Book - Sex and internal secretions (1961) 1

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reciprocal cross the value was 31. Aside from some indication of preferential X-YY segregation in the triploid staminate parent when mated to the 2N female, the data fit expectations for the segregations of the Y chromosomes rather well. Staminate flowers were unaffected by such environmental variables as temperature and day length, whereas the monoecious and some pistillate types tended to increase in maleness at the high temperature of 80°F. and short day length (Janick, 1955 L

D. ASPARAGUS

Asparagus officinalis plants are ordinarily staminate or pistillate with occasional rudimentary organs of the opposite sex appearing in both the staminate and pistillate flowers. The staminate and pistillate plants ordinarily represent approximately equal numbers. The rudimentary organs of the male sex sometimes develop and form seed. Rick and Hanna (1943) have showed that when such seeds were planted, 155 males to 43 females were produced. The data suggested that maleness depends on a dominant gene with the homozygous and heterozygous types indistinguishable. This conclusion was supported by Sneep (1953). The data further showed that the proportion of staminate plants producing seeds was apparently influenced by both heredity and environment, in that seed production in these staminate plants was enhanced in some inbred lines but at the same time showed rather wide variability from plant to plant.

E. HUMULUS

Humulus sex chromosomes have been identified by Jacobsen (1957) in two species, H. lupidus and H. japonicus. H. lupulus has a complement of 20 chromosomes in mitosis. The X chromosome is identifiable and separable from the Y chromosome in both mitosis and meiosis. The X chromosome is longer than the Y but is of medium size compared with the autosomes. H. japonicus has 17 chromosomes in the male and 16 chromosomes in the female at mitosis. There are two Y chromosomes Yi and Y2 and an X in the male in both mitotic and meiotic divisions. The female has two X chromosomes. In both species the sex chromosomes in prophase and prometaphase


are differentiated to show the position and extent of the homologous and differential segments. The Y chromosomes are highly heterochromatic. Based on Ono's 1940 work on triploids derived from crosses of diploids and colchicine induced tetraploids in H. japoni'cMs, Westergaard (1958j concludes that the preliminary evidence suggests that sex determination in H. japonicus follows the arrangement of Drosophila in that the X chromosomes are female determining and the autosomes carry the male inheritance. Sex differentiation in other sex dimorphic higher plants follows patterns like those represented by one or another of the plant species discussed above.

VII. Mating Types

Species without morphologic sex differences, which occur as unicellular and as haploid forms, often show differences in their behavioral relations to each other. The types may be alternate. Blakeslee (1904) first called attention to these reactions in heterothallic fungi in which the opposite mating types were so indistinguishable morphologically that opposite types were designated as + and — . Preliminary criteria, to be met in assigning the + and — types, were: (1) the individuals studied should be shown to be in fact sexually dimorphic and not merely hermaphrodites or sex intergrades; (2) tests should include a large number of races in order to show that the differences are truly related to behavioral differences in reproduction and are not secondary characters peculiar to a race; and (3) the strengths of the reactions should be graded in order to correlate them with any sex differences that might be observed (Satina and Blakeslee, 1925). From more than a quarter century of study, Blakeslee and his group working on some 2000 races included in 30 species of 15 genera came to the belief that over this large group of heterothallic mucors strict sexual dimorphism was the rule. Similar systems have extended the concept far beyond this group of fungi.

In fungi Raper (1960) emphasizes the role of gene differences in the control of sex. Genetic mutations have furnished evidence to show that future sexual capacity follows segregation of genetic factors at meiosis. These factors impose changes in differentia


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tion Avhich affect type compatibilities. The work of Esser and Straub (1958) on 21 irradiation mutant strains is cited. Of the 21 strains, 18 were sterile when grown alone. These mutants could be divided into qualitatively different groups in terms of the stages at which sexual isolation was achieved. Three strains developed only vegetative mycelia; 3, ascognia but no protoperithecia; 6, few to many protoperithecia but no perithecia; 6, sterile perithecia; and 3, fertile perithecia with nondischarging asci. Four mutant types were observed more than once. The results suggested single factor changes each affecting a single essential factor product significant to further sexual development. Restoration occurred by pairing with wild type alleles in heterokaryons derived from hyphal fusions between the two defective strains. Fertility is sometimes noted in pairing of self-fertile strains apparently mediated through the cytoplasm. Diffusible agents, hormones and surface agents may all play a part in fertility. In some features the results in fungi suggest the wide range in fertility phenotypes of gene origin so frecjuently isolated in Drosophila experiments. Together with much other material they furnish further evidence for a multigenic basis for sex-controlled characteristics.

Physiologic differentiation of individuals of a species into diverse mating types was notably extended by Sonneborn's (1937) discovery that in Paramecium aurelia two classes of individuals exist. Members of different classes unite for conjugation; members of the same classes do not. Information on these types has accumulated rapidly during the last few years (Jennings, 1939; Sonneborn, 1947, 1949, 1957). As a rule P. aurelia has two and only two interbreeding mating types in a variety. In general mating types from different varieties do not react to each other. Death or low viability follows in a few cleavages for some of the rarely interbreeding mating types. In P. bursa n'a Jennings and his group discovered six varieties each of them comprising a set of mating types. A system of at least four mating types is known for varieties I, III and VI; eight are found in variety II; IV has two and V is represented by but one. Simihir


mating type systems are found in other genera, i.e., Euplotes (Kimball, 1939) .

