent flocks of birds, are all evolved strategies for survival in a predatory world. From these very obvious adaptations to the microscopic mutations affecting genes, the evolutionary processes are now seen to be universal. In 1976, Richard Dawkins, while based at the University of Oxford, consolidated two decades of evolutionary study in his iconoclastic book The Selfish Gene, which was seen by many scientists as the perfect modern encapsulation of Darwin's original vision. However, while the concept of competition—which is the main driving force in the vision of both Dawkins and Darwin—is commonplace in nature, it is not the only driving factor in the struggle for survival.
In 1878, at a time when Darwin was still alive, a German professor, Anton de Bary, drew attention to the fact that different life-forms sometimes gained an advantage through living together. He called such living interactions “symbioses.” It was hardly a new observation. Herodotus described how the plover was known to take leeches out of the mouths of crocodiles, Aristotle observed a similar relationship between a bivalve mollusk and a crustacean, and Cicero was so impressed by many such examples to draw the moral that humans might learn from such friendships in nature. Honey bees appear to have an intimate relationship with flowering plants, with the plant supplying the bees with nectar and the bees assisting in the transfer of pollen to other plants, thus enhancing their success in reproduction. In the cleaner stations of the oceans, predators such as sharks and groupers line up as if arriving at a taxi stand, to have parasites and debris cleaned from their skins and mouths by tiny fish or shrimps. Anywhere outside the cleaner stations and the small fish and shrimps would be seen as food.
In the late 1800s, de Bary and another German naturalist, Albert Bernhard Frank, put the study of symbiosis onto a more firm scientific footing, defining the concept and pioneering the study of the biological and evolutionary implications. It is a common mistake to think of symbiosis exclusively in terms of mutualism. Let us immediately clarify the fact that symbiosis is not about Mr. Nice Guy, who comes along and shakes hands with Ms. Nice Girl, and everything is hunky-dory from then on. Only one of the partners needs to benefit for the association to be regarded as a symbiosis. In fact, symbiosis often begins with outright parasitism, which may progress to mutualism. Biologists who study symbiosis today see many examples that would be placed somewhere in between the two extremes. Even in its mutualistic form, symbiosis is about tough bargaining and hard compromising, with survival of the partnership, and thus the partners, depending on the outcome.
One of the first such living associations to be studied by naturalists were the lichens that coat rocks and stones, like the monuments of Stonehenge. Lichens had previously been categorized as a formal branch of the biological tree, with a variety of different genera and species. But now they were shown to be not species at all but intimate partnerships of algae and fungi.
Frank discovered something very important about the association of fungi and plants in general. When folks go to a garden center to buy some seedling plants in their pots, they have little idea that what they assume are roots when they shake the root ball out of the plastic pot are for the most part a ball of fungus. All of the land plants have fungal partners that grow into their roots to fashion an intimate symbiosis, with the plant supplying the fungus with carbohydrates for energy and the fungus supplying the plant with water and minerals. This arrangement is called a “mycorrhiza,” which literally means a fungal root. Some woods are underpinned by a vast mass of fungi underground that extends as a contiguous living system to feed the entire wood.
There are a few simple terms we need to grasp. The study of symbiosis is called “symbiology,” and the biologists who work in this discipline are called “symbiologists”; the interacting partners in a symbiosis are called “symbionts”; and the partnership as a whole is called a “holobiont.” As we have seen, symbiosis includes the smash-and-grab of parasitism, where only one of the partners benefits at the expense of its partner, as well as mutualism, in which two or more partners share the spoils. Today we know that symbioses are omnipresent in nature, from the coral reefs to the prairies and from the rain forests to the wind-blasted valleys of Antarctica. From its i
nception, the definition of symbiosis implied that it was a force in evolution, referred to as “symbiogenesis.” Symbiotic partnerships also include different types of partnerships, depending on what is being shared. The root symbioses of plants involve the sharing of the products of living chemistry, or “metabolism,” of plant and fungus, so these are called “metabolic symbioses.” Other metabolic symbioses include the partnership of alga and fungus in lichens and the gut bacteria that play an important role in human nutrition and immunology. Meanwhile, the cleaner-station symbioses involve a sharing of behaviors, so these are called “behavioral symbioses.”