Heredity and Development: Second Edition (1972)

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HEREDITY AND DEVELOPMENT: SECOND EDITION 209 9 The Genetics of Man Humiliating as it may seem, our understanding of inheritance in man is founded heavily on what was discovered in other organisms such as peas, Drosophila, corn, mice, Neurospora, and more recently, microorganisms. Man is not a very good organism for genetic research. His generation time is much too long—most geneticists would be dead before an F3 appeared. He has so many chromosomes, 23 pairs, that it is extremely difficult to detect linkage groups. He would be most expensive to maintain as a laboratory ani- mal and some of his mores prevent sound experimentation. For example, abundant offspring, brother-sister matings to develop highly homozygous strains, backcrosses of F1 individuals to members of the parent generation, crosses based on the design of the experiment rather than emotion are not de rigueur. Matings occur in man for many reasons, all thought excellent at the time, but rarely, if ever, is one of the reasons the advancement of genetics. But thanks to more amenable organisms and the near-universality of genetic principles, a firm foundation for a genetics of man has been laid. Neverthe- less, many of the statements that will be made in this chapter are more in the nature of probable hypothesis than of fact. Many patterns of inheritance, orig- inally thought to be clear examples of autosomal recessives, autosomal domi- nants, sex-linked genes, and so on, have been shown by later data to be more complex. A human geneticist attempts to deduce genotypes from the observed phe- notypes of parents and offspring. He has developed a symbolism that allows one to easily recognize males, females, parents, offspring, and 

HEREDITY AND DEVELOPMENT: SECOND EDITION 210 individuals with and without the phenotype being studied. Thus males are represented by a and females by a O. Husband and wife are represented as —O and their children on lines below them. If an individual possesses the trait being studied he is shown as either ■ or ● depending on the sex. Figure 9–1 shows a hypothetical example of the inheritance of red hair (r), which seems to be an autosomal recessive to non-red hair (R). In the cross labelled 1, neither parent had red hair but two of the children did. We can assume, therefore, that each parent was Rr. The red-haired daughter (rr) mar- ried a man who did not have red hair. He could be either RR or Rr (cross 2). They had four children, none with red hair. This number of children is too small to establish the genotype of the father. If he were RR, none of his chil- dren could have red hair. If he were Rr, one would expect half of them to have red hair and half not. However, the first four children could have non- red hair and he still be Rr. The chance of his first child not having red hair would be one in two. For the first four children not to have red hair, the chance would be 1/2×1/2×1/2×1/2×=1/16. Thus it is probable that he was RR but there is one chance in sixteen that he was Rr. The red-haired son married a red-haired girl (cross 3) and all of the chil- dren had red hair, as would be expected from a cross of two homozygous recessives. Finally in our hypothetical cross 4, two of the first cousins marry and, since one of the children has red hair, the mother must have been heterozygous. 9–1 A hypothetical pedigree of the inheritance of red hair. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 211 Autosomal Recessives. A very large number of traits in man are believed to be due to autosomal recessive genes. The following list shows some of the cases that are fairly well established. albinism skin and eyes without dark pigment alkaptonuria homogentisic acid in urine (see p. 143) amaurotic family idiocy retarded development of body and brain; death in infancy (Tay-Sachs Disease) analbuminemia lack of serum albumen anophthalmos lack of eyes bird-headed dwarf abnormally shaped head congenital cataract opacity of lens color blindness lack of cones in eye congenital deafmutism deaf at birth; rarely learns to speak cretinism abnormal development due to defective thyroid Friedreich’s ataxia degeneration of parts of nervous system hermaphroditism ovary and testis in same individual hypotrichosis little or no hair lactase deficiency lactase enzyme absent in adults microcephaly brain greatly reduced in size muscular atrophy degeneration of muscles. Death in infancy muscular dystrophy degeneration of muscles in later life pernicious anemia abnormal blood cells; caused by lack of absorption of vitamin B12 in intestine phenylketonuria mental retardation due to lack of an enzyme pituitary dwarfism small size due to deficiency in growth hormone of the pituitary Even this short list reveals the broad spectrum of phenotypes caused by homozygosity for autosomal genes. Some genes, such as the one causing alkaptonuria, have been implicated in biochemical reactions. Others, such as the gene causing amaurotic family idiocy, seem to have less precise effects. Even in this case, however, a reasonable hypothesis is that all genes have their primary effect at the molecular level: research has revealed this level for some genes but not for others. The close relation of genes to metabolic pathways, first adequately demon- strated by Beadle and Tatum in Neurospora (page 144), has its counterpart in man. Figure 9–2 shows some of the reactions involving the amino acids phenylalanine and tyrosine and the abnormalities that arise if these reactions are blocked. Presumably all of the reactions shown are catalyzed by enzymes formed under the controlling action of genes. In some instances mutations have occurred altering these enzymes. When these genes are homozygous, specific abnormalities may result. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 212 9–2 Metabolism of phenylalanine. Some of the metabolic pathways for the metabolism of this amino acid are shown. Genetic defects are known that are the result of the inhibition of specific enzymes involved in the reactions. The abnormality may be relatively mild, as in the case of albinism. All of the other abnormalities shown in Figure 9–2 are severe and, if untreated, lead to a wasted human life. Autosomal Dominants. Numerous dominant autosomal genes are also known for man. As you might suspect, they are much easier to study since both the homozygotes and the heterozygotes exhibit the phenotype. Here are some of them. achondroplasia skull and other skeletal abnormalities aniridia absence of iris baldness possibly a recessive in females brachydactyly short fingers canine teeth upper canines absent hereditary cataract opacity of lens cleft palate separation of palate and often of upper lip corneal dystrophy clouding of the cornea congenital deafness can be caused by many different genes 