Mating systems have been demonstrated for some species of bacteria. A strain in order to show conjugation followed by transfer of separate genetic entities requires at least two different types of individuals. Ravin (1960) has recently reviewed this subject for bacteria. The F+ and the F" cell types when intermixed will conjugate and show detectable rates of interchange for genetic materials in tests of subsequent progenies. The F~ and F~ when mixed do not show recombination. The F+ and F + when mixed may show low rates of interchange which have been suggested as due to the presence of physiologic F~ variants sometimes found in genetically F+ isolations. The postulated F+ and F~ factors suggest relations similar to those of some of the genes in higher animals or plants. The F+ factor has a property that may set it apart from these genes. In the presence of F + cells, F~ cells adopt the F+ mating type. The reaction is suggestive of that taking place within the male sex in Bonellia as observed by Baltzer.

In the absence of visible morphologic differences which enforce exchanges and recombinations of genetic materials, the physiologic or submicromorphologic conditions found in either haploid or diploid unicellular organisms accomplish the same objectives by establishing mating types. AVhether these differences are really comparable with sex and sex determination is still an open question. There may be some ground for thinking that there are precursors which assist in the develoiiment of such systems.

Vin. Environmental Modifications of Sex

A. AMPHIBIA

Amphibian sex chromosomes, Ambystoma, Siredon, Pleurodeles, Triton, Triturus,Rana, and Xenopus as found in nature are ZZ for the males and WZ for the females. Sex reversal of the normal sex phenotypes has been particularly successful in this class of animals and under a variety of conditions (for further information see Chapter l)y Burns). The haploid chromosonu" nuiuhers foi' the males of these various


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genera are 12, 14, and 18, with no sex chromosomal differentiation. Types having haploid, diploid, triploid, tetraploid, pentaploid, hexaploid, heptaploid, and various aneuploid chromosome numbers have been observed under experimental conditions (Humphrey and Fankhauser, 1956; Fankhauser and Humphrey, 1959). Humphrey ( 1945) induced sex reversal by grafting testicular jirimordia on to embryonic genetic female gonads. He showed that males having the genotype WW were viable, as were females having the same constitution. The somatic cells could be modified to either sex phenotype whereas the germ cells retained their genotypic constitutions as observed later under natural and hormone control as in fish.

The improvement of estrogenic hormones facilitated further studies on this problem. Under natural conditions the sex genes are effective sex determiners as normally they guide the developing organism into one or the other of the definite sex phenotypes. When the embryonic forms of newts or toads were exposed to relatively high concentrations of sex hormone-like substances of the other sex, growth and development were guided toward that sex rather than toward that expected from the chromosomal constitution of the somatic cells (Gallien, 1954, 1955, 1956; Chang and Witschi, 1955, 1956). When the male genotype was converted to the female phenotype through this treatment and was later bred to a normal male, the progenies as expected on the basis of the chromosomal constitution were all normal males. When the female WZ was sex-reversed to the male phenotype and then bred to a normal female the progenies were of three types, from a chromosome standpoint ZZ, WZ, and WW, the ratio being 1 male to 3 females. The derived WW type was then of female constitution showing that this chromosome carries genes which normally guide the organism to the female phenotyjie. WW individuals had an adequate gene content for normal development of either sex in this class of organisms. The observations on sex reversal in amphibia were reminiscent of the experimental analyses of sex differentiation by Baltzer on Bonellia (1935) in which he quoted Harrison (1933) as saying, "A score of different


factors may be involved and their effects most intricably interwoven. In order to resolve this tangle we have to inquire under as great a variety of experimental conditions as is possible to impose. Success will be assured by the implicity, precision, and completeness of our descriptions rather than by a specious facility in ascribing causes to particular events." Bonellia showed the way for synthetic hormone in that contact of the embryonic form with the female was sufficient to direct development into the male type.


Sex determination in fish as in Amphibia seems to be of such a nature that the results of hormone treatments are revealed more clearly than in Drosophila or mammals. Winge (1922) found 46 chromosomes in both male and female guppies. Lebistes reticulatus has 22 pairs of autosomes and 2 X chromosomes in the female and 22 pairs of autosomes and an XY chromosome set in the male. Normally the Y chromosome is found only in the male and is transmitted to only male progeny. The genetic factors contained in the differential segment of this chromosome are not found in the females, but are transmitted to all the young of the male sex. The pairing segment on the other hand crosses over with the X. Whether the

Y chromosome itself also is sex deciding is uncertain. As Winge said in 1922, "experiences gained from the Drosophilia researches have proved that one must indeed take care not to state anything certain on this subject."

