MUTATIONS Sudden Change

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Shifts in chromosome combinations, with or without crossovers, can produce unique organisms with characteristics not quite like any organism that appeared in the past nor likely to appear in the reasonable future. They may even produce novelties in individual characteristics since genes can affect one another, and a gene surrounded by unusual neighbors can produce unexpected effects.

Matters can go further still, however, in the direction of novelty. It is possible for chromosomes to undergo more serious changes, either structural or chemical, so that entirely new characteristics are produced that might not otherwise exist. Such changes are called mutations.

We must be careful how we use this term. A child may possess some characteristics not present in either parent through the mere shuffling of chromosomes and not through mutation.

Suppose, for instance, that a man is heterozygous to eye color, carrying one gene for brown eyes and one for blue eyes. His eyes would, of course, be brown since the gene for brown eyes is dominant over that for blue. Half the sperm cells he produces would carry a single gene for brown eyes in its half set of chromosomes. The other half would carry a single gene for blue eyes. If his wife were similarly heterozygous (and therefore also had brown eyes), half her egg cells would carry the gene for brown eyes and half the gene for blue.

It might follow in this marriage, then, that a sperm carrying the gene for blue eyes might fertilize an egg carrying the gene for blue eyes. The child would then be homozygous, with two genes for blue eyes, and he would definitely be blue-eyed. In this way, two brown-eyed parents might have a blue-eyed child and this would not be a mutation. If the parents’ ancestry were traced further back, blue-eyed individuals would undoubtedly be found on both sides of the family tree.

If, however, there were no record of, say, anything but normal color vision in a child’s ancestry, and he were born color-blind, that could be assumed to be the result of a mutation. Such a mutation could then be passed on by the normal modes of inheritance and a certain proportion of the child’s eventual descendants would be color-blind.

A mutation may be associated with changes in chromosome structure sufficiently drastic to be visible under the microscope. Such chromosome mutations can arise in several ways. Chromosomes may undergo replication without the cell itself dividing. In that way, cells can develop with two, three, or four times the normal complement of chromosomes, and organisms made up of cells displaying such polyploidy can be markedly different from the norm. This situation is found chiefly among plants and among some groups of invertebrates. It does not usually occur in mammals, and when it does it leads to quick death.

Less extreme changes take place, too, as when a particular chromosome breaks and fails to reunite, or when several break and then reunite incorrectly. Under such conditions, the mechanism by which chromosomes are distributed among the daughter cells is not likely to work correctly. Sex cells may then be produced with a piece of chromosome (or a whole one) missing, or with an extra piece (or whole chromosome) present.

In 1959, such a situation was found to exist in the case of persons suffering from a long-known disease called Down’s syndrome.[2] Each person so afflicted has 47 chromosomes in place of the normal 46. It turned out that the 21st pair of chromosomes (using a convention whereby the chromosome pairs are numbered in order of decreasing size) consists of three individuals rather than two. The existence of this chromosome abnormality clearly demonstrated what had previously been strongly suspected—that Down’s syndrome originates as a mutation and is inborn (see the figure on the next page).

Karyotype of a female patient with Down’s syndrome (Mongolism). During meiosis both chromosomes No. 21 of the mother, instead of just one, went to the ovum. Fertilization added the father’s chromosome, which made three Nos. 21 instead of the normal pair. (Compare with the normal karyotype on page 4.)

Most mutations, however, are not associated with any noticeable change in chromosome structure. There are, instead, more subtle changes in the chemical structure of the genes that make up the chromosome. Then we have gene mutations.

The process by which a gene produces its own replica is complicated and, while it rarely goes wrong, it does misfire on occasion. Then, too, even when a gene molecule is replicated perfectly, it may undergo change afterward through the action upon it of some chemical or other environmental influence. In either case, a new variety of a particular gene is produced and, if present in a sex cell, it may be passed on to descendants through an indefinite number of generations.

Of course, chromosome or gene mutations may take place in ordinary cells rather than in sex cells. Such changes in ordinary cells are somatic mutations. When mutated body cells divide, new cells with changed characteristics are produced. These changes may be trivial, or they may be serious. It is often suggested, for instance, that cancer may result from a somatic mutation in which certain cells lose the capacity to regulate their growth properly. Since somatic mutations do not involve the sex cells, they are confined to the individual and are not passed on to the offspring.