HEREDITY AND DEVELOPMENT: SECOND EDITION 213 diabetes insipidus excessive urine due to lack of a pituitary hormone distichiasis two rows of eyebrows ear malformation external ear curled heart block abnormal heart contractions Huntington’s chorea degeneration of the nervous system porcupine man scaly skin (see page 9) mid-digital hair hair on middle digit myopia nearsightedness night blindness poor vision in the dark PTC taster ability to taste phenylthiocarbamide piebald lack of pigment in patches of hair and skin polydactyly extra fingers and toes Raynaud’s disease cold fingers and toes due to poor circulation retinoblastoma tumors develop in retina split hand defect of hands syndactyly fusion of fingers or of toes premature white hair white hair developed during youth Again one can observe a great variety of defects. One of the phenotypes, cataract, appears in the list of dominant autosomal mutations and in the auto- somal recessive list as well. Cataract can be produced in many ways, proba- bly by numerous different genes and by non-genetic factors as well (such as X-rays, trauma, old age). This is true for many of the conditions shown in these lists. One must not assume that the condition is caused only by muta- tions at a single locus. Sex-Linked Inheritance. In man, as in Drosophila, the female is XX and the male XY. Numerous genes are known for the X chromosome but, so far, there is no well established case of a Y chromosome gene. The Y is, however, very important in sex determination. For many years it was believed that genes for the porcupine man, described by Darwin (page 9), as well as those for syndactyly (webbed toes), were carried by the Y. Both are now believed to be autosomal. The pattern of transmission of the X and Y is shown in Figure 4–4 (bottom). The males inherit their X chromosomes solely from their mothers and transmit them solely to their daughters. Females receive one X from their father and one from their mother. A recessive gene on the X will always be expressed in the male, which has no locus on the Y to mask its effect. Females are rarely homozygous for recessive mutants carried on the X. This is a consequence of the mutants being so rare that it is most unusual for them to come together in the same individual. Heterozygous females are known as ‘carriers.’ 