A fairly large number of genes had been demonstrated in the X, Y, and autosomes of this species by 1934. Genes which showed X linkage showed crossing over to the Y chromosome and vice versa (Winge, 1934; Winge and Ditlevsen, 1948) . The amount of crossing over showed some variation depending on what genes were present in the two chromosomes. A locus was found in the

Y chromosome containing a set of allelomorphic genes which could not cross over to the X chromosome. These alleles were completely linked with a male-determining clement found in this Y chromosome and located near its end. The pattern of inheritance for chromosome sex determination


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BIOLOGIC BASIS OF SEX


was apparently XX for the female and XY for the male. Events observed in selection experiments for sex completely altered this behavior. A pair of autosomes took over the role of the sex chromosomes in the experimentally produced race. The males as well as the females were found to have the XX chromosome arrangement. In effect the X chromosomes became autosomes and the X-linked genes were transmitted autosomally. Pure males and pure females were generally obtained in the progeny for this race, but sex differentiation was so weak that the sex percentage was subject to wide variations betweeen broods and the expected 50 per cent males to females was observed only during the spring months. Winge interpreted these results as indicating that there were both masculine and feminine elements present in the autosomes as well as in the XY chromosomes which contributed to the determination of sex. Selection sorts out different proportions of these elements and a change occurs in the mechanism forming the sex phenotype. XY females were produced which when crossed to XY male segregates gave as expected 3 males to 1 female. On this basis the YY individuals were found. The YY males on crossing with normal females produced only male offspring just as previously the XX males when crossed to normal females gave only female offspring.

Changes of a similar type have been found in nature. Gordon (1946, 1947) observed wild stocks of the platyfish, Platypoecilus maculatus, from Mexico which were XX for the female and XY for the male. Platyfish from rivers in British Honduras on the other hand were WZ for the female and ZZ for the male. The W and Y chromosomes have many common characteristics. Breeding data on domesticated platyfish uncovered similar exceptional chromosomal types with corresponding differences in the sex transmission. Brcidci" (1942) observed an exceptional WZ male which when mated to a normal female WZ had 51 daughters and 13 sons in the progeny. The ratio is such as to indicate that the females were a mixture of WW and WZ genotypes. That this was probable was indicated by the work of Bellamy and Qucal (1951). Again an exceptional WZ male in


niatings with WZ females had female progenies of two types, WW and WZ, the males being ZZ. The WW females were proved by mating to normal males, ZZ, and obtaining progenies which were entirely females. The results indicated that the WW females were less fertile and so would soon be replaced in. nature by the WZ type. Aida (1921, 1936) located genes in the X and the Y chromosomes of another genus of fishes, the medaka, Oryzias latipes, and studied the effects of these chromosomes on sex determination and sex reversal. The chromosome number for the diploid was apparently 48 with no prominent morphologic difference between the X and Y chromosomes. The males were XY and the females XX. By selection for high male ratios, lines were established in which the male offspring far exceeded those which were female. Females having the genotype XY were isolated which on crossing to normal males gave the ratio of 3' males to 1 female. One-third of the male offspring were of the YY constitution so that as with the platyfish this type was viable. In interpreting these results the primary sexual characteristics are held to be determined by respective genes distributed throughout the autosomes and set into activity by stimulating genes. The female genes were held to require greater stimulation than the male genes to be active and produce their jihcnotypes. Sex was viewed as determined by the differences in quantity of the stimulating genes. Between these two quantities a threshold was postulated above which the female and below which the male genes were stimulated. Sex I'eversal and differences in sex ratios among the offspring of these fish from sex reversed males were explained as due to fluctuations of the stimulating jjower or potency of the X chromosome.

Yamamoto (1953, 1959a, b) showed the l)ossibility of reversing the phenotypic sex by incorporating sex hormone-like substances in the diets of the developing young. Functional sex reversal of the male genotypes XY to those having female phenotyi)es was accomplished by introducing estrone or stilbestrol into the diet for ft to 10 weeks to the extent of 50 /i.g. per gm. diet from 1-day-old fry to those 11 to 16 mm. in length. Mating these estrone sex:


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reversed mothers XY, to normal males XY, resulted in progenies containing 1 female to 2.2 to 2.4 males where the expected theoretic relation would be 1 female to 3 males. The male progenies were submitted to test crosses. It was shown that the YY individuals were, as expected, males. With the removal of hormone feeding the normal sexdetermining mechanism reestablished itself as XX for the female and XY for the male in the following generation. The hormone feeding had apparently, through its excess female-stimulating growth capacities, caused the somatic tract of the fish to develop throughout as a female l)ut did not in any way influence the fundamental genetic constitution of the cells. In at least one case (1957j, Yamamoto has shown that true intersexes can be produced having the genotype XY. The secondary sex characters were intermediate between both sexes. The gonads became ovotestes, testicular elements in the anterior and ovarian components in the posterior region. By use of the same technique, but substituting methyl testosterone as the hormonal additive to the diet at the beginning of the indifferent gonad stage and continuing through sex differentiation, it has been possible where quantities of 50 ;ag. per gm. diet were fed in the diet to cause both genetic sexes XX or XY to differentiate into males with rudimentary testes which eventually become neuters on becoming fullgrown fish. Intermediate dosages resulted in XX individuals becoming males and in 3 cases intersexes. These phenotypic males of the XX type became fertile, ])roducing spermatozoa which on fertilization of eggs of normal females gave all female progeny. Again the effect of the sex hormone was temporary in that only the treated generations showed the sex reversal, their progeny returning to the customary XX female and XY male types. Sex reversals have been accomplished on fish that were themselves progeny of sexreversed parents. Genetic analyses showed that the sex-reversed males were all XY genotypes rather than YY genotypes. This was accounted for through the low viability of the males of the YY genotype.