Spontaneous Mutations

Mutations that take place in the ordinary course of nature, without man’s interference, are spontaneous mutations. Most of these arise out of the very nature of the complicated mechanism of gene replication. Copies of genes are formed out of a large number of small units that must be lined up in just the right pattern to form one particular gene and no other.

Ideally, matters are so arranged within the cell that the necessary changes giving rise to the desired pattern are just those that have a maximum probability. Other changes are less likely to happen but are not absolutely excluded. Sometimes through the accidental jostling of molecules a wrong turn may be taken, and the result is a spontaneous mutation.

We might consider a mutation to be either “good” or “bad” in the sense that any change that helps a creature live more easily and comfortably is good and that the reverse is bad.

It seems reasonable that random changes in the gene pattern are almost sure to be bad. Consider that any creature, including man, is the product of millions of years of evolution. In every generation those individuals with a gene pattern that fit them better for their environment won out over those with less effective patterns—won out in the race for food, for mates, and for safety. The “more fit” had more offspring and crowded out the “less fit”.

By now, then, the set of genes with which we are normally equipped is the end product of long ages of such natural selection. A random change cannot be expected to improve it any more than random changes would improve any very complex, intricate, and delicate structure.

Evolution of the horse (skull, hindfoot, and forefoot shown). Note the changes over a 60-million-year period from the Eocene era to the present.

Pleistocene and Recent
Pliocene
Miocene
Oligocene
Eocene

Yet over the eons, creatures have indeed changed, largely through the effects of mutation. If mutations are almost always for the worse, how can one explain that evolution seems to progress toward the better and that out of a primitive form as simple as an amoeba, for instance, there eventually emerged man?

In the first place, environment is not fixed. Climate changes, conditions change, the food supply may change, the nature of living enemies may change. A gene pattern that is very useful under one set of conditions may be less useful under another.

Suppose, for instance, that man had lived in tropical areas for thousands of years and had developed a heavily pigmented skin as a protection against sunburn. Any child who, through a mutation, found himself incapable of forming much pigment, would be at a severe disadvantage in the outdoor activities engaged in by his tribe. He would not do well and such a mutated gene would never establish itself for long.

If a number of these men migrated to northern Europe, however, children with dark skin would absorb insufficient sunlight during the long winter when the sun was low in the sky, and visible for brief periods only. Dark-skinned children would, under such conditions, tend to suffer from rickets.

Mutant children with pale skin would absorb more of what weak sunlight there was and would suffer less. There would be little danger of sunburn so there would be no penalty counteracting this new advantage of pale skins. It would be the dark-skinned people who would tend to die out. In the end, you would have dark skins in Africa and pale skins in Scandinavia, and both would be “fit”.

In the same way, any child born into a primitive hunting society who found himself with a mutated gene that brought about nearsightedness would be at a distinct disadvantage. In a modern technological society, however, nearsighted individuals, doing more poorly at outdoor games, are often driven into quieter activities that involve reading, thinking, and studying. This may lead to a career as a scientist, scholar, or professional man, categories that are valuable in such a society and are encouraged. Nearsightedness would therefore spread more generally through civilized societies than through primitive ones.

Then, too, a gene may be advantageous when it occurs in low numbers and disadvantageous when it occurs in high numbers. Suppose there were a gene among humans that so affected the personality as to make it difficult for a human being to endure crowded conditions. Such individuals would make good explorers, farmers, and herdsmen, but poor city dwellers. Even in our modern urbanized society, such a gene in moderate concentration would be good, since we still need our outdoorsmen. In high concentration, it would be bad, for then the existence of areas of high population density (on which our society now seems to depend) might become impossible.

In any species, then, each gene exists in a number of varieties upon which an absolute “good” or “bad” cannot be unequivocally stamped. These varieties make up the gene pool, and it is this gene pool that makes evolution possible.

A species with an invariable set of genes could not change to suit altered conditions. Even a slight shift in the nature of the environment might suffice to wipe it out.