HEREDITY AND DEVELOPMENT: SECOND EDITION 214 They transmit the mutant allele to half of their sons and the normal allele to the other half. In the rare event of a cross between a male with an X chromo- some mutant and a carrier female, half of the daughters will be homozygous for the mutant allele. Darwin and other pre-Mendelians were aware that some traits, such as color blindness, seemed to be restricted largely to males and to appear in alternate generations: in an individual, his grandsons, and great-great grand- sons but not in his sons or great grandsons (page 12). Much later it was real- ized that these were cases of X chromosome inheritance. It is highly probable that the following genes are on the X. In many cases similar phenotypes seem to be caused by different genes and some of the phe- notypes closely resemble conditions that do not have a hereditary basis. ocular albinism iris nearly colorless albinism with deafness little or no pigment; little or no hearing congenital cataract opacity of the lens color blindness nearly complete absence of cones in eye congenital deafness one of the many genes causing deafness diabetes insipidus excess urine related to neurohypophyseal abnormality ectodermal dysplasia absence of teeth, hair, and sweat glands G6PD absence or deficiency of the enzyme glu- cose-6-phosphate dehydrogenase classical hemophilia defective coagulation of blood hypophosphatemia low blood phosphorus resulting in rickets not cured by vitamin D ichthyosis scaly skin megalocornea enlarged cornea mental deficiency many genes, including those on the X, can be a cause microphthalmia eyes reduced or absent muscular dystrophy degeneration of muscles night blindness poor vision at night retinoschisis degeneration of the retina Most of the X chromosome mutants behave as recessives. They will, natu- rally, be expressed in males whether they are dominant or recessive. One would have to study a homozygous female to decide whether the mutant is dominant or recessive and, for many of the mutants, no homozygous female has ever been discovered. This is due mainly to the rarity of the mutant genes: the chance of two appearing in the same individual is so small that it is almost never observed. Moreover some of these 

HEREDITY AND DEVELOPMENT: SECOND EDITION 215 mutants cause early death, or sterility, in the males. These individuals do not breed and there is no possibility of a homozygous daughter ever being formed (apart from a new mutation). Genetics of Erythrocytes. More is known about the genetics of erythro- cytes than for any other human cell. The mutants fall into two major classes: those affecting hemoglobin and those affecting the proteins and other molecules on the surface of the erythrocyte. A hemoglobin molecule is composed of four subunits: two kinds of polypeptides, each represented twice (page 178). There are, however, five main types of polypeptides, each symbolized by a Greek letter. The most common type of hemoglobin in adults is hemoglobin A. It is composed of two alpha (α) and two beta (β) polypeptides. The other kinds of polypeptides are known as gamma (γ), delta (δ), and epsilon (ε). A human being, in his growth from embryo to adult, produces a sequence of different kinds of hemoglobin. The earliest to be formed is embryonic hemoglobin: composed of two α and two ε polypeptides. Later, fetal hemoglobin is formed: composed of two α and two γ chains. Finally there is the adult type with two α and two β chains. The rare adult hemoglobin, hemoglobin A2, is composed of two α and two δ chains. These five basic polypeptides are under the control of five different cistrons, or genes. The activation or repression of these cistrons at different periods in human development is a fascinating phenomenon. But this is only the beginning of the complexity. Earlier we saw that a change in the β cistron resulted in the substitution of one amino acid for another and the conse- quence was sickle cell hemoglobin (page 182). The number of similar genetic changes now known in these different cistrons is in the hundreds. The surface of an erythrocyte has numerous gene-controlled molecules that act as antigens, that is, cause the production of antibodies under suitable conditions. The first of these to be discovered was the ABO blood group (page 119). There are two main antigens, A and B, each controlled by a gene. The A, or IA, gene produces antigen A and the B, or IB, gene produces anti- gen B. An IAIB individual produces both antigens. There is another allele, O or IO, at this locus; it produces no antigen. Subsequently it has been discov- ered that there is more complexity. For example, the A gene is now known to have three variants, A1, A2, and A3. The MN blood groups are also due to specific antigens on the surface of the erythrocyte, which are controlled by the LM and LN alleles. An LMLN individual has both the M and N antigens on his erythrocytes. No allele is yet known that prevents the formation of an antigen at this 