These observations are similar to those observed in some of the Amphibia and are also of interest in connection with the regu


lar sex mechanisms which have developed for Sciara or for those of occasional abnormal types as those observed in Drosophila and man. These cases make it evident that phenotypic sex may be derived in a quite different manner from that adduced by the sex promoting genes carried through the germ line, even though the germ line may be nourished by the products of the phenotypic somatic cells. The time in development when the presence of hormone in excess of and external to the organism's own gene initiated sex organizers, if it is to be effective, would seem to be important. The brief embryonic stage before the determinative changes in sex primordia have occurred, the neutral stage or stage of bisexual potentiality, is likely to be most influenced by external agencies that redirect sex differentiation. Developraentally speaking, this period is rather short for the primary sex organs, although possibly longer in terms of some secondary sex characters such as the breasts in man.

IX. Sex and Parthenogenesis in Birds

Sex in birds follows the general ZW -|2A for the female and ZZ + 2A for the male; sex-linked genes follow this pattern. Although breeding results in general follow expected orthodox lines, the birds are subject to much mosaic variation in their color patterns as well as significant sterility relations in species hybrids. Sectorial mosaics are prominent. Some of these can be accounted for by nondisjunction, polyspermy, binucleate eggs fertilized by difi"erent sperm, development of supernumerary sperm and other known genetic means, whereas others still lack adequate information. Gynandromorphs have been described, but are subject to question in view of the plumage characteristics observed in mosaics and because of the fact that the sex hormones are such that striking plumage differentiations may occur if for any reason, for instance disease, the hormone-producing organs are removed from the birds. In ordinary fowl the ovary produces hormones which suppress male plumage, whereas in the seabright male a gene controlled change in the testis has taken over this functional attribute. Mottling and flecking are also common, particularly in the plumage pat


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terns although seldom in the structural elements of the body. This may be interpreted in a variety of ways, including mutation and various types of chromosomal interchange in either somatic cells or those incorporated into the germ cell tract. The permanence of feather type differentiation in grafts has been demonstrated by Danforth (1932) and others. Conditions for sex variability have certainly been demonstrated as present in the bird (Hollander, 1944). Crosses between species of birds have led to sterile hybrids and to rather extensive discussions of sex reversal in the development of such forms. In their hybrids betweeen pigeons and ring doves. Cole and Hollander (1950j presented a summary of their evidence as well as a review of this literature. Female hybrids rarely resulted from pigeon sires mated to dove females but were readily produced in the reciprocal crosses. Surviving female hybrids produced no eggs. Male hybrids produced abundant sperm but varied greatly in the proportion of sperm which seemed normal. In the backcrosses to pigeons practically no fertility was shown, but in back-crosses to doves over 2 per cent gave fertile eggs and 9 of these eggs hatched. All back-cross specimens were males and have proven sterile, but testes and semen were not examined. With minor exceptions the expression of some 20 mutant genes studied was not different from that of the pure species. Recessives were not expressed in the hybrids whereas most of the dominants gave their customary phenotypes. Sex-linked mutants were transmitted as expected for each sex. This was particularly important as the result of the inheritance of these sex-linked characteristics showed that sex reversal did not occur.

Eggs from virgin hens are known occasionally to undergo some development of the germinal discs. In dark Cornish chickens Poole and Olsen (1958) observed that some parthenogenetic development was present in 57 per cent of the eggs from their total flock. Factors stimulatory to parthenogenesis were noticeably higher in hens of some strains than in those of others. Birds within the flock differed in jmrthenogenetic rates from 100 per cent to 43 per cent. After incubation for a 9- to 10-day period, 3.9 per cent of the A strain, 0.7 per cent of the B strain,


0.4 per cent of the C strain showed some parthenogenetic development. In the experience of these observers these birds showed more development than is found generally in the domestic fowl. Yao and Olsen (1955) showed that, in 95 per cent of the instances when parthenogenetic development was encountered, the growth consisted solely of extra embryonic membranes. In the remaining 5 per cent growth was more advanced, ranging from the presence of blood and blood vessels only, to the presence of well formed embryos in others. The cells were diploid and were able to reproduce themselves by mitotic division. When work on the turkey was begun in 1952, 17 per cent of the eggs began a limited cleavage on being incubated. Two embryos attained the size of normal 3-day embryos. In 1958, among 7269 eggs, 15 per cent were found to contain blood of embryonic origin. Embryos of various ages were encountered in 9 per cent. Fifteen poults of parthenogenetic origin were hatched in the 1958 season. No multinucleated or polyploid cells were found in these turkeys. These poults, as with others, have always been males. Survival of parthenogenetic types generally ranges from a few hours to several days.