The possession of a gene pool lends flexibility, however. As conditions change, one combination of varieties might gain over another and this, in turn, might produce changes in body characteristics that would then further alter the relative “goodness” or “badness” of certain gene patterns.

Thus, over the past million years, for example, the human brain has, through mutations and appropriate shifts in emphasis within the gene pool, increased notably in size.

Genetic Load

Some gene mutations produce characteristics so undesirable that it is difficult to imagine any reasonable change in environmental conditions that would make them beneficial. There are mutations that lead to the nondevelopment of hands and feet, to the production of blood that will not clot, to serious malformations of essential organs, and so on. Such mutations are unqualifiedly bad.

The badness may be so severe that a fertilized ovum may be incapable of development; or, if it develops, the fetus miscarries or the child is stillborn; or, if the child is born alive, it dies before it matures so that it can never have children of its own. Any mutation that brings about death before the gene producing it can be passed on to another generation is a lethal mutation.

A gene governing a lethal characteristic may be dominant. It will then kill even though the corresponding gene on the other chromosome of the pair is normal. Under such conditions, the lethal gene is removed in the same generation in which it is formed.

The lethal gene may, on the other hand, be recessive. Its effect is then not evident if the gene it is paired with is normal. The normal gene carries on for both.

When this is the case, the lethal gene will remain in existence and will, every once in a while, make itself evident. If two people, each serving as a carrier for such a gene, have children, a sperm cell carrying a lethal may fertilize an egg cell carrying the same type of lethal, with sad results.

Every species, including man, includes individuals who carry undesirable genes. These undesirable genes may be passed along for generations, even if dominant, before natural selection culls them out. The more seriously undesirable they are, the more quickly they are removed, but even outright lethal genes will be included among the chromosomes from generation to generation provided they are recessive. These deleterious genes make up the genetic load.

The only way to avoid a genetic load is to have no mutations and therefore no gene pool. The gene pool is necessary for the flexibility that will allow a species to survive and evolve over the eons and the genetic load is the price that must be paid for that. Generally, the capacity for a species to reproduce itself is sufficiently high to make up, quite easily, the numbers lost through the combination of deleterious genes.

The size of a genetic load depends on two factors: The rate at which a deleterious gene is produced through mutation, and the rate at which it is removed by natural selection. When the rate of removal equals the rate of production, a condition of genetic equilibrium is reached and the level of occurrence of that gene then remains stable over the generations.

Even though deleterious genes are removed relatively rapidly, if dominant, and lethal genes are removed in the same generation in which they are formed, a new crop of deleterious genes will appear by mutation with every succeeding generation. The equilibrium level for such dominant deleterious genes is relatively low, however.

Deleterious genes that are recessive are removed much more slowly. Those persons with two such genes, who alone show the bad effects, are like the visible portion of an iceberg and represent only a small part of the whole. The heterozygotes, or carriers, who possess a single gene of this sort, and who live out normal lives, keep that gene in being. If people in a particular population marry randomly and if one out of a million is born homozygous for a certain deleterious recessive gene (and dies of it), one out of five hundred is heterozygous for that same gene, shows no ill effects, and is capable of passing it on.

It may be that the heterozygote is not quite normal but does show some ill effects—not enough to incommode him seriously, perhaps, but enough to lower his chances slightly for mating and bearing children. In that case, the equilibrium level for that gene will be lower than it would otherwise be.

It may also be that the heterozygote experiences an actual advantage over the normal individual under some conditions. There is a recessive gene, for instance, that produces a serious disease called sickle-cell anemia. People possessing two such genes usually die young. A heterozygote possessing only one of these genes is not seriously affected and has red blood cells that are, apparently, less appetizing to malaria parasites. The heterozygote therefore experiences a positive advantage if he lives in a region where the incidence of certain kinds of malaria is high. The equilibrium level of the sickle-cell anemia gene can, in other words, be higher in malarial regions than elsewhere.

Here is one subject area in which additional research is urgently needed. It may be that the usefulness of a single deleterious gene is greater than we may suspect in many cases, and that there are greater advantages to heterozygousness than we know. This may be the basis of what is sometimes called “hybrid vigor”. In a world in which human beings are more mobile than they have ever been in history and in which intercultural marriages are increasingly common, information on this point is particularly important.