HEREDITY AND DEVELOPMENT: SECOND EDITION 216 locus, corresponding to the IO allele in the ABO blood groups. However, there are other alleles now known for the L locus. Another series of alleles affecting a protein on the surface of human ery- throcytes and having important medical consequences was discovered in a most interesting manner. Blood from a Rhesus monkey was injected into a rabbit and antibodies were produced in the rabbit to the antigens of the mon- key erythrocytes. When serum from the rabbit was later mixed with blood of the Rhesus monkey, the monkey erythrocytes were agglutinated. This was to be expected but the results of the next experiment were not. Serum from the rabbit, with the antibodies to the Rhesus erythrocytes, was mixed with human blood. The human erythrocytes were also agglutinated, suggesting that at least one of their antigens was the same as one of the antigens of the monkey. Subsequently it was discovered that about 85 per cent of the human beings tested have the Rhesus antigen; 15 per cent do not. Genetic analysis revealed that presence of the antigen (R) is dominant to its absence (r). It is now known that several antigens and alleles are involved. The genetics is complex but the following simplified account of the effects of this gene is correct, though incomplete. The R and r alleles are autosomal and are inherited in a simple Mendelian manner. Any individual will have two of the various alleles at this locus. Some crosses can result in a serious disease of the newborn: erythroblastosis fetalis. This involves the destruction of the baby’s erythrocytes and, if untreated, death often occurs shortly after birth. Erythroblastosis fetalis occurs when the father is Rh-positive, that is, RR or Rr and the mother is Rh-negative, that is rr. If the first child conceived is Rr, its corpuscles will have the Rhesus antigen. If some of the baby’s ery- throcytes enter the mother’s blood vessels, she will produce antibodies to the antigen. Normally there is no way that this could happen: the circulatory sys- tems of the mother and the baby in the uterus are separate. However, a trauma could occur, especially at the time of birth, and some of the baby’s erythro- cytes enter the maternal bloodstream. The first child is rarely affected. If a second Rh-positive child is con- ceived, the consequences may be grave. The mother’s blood already contains antibodies to the antigen on the baby’s erythrocytes. These antibodies may pass across the placental membranes and agglutinate the erythrocytes of this second baby. The agglutinated erythrocytes are destroyed, a severe anemia results, and the baby’s blood-forming system is stimulated into abnormal activity. The frequency of these events—an Rh-negative mother first conceiving an Rh-positive child, then producing antibodies against the Rhesus anti- 

HEREDITY AND DEVELOPMENT: SECOND EDITION 217 gen, and a second Rh-positive child being conceived and erythroblastosis fetalis occurring—is less than half a per cent of all pregnancies. In this type of cross, however, about 90 per cent of all Rh-positive babies are affected after the mother has produced the antibodies. Many babies can be saved if their blood is replaced soon after birth. If there has not already been brain or other damage, the baby may develop nor- mally. Once the baby is no longer exposed to the mother’s antibodies, further damage will not occur. An Rh-negative woman will also produce antibodies if she is given a trans- fusion of Rh-positive blood. If this occurs before she conceives her first Rh- positive baby, this baby could develop erythroblastosis fetalis. Sex Determination. The remarkable analysis of sex determination in Drosophila was made possible by the spontaneous occurrence of individuals with different numbers of chromosomes (page 112). Drosophila males are XY and females XX. The question, ‘Is maleness a consequence of an individ- ual having a Y, or only one X, or both an X and a Y?’ was answered when a fly was discovered with a single X and no Y: it was a male. Sex determina- tion in Drosophila was eventually interpreted as a consequence of the balance between the number of X chromosomes and the autosomes (Fig. 5–8). The Y seemed to be of slight importance. Many biologists at first assumed that the Drosophila pattern applied also to man. They could do little more, since it was nearly impossible to study the chromosomes of man. In fact, it was not until 1956 that the number was accu- rately determined for man: 23 pairs. In recent years there has been enormous progress in the study of human chromosomes. Such a study requires large numbers of human cells in the process of mitosis. It has been found that, if a small amount of blood is placed in the proper culture medium, the leukocytes will begin to divide. The cells are then fixed, stained with a nuclear dye, and spread on a microscope slide. It is then possible to study all of the chromosomes in the diploid set. The chromosomes vary in length and in their structure. It is not possible to recog- nize all of them individually but they can be placed in seven easily recog- nized groups (Fig. 9–3), which are based on the length of the chromosomes and on the position of the centromere. A discovery that was made in the cat was later extended to man. If the epi- dermal cells scraped from the inside of the cheek are stained, and studied, it is found that the resting nucleus has a small, deeply staining area, which was given the name Barr body after its discoverer Murray Barr. The Barr body is a condensed X chromosome. A normal female 