In ex]:>eriments with fowl pox it has been shown that the number of eggs developing parthenogenetically increases considerably following vaccination. The factors leading to parthenogenesis are considered to be the genetic characteristics of the strain of birds and the presence of an activating agent or agents in the blood stream of the hens.

The parthenogenetic forms are of particular interest to the problem of sex determination. The females should l)e producing two types of oocytes Z -I- A and W -h A of which presumably the Z + A alone survive since the embryos capable of being sexed are all males. The embryos are also diploids. The 2Z -I- 2A could be derived from a fusion of the Z -H A polav body nuclei as noted earlier or possibly chromosome doubling coming later in the early cleavage. A genetic element seems partially to control the parthenogenetic process. Chromosome doubling would lead to cells with identical pairs of chromosomes. The gene would be homozygous. Inbreeding of poultry leads to a continning and rai^id loss in the vialiility of


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most strains of chickens. A greater loss would be expected for truly homozygous chickens or poults as birds are known for the large numbers of sublethal genes they carry. In fact, it is surprising that any survive to the adult stage.

The doubling of the W and A type would result in individuals lacking the Z chromosome. From what was observed in Amphibia and fish the WW + 2A, individual if it survived, would be expected to be female. Since this type has not as yet been detected it may be inferred that it is inviable because of loss of certain essential genes in the Z chromosome.

X. Sex Determination in Mammals

A. GOAT HERMAPHRODITES

Goat hermaphroditism as reported by Asdell (1936), Eaton (1943, 1945) and Kondo (1952, 1955a, b) is of particular interest when comjjared with human hermaphroditism as observed by Overzier (1955) and of testicular feminization as reported by Jacobs, Baikie, Court Brown, Forrest, Roy, Stewart and Lennox (1959) and others. In each species the phenotypic range in sexual development extended from nearly perfect female to nearly perfect male, with the most frequent class as an intermediate. External appearance of each was partially correlated with internal structure. When internal female structures as the INIiillerian ducts were present, the external appearance was more female-like. When the male structures AVolffian ducts were developed, the external api^earance was more male-like. The presence of the dual systems within certain of these hermaphroditic types indicates, as in Drosophila, that there is independence of development of each system without a socalled turning point calling for differentiation of the female sex followed by that of the male sex or vice versa.

In goats the hermaphroditic types were traced to the action of a recessive autosomal gene (Eaton, 1945; Kondo, 1952, 1955a, b). This gene apparently acts only on the female zygote. In homozygous condition the eml)ryos bearing them develop simultaneously toward the male as well as toward the female types. This development resembles closely that of the Hr gene in Drosophila,


because, although Hr is dominant and the one in goats is recessive, they both operate only on the female type and both tend to develop jointly both male and female systems in sexual development.

One jarring note comes in relating the cytologic basis for sex determination in goats with that for the intersexes. The sex ratios for the different crosses clearly place the hermaphrodites as genetic females expected to have the XX chromosome constitution. The XX constitution would then also agree with that found for human hermaphrodites as discussed later in this paper. Makino (1950) has shown for one case of the intersexual goat that its sex chromosomes were of the male type. Makino's excellent studies with other species made this observation of particular significance as it was contrary to the other morphologic and genetic evidence on these hermaphrodites. The implications were fully realized by Makino when the cytologic observations were made so that as far as possible the observations should be critical on this point. However, there are several sources of cell variation that suggest the desirability of further checks. The chromosome number of the goat is large, normal mitoses rarely appear in the gonads of the intersexes, and the chromosomes of the goat's spermatogenesis are so small as to make difficult details of structure or identification. Some of the difficulties possibly could be avoided by making tissue cultures and determining the somatic chromosome numbers of their cells.

Kondo (1955b) has shown that under the breeding conditions of Japan when the sire was heterozygous, the percentage of intersexes actually approached the expected value 7.3 per cent. When the sires were homozygous recessive individual matings showed 14.6 per cent hermaphrodites as was expected. Continued mating of homozygotes should show 25 per cent of the total kids hermaphrodites, or the equivalent of 50 per cent of the female progeny.

Hermaphroditism in goats has a further advantage in that the locus is apparently linked closely to the horned or polled condition. The horned condition, in consequence, becomes a valuable indicator marking the presence of the hermaphroditic factor in the


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BIOLOGIC BASIS OF SEX


otherwise indistinguishable male types. With these characteristics the goat types have remarkable advantages over other species for the solution of problems of hermaphroditism.

The gene for goat hermaphroditism has even more interest when it is contrasted with that of another gene, tra, discovered by Sturtevant (1945). Tra is recessive wdth no distinguishable heterozygous effect. In the homozygous state it converts the zygotic female into a form with completely male genitalia and internal reproductive tract with no evidence of the female sexual reproductive system. The gene effects in Drosophila are more extreme than those in goats but are concordant in showing that there are loci in the autosomes which may be occupied by recessive genes having direct effects on phenotypic development of the genotypic female. This evidence indicates the significance of these genes rather than the happenstance of their being in the autosome, X or Y chromosome.