Mutation Rates

It is easier to observe the removal of genes through death or through failure to reproduce than to observe their production through mutation. It is particularly difficult to study their production in human beings, since men have comparatively long lifetimes and few children, and since their mating habits cannot well be controlled.

For this reason, geneticists have experimented with species much simpler than man—smaller organisms that are short-lived, produce many offspring, and that can be penned up and allowed to mate only under fixed conditions. Such creatures may have fewer chromosomes than man does and the sites of mutation are more easily pinned down.

An important assumption made in such experiments is that the machinery of inheritance and mutation is essentially the same in all creatures and that therefore knowledge gained from very simple species (even from bacteria) is applicable to man. There is overwhelming evidence to indicate that this is true in general, although there are specific instances where it is not completely true and scientists must tread softly while drawing conclusions.

The animals most commonly used in studies of genetics and mutations are certain species of fruit flies, called Drosophila. The American geneticist, Hermann J. Muller, devised techniques whereby he could study the occurrence of lethal mutations anywhere along one of the four pairs of chromosomes possessed by Drosophilia.

A lethal gene, he found, might well be produced somewhere along the length of a particular chromosome once out of every two hundred times that chromosome underwent replication. This means that out of every 200 sex cells produced by Drosophilia, one would contain a lethal gene somewhere along the length of that chromosome.

Geneticist Hermann J. Muller studying Drosophila in his laboratory. Dr. Muller won a Nobel Prize in 1946 for showing that radiation can cause mutations. (See page 34.)

That particular chromosome, however, contained at least 500 genes capable of undergoing a lethal mutation. If each of those genes is equally likely to undergo such a mutation, then the chance that any one particular gene is lethal is one out of 200 × 500, or 1 out of 100,000.

This is a typical mutation rate for a gene in higher organisms generally, as far as geneticists can tell (though the rates are lower among bacteria and viruses). Naturally, a chance for mutation takes place every time a new individual is born. Fruit flies have many more offspring per year than human beings, since their generations are shorter and they produce more young at a time. For that reason, though the mutation rate may be the same in fruit flies as in man, many more actual mutations are produced per unit time in fruit flies than in men.

This does not mean that the situation may be ignored in the case of man. Suppose the rate for production of a particular deleterious gene in man is 1 out of 100,000. It is estimated that a human being has at least 10,000 different genes, and therefore the chance that at least one of the genes in a sex cell is deleterious is 10,000 out of 100,000 or 1 out of 10.

Furthermore, it is estimated that the number of gene mutations that are weakly deleterious are four times as numerous as those that are strongly deleterious or lethal. The chances that at least one gene in a sex cell is at least weakly deleterious then would be 4 + 1 out of 10, or 1 out of 2.

Naturally, these deleterious genes are not necessarily spread out evenly among human beings with one to a sex cell. Some sex cells will be carrying more than one, thus increasing the number that may be expected to carry none at all. Even so, it is supposed that very nearly half the sex cells produced by humanity carry at least one deleterious gene.

Even though only half the sex cells are free of deleterious genes, it is still possible to produce a satisfactory new generation of men. Yet one can see that the genetic load is quite heavy and that anything that would tend to increase it would certainly be undesirable, and perhaps even dangerous.

We tend to increase the genetic load by reducing the rate at which deleterious genes are removed, that is, by taking care of the sick and retarded, and by trying to prevent discomfort and death at all levels.

There is, however, no humane alternative to this. What’s more, it is, by and large, only those with slightly deleterious genes who are preserved genetically. It is those persons with nearsightedness, with diabetes, and so on, who, with the aid of glasses, insulin, or other props, can go on to live normal lives and have children in the usual numbers. Those with strongly deleterious genes either die despite all that can be done for them even today or, at the least, do not have a chance to have many children.

The danger of an increase in the genetic load rests more heavily, then, at the other end—at measures that (usually inadvertently or unintentionally) increase the rate of production of mutant genes. It is to this matter we will now turn.

                                                                                                                                                                                                                                                                                                           

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