HEREDITY AND DEVELOPMENT: SECOND EDITION 218 9–3 Human chromosomes. The metaphase chromosomes of a human female are grouped on the basis of size and position of the centromere. A male would have only a single X, that is there would be one less chromosome in Group C. His Y would resemble one of the G Group chromosomes. 

HEREDITY AND DEVELOPMENT: SECOND EDITION 219 has only one Barr body. This means that her other X chromosome is not con- densed. There is no Barr body in the nucleus of normal males, which means that the single X is not condensed. When the various techniques for the study of human chromosomes were perfected, they were used for some difficult medical problems, ones that had baffled diagnosticians. For example, there is a condition known as Turner’s syndrome. The afflicted individuals are female on the basis of most of their characteristics. They have the external genitalia of females, but are short, have broad and flat chests, wide necks, and little or no enlargement of the breasts. When it has been possible to check, it is found that the ovaries are absent or vestigial. Menstruation never occurs. A related condition is Klinefelter’s syndrome. These individuals have the external genitalia of males but the testes do not mature, sterility is usual, and there may be a slight enlargement of the breasts. The nuclei of individuals with Turner’s syndrome were studied and were found to have no Barr body. Furthermore, these individuals have only 45 chromosomes instead of the normal 46. Upon closer analysis it was found that the missing chromosome was of group C—the group that includes the X chromosomes. The data strongly suggest that individuals with Turner’s syn- drome have only a single X chromosome. Such a condition is called XO, the O indicating the absense of the second sex chromosome. Individuals with Klinefelter’s syndrome, although males in most respects, were found to have one Barr body and 47 chromosomes. In this case there are two Xs and one Y. Thus, these individuals are XXY. One should compare these conditions with Drosophila (Fig. 5–8). In Drosophila an XO individual is male; in man, female. An XXY Drosophila is female; in man, male. In Drosophila the number of X chromosomes in rela- tion to the autosomes is the primary determinant of sex. In man, maleness is due to the presence of a Y, femaleness to its absence. Other variations in the number of sex chromosomes in human beings have been discovered. For example, females of these types have been detected: XXX, XXXX, and XXXXX. Such individuals have 2, 3, and 4 Barr bodies respectively, the rule being, for both females and males, one less Barr body than the number of X chromosomes. All of these females suffer some degree of mental retardation and often other defects. Some are fertile. In meiosis ova are produced with abnormal numbers of X chromosomes and consequently these females may be the mothers of a variety of abnormal children. Males have their troubles, too: XYY, XXXY, XXYY, XXXXY, and 