B. SEX IN THE MOUSE

The mouse has the XY + 38 A chromosomal arrangement for the males and XX + 38 A for the females. Similar karyotype patterns have been reviewed for some Amphibia and fish. Other Amphibia and fish may have their karyotypes reversed as both forms are found in nature or observed in breeding studies. Similar reversals may be made experimentally in the phenotypes even though the genotypes remain unaltered. Birds show the sex differentiating arrangement of ZW for the females and ZZ for the males. Parthenogenesis seems to lead to males of ZZ type in domestic fowl and turkeys. In an evolutionary sense the mammals could have originated from and perpetuated either of the major karyotype sex arrangements.

Mice and men are alike in that the X has female-determining properties and the Y male potencies. How much part the genes in the autosomes have in sex develojoment is not yet clear. Welshons and Russell (1959) have shown that mice of the presumed X() constitution are females and arc fertile. They have 39 as the modal number of chromosomes found in their bone marrow cells, wiiereas the genetically proven XX types have 40 cln'omosomcs. X ('hroinosoinc


linked genes' behavior substantiate the chromosomal constitutions of XO and XX as females and XY as males.

These results are further supported by the breeding behavior of the X-linked recessive gene, scurfy (Russell, Russell and Gower,. 1959). This gene is lethal to the hemizygous males before breeding. The genetics of the scurfy females have been analyzed by transplanting the ovaries to normal recipient females and obtaining offspring from them. In the scurfy stock the XO type occurred as 0.9 per cent of the progeny. The YO progeny w^ere not identified and probably die prematurely. Nondisjunction of the X and Y chromosomes in the males could result in sperm carrying neither X nor Y chromosomes. These sperm on fertilization of the X egg would give an XO + 2A type individual. Because the result is a female, this would support the Y chromosome as of male potency. The mouse arrangement may then be expected to be like Melandrium in which a well worked out series of types is known.

Sex ratio in mice is strain dependent over what has thus far proven to be a 10 to 15 per cent range. Weir (1958) has shown that for two strains of mice established by selecting for low and high pH, the sex ratio figures were 33 and 53 per cent for artificially inseminated mice and 41 and 52 per cent for natural matings of these respective strains. The differential pH values for the bloods of the low line were 7.498 ± 0.006 and for the high line 7.557 ± 0.007 as of the sixth generation of selection. The parents with the more alkaline bloods tended to have greater percentages of males in their progenies. These results direct attention to the genotype dependent phenotypic factor which may be of some importance for variations in sex ratios.

C. SEX AND STERILITY IN THE CAT

The tortoiseshell male cat has long interested geneticists because it has seemed that by theory it should not be. However, nature has wonderful ways of circumventing best laid hypotheses, sometimes when they are fals(\ sometimes when they have not been probed dee])ly enough. The yellow gene for coat color in cats is sex-linked. This gene operates on an autosomal background of ^(■lu's for black oi' tabby. Tlu^ females may


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be phenotypically orange as the double dose, 0/0, covers up the effects of the other coat color genes; or tortoiseshell, 0/+; or black or tabby, +/+. The males may be orange, '0/, black or tabby, +/, and the type unexpected tortoise. The tortoiseshell males are timid, keep away from other males, and are generally sterile. Testes are of much reduced size and solid consistency. Exceptionally, tortoiseshell males may mate and offspring presumed from the matings may be born. Active study of these males commenced as early as 1904. Komai (1952) has offered a unified hypothesis for their origin. Komai and Ishihara (1956) have contributed added information and a review of the literature to which the reader is referred.

The cat has 38 chromosomes including an X-Y pair for the males. The tortoise males agree in having this arrangement (Ishihara, 1956) , the X being 3 or 4 times the length of the Y in all cytologic preparations from Japanese cats. Komai (1952) visualizes the cat X chromosomes as composed of a pairing segment containing the kinetochore and gene loci among which is that for the orange gene and a differential segment, not found in the Y chromosome, containing the factor-complex for femaleness. The Y chromosome is visualized as having a segment containing the kinetochore and capable of pairing with the X chromosome. This segment may cross over with the X so that it may acquire the locus for orange or its wild type. The Y chromosome is viewed as containing two differential segments. The one carrying the factor complex for maleness is located to correspond with the X differential segment carrying the female sex factor. The second Y differential segment is at the other end of the chromosome and contains the male fertility complex. The tortoiseshell sterile males are interpreted as caused by a Y chromosome crossing over with the X chromosome to incorporate the male segment and the gene in the resulting Y chromosome but with the loss of the male fertility segment. The gamete carrying this modified Y fertilizing an egg with a normal X chromosome containing the wild type instead of the gene develops into the sterile tortoiseshell male. The data show that the probability of these events occurring is small. Komai records as reliable ■65 tortoiseshell male cats where the inci


dence of the O gene in the whole population of Japanese cats is 25 to 40 per cent. Of the 65, 3 were apparently fertile. These cases and the few others found in the literature are regarded as caused by those rare occasions when the Y chromosome incorporates the gene but retains the male fertility complex as might occur in double crossing over. The hypothesized factor locations and crossing over arrangements also may explain the unexpected black females which are known to occur in some matings. Although not mentioned, black males and orange males showing the same sterility features as the sterile tortoiseshell males should also be found in the cat poi)ulation. If found they would further strengthen the hypotheses.

It is difficult to understand why, even with its low initial frequency, the fertile tortoiseshell male would not establish itself in the Japanese cat population, inasmuch as they are so admired and sought after by all the people if any tortoiseshell males became as fertile as the tortoiseshell male "lucifer" (Bamber and Herdman, 1932) known to have sired 56 kittens.

Ishihara's work (1956) seems to close the door on another attractive hypothesis to explain the origin of these unexpected cat types. Tortoiseshell male reproductive organs include small, firm testes showing reduced spermatogonial development. Together with the interaction of the gene with the wild type allele they suggest the human types XXY + 2A which may arise from nondisjunction. However, the chromosome type is shown to be XY -f- 2A = 38 which is fatal to this hypothesis.

It is of interest that Komai in 1952 postulated the male complex and fertility factors in the Y chromosome of a mammal. The case has a further parallel in the plant Melandrium in that the work of both Westergaard (1946) and Warmke (1946) indicated the Y chromosomes of this plant to contain such factor complexes although in differing arrangements.

D. DEVIATE SEX TYPES IN CATTLE AND SWINE

As a caution in the mushrooming of cytologic interjiretations of sex development, attention may be directed to the freemartin types known particularly from the work of


52


BIOLOGIC BASIS OF SEX


Keller and Tandler (1916), Lillie (1917), and the researches stimulated by their observations on cattle twins. The freemartin in cattle develops in the same uterus with its twin male. The blood circulations anastomose so that blood and the products it contains are common to both fetuses during development. The development of the female twin is intersexual, presumably because of substances contributed by the male twin to the common blood during uterine growth. The freemartin intersexuality may be graded into perfectly functioning fertile females to types with external female genitalia and typically male sex cords except germ cells are absent, vasa efferentia, and elements of the vasa deferentia. The conditions are similar to those discussed for amphibia, fish, and rabbits in which early sex development passes through neutral stages during which it may be directed toward one sex or the other by the right environmental stimuli.

Intersexes in swine have been interpreted as owing to similar causes (Hughes, 1929; Andersson, 1956) although the resulting phenotypes may not be quite as extreme. The resulting intersexes for both cattle and swine presumably are not caused by chromosomal misbehavior but to the right environmental stimuli operating on suitable gene backgrounds. The observations of Johnston, Zeller and Cantwell (1958) on 25 intersexual pigs all from one breeding group of Yorkshires suggest significant inheritance effects. The intersexes were of two types, "male pseudohermaphrodites" and "true hermaphrodites," but there was some intergrading of their phenotypes suggesting that they may be the products of like causes. Common organs between the two groups included uteri, vulvae, vaginae, testes, epididymis, and penis or enlarged clitori. The "true hermaphrodites" were separated on the basis of no prostates, bulbo-urethral glands, or seminal vesicles as well as having testes or ovotestes with ovaries. A similar case was described by Hammond (1912) but, as in one of the above cases, the supposed ovaries when sectioned seemed to be lymphatic tissue. Favorable nerve tissue^ from 6 of the Yorkshire pigs was examined foi- nuclear chromatin. The cases were found chromatin positive. Phenotypically these cases also have parall(>ls in mice and man.


E. .SEX-iN man: chromosomal basis

A surprise even to its discoverers, Tjio and Levan (1956), came with the observation that the somatic number of chromosomes in cultures of human tissue was 46 rather than the previously supposed 48. Search for the true number has been going on for more than half a century. In early investigations the numbers reported varied widely. Difficulties of proper fixation and spreading of the chromosomes of human cells accounted for most of this variation and the numerous erroneous interpretations. Among the observations that of de Winiwarter (1912) was of particular interest in showing the chromosome number as 46 autosomes plus one sex chromosome with the Y being absent. This number was also found later by de Winiwarter and Oguma (1926). Observations by Painter (1921, 1923) showed 46 chromosomes plus an X and a Y, a total of 48. This number was subsequently reported by a series of able investigators, Evans and Swezy (1929), Minouchi and Ohta (1934), Shiwago and Andres (1932), Andres and Navashin (1936), Roller (1937), Hsu (1952), Mittwoch (1952), and Darlington and Haque (1955). As Tjio and Levan indicated, the acceptance of 48 as the correct number, with X and Y as the sex chromosome arrangement, was so general that when Drs. Eva Hanson-Melander and S. Kullander had earlier found 46 chromosomes in the liver cells of the material they were studying they temporarily gave up the study. In the few years since 1956, the acceptance of 46 chromosomes as the normal complement of man has become nearly universal. There are 22 paired autosomes plus the X and Y sex chromosomes.