HEREDITY AND DEVELOPMENT: SECOND EDITION 220 XXXYY types have been found. All suffer mental retardation as well as mor- phological and physiological defects—usually of the Klinefelter’s syndrome type. Some are fertile. The XYY male has stimulated considerable interest and concern. Some are apparently normal in behavior and appearance. Others are extremely tall. There is evidence to suggest that some XYY individuals may be abnormally aggressive and institutions for the criminally insane have a higher frequency XYY of males than is present in the general population. There are not, as yet, sufficient data to give accurate figures for the per- centages of individuals with abnormal numbers of chromosomes. These are some estimates: XXY 1 per 500 male births (0.2%) XYY 1 per 2000 male births (0.05%) XO 1 per 3500 female births (0.03%) In all of the cases described so far the autosomes have been normal, that is, two of each type have been present in the diploid nucleus. They too can vary in number. Abnormal Numbers of Autosomes. Physicians have long recognized a pattern of defectiveness in children known as Down’s syndrome (or Mon- goloid idiocy). Growth and mental development are greatly retarded and death usually occurs in childhood. Cytological analysis has shown that these children have an extra chromosome in the G group (Fig. 9–3). The G group in a normal individual contains two pairs of small autosomes (the Y is in this group also), which are given the numbers 21 and 22. It is not possible to dis- tinguish chromosome 21 from 22. In Down’s syndrome there are five G auto- somes, and by convention, it is assumed that the extra one is a chromosome 21. Thus there are two chromosomes 22 and three chromosomes 21. When one of the chromosomes is represented three times, rather than the normal two, the condition is referred to as trisomy. Down’s syndrome, therefore, is associated with trisomy 21. The frequency of Down’s syndrome is about one per 500 live births (0.2%). Mothers over 40 are far more likely to have children with Down’s syndrome than mothers in their 20’s. Trisomy is known for other autosomes as well: chromosome 16, chromo- some 18, and one of the chromosomes of the D group. These variations in chromosome number, of both sex chromosomes and autosomes, are assumed to be due to errors in meiosis. Such errors are not peculiar to man: they were discovered much earlier in Drosophila 

HEREDITY AND DEVELOPMENT: SECOND EDITION 221 and are known for all species that have been carefully studied. Human geneti- cists and physicians are beginning to believe that babies with abnormal chro- mosome numbers may be conceived with a fairly high frequency. About 10 per cent of all conceptions result in spontaneous abortions and many of the aborted babies have abnormal numbers of chromosomes. Whereas the fre- quency of Down’s syndrome in newborn babies is about one in 500, the fre- quency in spontaneous abortions is about one in 40. Turner’s syndrome is about 200 times more frequent in spontaneous abortions than in live births. Thus, spontaneous abortion appears to be a powerful mechanism for pre- venting the birth of individuals with defective complements of chromo- somes. At the present time about one-quarter of spontaneous abortions can be correlated with gross chromosomal defects. This is a new field of research and, as the methods of study improve, it is expected that the proportion will increase. It is also probable that many spontaneous abortions are of embryos that have specific gene defects (as distinct from the gross chromosomal defects). The Genetic Basis of Intelligence. Geneticists have usually been success- ful in discovering the pattern of inheritance for those phenotypes they can easily identify. Not surprisingly, their success has been limited when the characteristics being studied are vague. Intelligence may be taken as an example of a phenomenon that is difficult to study. If you will consult a dictionary, you will find that the term is vague. A person may be described as ‘highly intelligent’ if he is unusually gifted in one field, such as mathematics, even though he is hopeless in others, such as writing. Another ‘highly intelligent’ person may be a gifted writer who is incapable of all but the simplest mathematics. Numerous sorts of IQ tests have been devised to measure intelligence but there are endless debates about their validity. Tests that restrict themselves to specific behaviors: abilities to recognize geometrical patterns and relation- ships, musical ability, manual dexterity, and so on, may have a greater valid- ity. The fact remains, however that success in measuring intelligence will be limited until the phenomenon can be better defined. In spite of these reservations, it is abundantly clear that differences in intel- ligence exist and that they may have some basis in heredity. There is also a general relation between what an individual scores on IQ tests and intellec- tual abilities as measured in other ways. Individuals with an IQ in the range 50–70 are classed as ‘feebleminded.’ Very few of these individuals can lead a fully independent life in a complex society; they must be helped and super- vised. With rare exceptions, no environment, 

HEREDITY AND DEVELOPMENT: SECOND EDITION 222 school, or medical treatment can bring about a behavior pattern of the sort associated with high IQ. The greatest problem for the geneticist concerned with the inheritance of intelligence is that what is measured is a consequence not only of what is inherited but also of the cultural milieu in which the person has lived. Suc- cess on an intelligence test is greatly influenced by innate ability but to this we must add the influences of the home environment, schools, mass media, books, friends, opportunities, community, and the historic period in which a person lives. Some geneticists have made a guess that heredity contributes about 80 per cent and the environment 20 per cent to one’s performance on an intelligence test. Considering the difficulties involved, you may wonder why attempts are made to measure intelligence and aptitudes. Some of the good reasons are based on a desire to provide opportunities more suitable to the individual’s abilities. A young person, upon finishing school, must make the most impor- tant decisions of his life—among them the choice of a career. These choices are made, more often than not, on the basis of very incomplete information about the variety of available careers and about one’s own abilities. An indi- vidual may never have the opportunity to discover for himself what he can do best and then to live a life that will allow this to come about. It is a reasonable hypothesis that, to the extent that individuals have lives matched to their abilities, the gains to the individuals and to the society will be increased. If this is to come about, one of the things necessary will be improved methods for measuring individual differences and, on the basis of this information, improved capabilities to predict future behavior. Of course, this could be done without having exact information on the relative influ- ences of heredity and environment on what is being measured. In the present state of our knowledge, many individuals believe that the dangers are greater than the benefits of any attempt to guide one’s future on the basis of tests—no matter how carefully constructed. Such information might be used to make opportunities available; it might also be used to deny opportunities. An individual may have superior abilities in some areas and inferior abilities in others. If he were unfortunate enough to be tested only in the areas of his lesser abilities, and his future plans made on the basis of these tests, the results might be disastrous to the individual and harmful to society. Another situation in which notions about intelligence have had harmful consequences is where it is assumed that groups differ in their intelligence. It is often assumed that women are less intelligent than men and that blacks are less intelligent than whites, and so on. At times these beliefs are held even if the available evidence seems to suggest other- 

HEREDITY AND DEVELOPMENT: SECOND EDITION 223 wise. During the school years, girls generally do somewhat better than boys on intelligence tests. In this and similar cases, however, there is a very broad overlap in abilities and the differences within each group are far greater than the means between the groups. And there is abundant evidence to show that, when any group is denied opportunity, that group makes a lesser contribution to society. In spite of the enormous amount of time and effort that has gone into attempts to measure intelligence, it is the overwhelming opinion of geneti- cists, psychologists, and sociologists that no innate differences in ability have been demonstrated for various races and ethnic groups. As of today, one can- not say that the intelligence of men or women or of blacks and whites is dif- ferent; neither can one say they are the same. Let us suppose that it does become possible to demonstrate true innate dif- ferences. What should be done with such information? As an example, let us suppose that the intelligence of females averages slightly higher than that of males. Remember that, on the average, the muscular development of males is superior to that of females. A program that might take advantage of these differences would be to restrict those careers that demand a higher intelli- gence to women and those that require a higher proportion of brawn to men. An alternative solution might be to find the bright males (black, white etc.) and bright females (black, white etc.) for the more intellectually demanding positions and leave the more muscular jobs for those best able to cope with them. Eugenics. During the nineteenth century tremendous advances were made in selecting superior strains of domestic animals and plants. Such selection had been productive for centuries and the then current examples were impres- sive to individuals such as Francis Galton (1822–1911) in England. He pro- posed a science of eugenics, which was to concern itself with improving the hereditary endowment of the human race. If one could select a superior horse or cabbage, why not a superior man? Geneticists have never doubted that this is theoretically possible. The tech- niques are simple and easily applied—again in theory. Let us assume, for example, that one wished to select for large size in the human population. One could proceed in exactly the same way as one would with domestic ani- mals or plants. Large individuals would be crossed with each other. Small individuals would be prevented from crossing. If this procedure were repeated, generation after generation, it is safe to predict that the size of the individuals in the human population would gradually increase. This same procedure could be followed for any phenotype that could be recognized and had an inherited basis. Imagine the difficulties in conducting such an experiment: Who would 

HEREDITY AND DEVELOPMENT: SECOND EDITION 224 decide what is ‘good’? That is, what phenotypes are judged desirable and, hence, are to be increased in frequency through selection? Most human beings would regard such a program as a repugnant intrusion on the way they intend to lead their lives. There is little likelihood, therefore, that in the near future man will use the techniques of animal husbandry to improve his breed. But if man is unwilling to select for what is ‘good,’ might he be willing to prevent what is ‘bad’? There are some inherited characteristics of man that most individuals would agree are undesirable: congenital deafness, blind- ness, gross deformities of the body, idiocy, and so on. What should be done about these cases? For years it was assumed that very little could be done since many of these abnormalities are caused by recessive genes and one could never identify the heterozygotes unless they produced a defective child. Geneticists are rapidly increasing their skill in detecting harmful reces- sive genes in heterozygotes. Furthermore, it is becoming more and more pos- sible to detect abnormal babies before they are born. For example, the tech- niques are fairly well developed for examining cells derived from the unborn and determining if there are any chromosomal abnormalities. What would you propose to do with this information? The answer must be a human answer—but a human answer based on scientific information. Questions 1. In man rare sex-linked mutants tend to be twice as frequent in females as in males. Can you suggest an explanatory hypothesis? 2. Individuals with Klinefelter’s syndrome are XXY males. A gene for color blindness is carried on the X. There are cases recorded where a father with normal vision and a mother heterozygous for color blindness produced a color-blind son with Klinefelter’s syndrome. What hypothe- ses can be suggested to explain this event? 3. A woman heterozygous for sex-linked hemophilia married a man who did not have hemophilia. They had three sons: one normal and two with hemophilia. They also had two daughters. One was normal. The other had hemophilia and she grew slowly and never reached sexual maturity. What explanatory hypotheses can you suggest? How might they be tested? 4. One of the original hypotheses to explain the inheritance of the ABO blood groups was based on the interaction of two loci, A and B. An A type individual could be AA bb or Aa bb. A B type individual could be aa BB or aa Bb. AB individuals could be AA BB, Aa BB, AA Bb, or Aa Bb. O type individuals could only be aa bb. What types of observa- tions could you make that would prove or disprove this hypothesis? 

HEREDITY AND DEVELOPMENT: SECOND EDITION 225 5. Suggest an explanatory hypothesis for this pedigree, the defect being deafmutism. (If you find the problem insoluble, refer to the Annals of Human Genetics 20:177–231). 6. Assume that it is possible to measure human intelligence accurately and that the mean intelligence of Group A is 15 per cent less than the mean of Group B. How would you suggest that this information be used? Suggested Readings Chapter 8 of the Readings reproduces an article by Joshua Lederberg in which he explores some of the possibilities of using genetics for human wel- fare. You will also find there additional references on human genetics and genetic engineering. CARTER, C.O. 1962. Human Heredity. Baltimore: Penguin Books. CLARKE, C.A. 1964. Genetics for the Clinician. Philadelphia: F.A. Davis. EMERY, ALAN E.H. 1968. Heredity, Disease, and Man. Berkeley: University of Califor- nia Press. KNUDSON, ALFRED G. JR. 1965. Genetics and Disease. New York: McGraw-Hill (Blakiston Division). LERNER, I.MICHAEL. 1968. Heredity, Evolution and Society. San Francisco: W.H. Freeman. MCKUSICK, VICTOR A. 1969. Human Genetics. Second Edition. Englewood Cliffs, N. J.: Prentice-Hall. OSBORN, FREDERICK. 1968. The Future of Human Heredity. An Introduction to Eugen- ics in Modern Society. New York: Weybright and Talley. PENROSE, LIONEL S. 1963. Outline of Human Genetics. London: Heinemann. REED, SHELDON C. 1963. Counseling in Medical Genetics. Philadelphia: Saunders. STERN, CURT. 1960. Principles of Human Genetics. Second Edition. San Francisco: W. H. Freeman. SUTTON, H.ELDON. 1965. An Introduction to Human Genetics. New York: Holt, Rine- hart and Winston. VOLPE, E.PETER. 1971. Human Heredity and Birth Defects. New York: Pegasus. 

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