The reasons which have warranted this change of viewpoint are no doubt many, but three improvements in technique are certainly significant. The first came as a consequence of simplifying the culture of human somatic cells. The second followed Hsu's (1952) recognition that pretreatment of these cells before fixation with hypotonic solutions tended to better spreads of the chromosomes on the division plates when subsefiuently stained by the squash techniciuo. Pretreatment of the cultures with


FOUNDATIONS FOR SEX


53


colchicine made the studies more attractive by increasing the numbers of usable cells that were in the metaphase of cell division.

Ford and Hamerton (1956) in an independent investigation, closely following that of Tjio and Levan, observed that the human cell complement contained 46 chromosomes. They, too, agreed with Painter and others that followed him that the male was XY and the female XX in composition. A flood of confirming evidence soon followed: Hsu, Pomerat and Moorhead (1957), Bender (1957), Syverton (1957), Ford, Jacobs and Lajtha (1958), Tjio and Puck (1958), Puck (1958), Chu and Giles (1959), and a number of others.

In most instances the results of the different investigators were surprisingly consistent in showing that the individual cell chromosome counts nearly always totaled 46. This was no doubt due in part to the desirability of single layers of somatic cells for identifying and separating the different chromosomes into distinct units. Chu and Giles' results illustrate this consistency. For 34 normal human subjects, including 29 American whites and 4 American Negroes, and one of unknown race, and regardless of sex, age, or tissue, the diploid chromosome number of the somatic cells was overwhelmingly 46. In only five individuals were other numbers observed in isolated cells. Out of 620 counts, 611 had 46 chromosomes; two individuals, whose majority of cells showed 46, had 3 cells with 45 chromosomes; three other individuals, the majority of whose cells showed 46, had 6 cells with 47 chromosomes. Average cell plates counted per individual was nearly 20.

The only recent observations at variance with these results were those of Kodani (1958) who studied spermatogonial and first meiotic metaphases in the testes from 15 Japanese and 8 whites. In these studies at least several good spermatogonial metaphases in which the chromosomes could be counted accurately, and secondly at least 15 spermatocyte metaphases in which the structure of individual chromosomes could be observed clearly, were made on each specimen. The numbers of cells studied in metaphase were generally above these numbers, one reaching 60 metaphases. Some variation was noted within individuals. Among


individuals, numbers of 46, 47, and 48 were observed. Among 15 Japanese, 9 had 46, 1 had 47, and 5 had 48 chromosomes, whereas among the whites 7 had 46, and 1 had 48. Sixteen of the 23 individuals had 46 chromosomes. Karyotype analyses indicated that the numerical variation was caused by a small supernumerary chromosome. On the basis of these observations it would appear that individuals within races may vary in chromosome number and yet be of normal phenotype. However, in view of the extensive observations by others, it seems unlikely that the variation between individuals is as large as that indicated. It will require much further study to establish any other number than 46 as the normal karyotype of man. This is particularly true in view of the work of Makino and Sasaki (1959) and Alakino and Sasaki cited by Ford (1960), in which they studied the human cell cultures of 39 Japanese and found without exception 46 chromosomes, and the earlier work of Ford and Hamerton (1956) on spermatogonial material where they, too, found 46 chromosomes in that tissue. The best features of these human chromosome studies will come in the identification of the individual chromosomes making up the human group. The chromosome pairs may be ordered according to their lengths. The longest chromosome is about 8 times the length of the smallest. The chromosomes may be classified according to their centromere positions. The chromosomes are said by most observers to be fairly easily separated into 7 groups. Separation of the individual chromosome pairs from each other and designation of the pairs so that they can be identified by trained investigators in all good chromosome preparations is not possible according to some ciualified cytologists and admitted difficult by all students. However, standardized reporting in the rapidly growing advances in human cell studies should refine observations, reduce errors, and encourage better techniques. With this in mind, 17 investigators working in this field met in Denver in 1959 in what has come to be called the "Denver conference" (Editorial, 1960). From an examination of the available evidence on chromosome morphologies an idiogram was set up as a standard for the somatic chromosome


54


BIOLOGIC BASIS OF SEX



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FOUNDATIONS FOR SEX


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complement of the normal human genome. A reproduction of this standard is presented in Figure 1.1, as kindly loaned by Dr. Theodore T. Puck for this purpose.

The autosomes were first ordered in relation to their size and such attributes as would help in their positive identification. Numbers were given to each chromosome as a means of permanent identification. Basically, identification is assisted by the ratio of the length of the long arm to that of the short arm; the centromeric index calculated from the ratio of the length of the shorter arm to the whole length of the chromosome ; and the presence or absence of satellites. Classification is assisted by dividing the chromosome pairs into seven groups. Groups 1-3. Large chromosomes with approximatel}^ median centromeres. The three chromosomes are readily distinguished from each other by size and centromere position. Group 4-6. Large chromosomes with submedian centromeres. The two chromosomes are difficult to distinguish, but chromosome 4 is slightly longer. Group 6-12. Medium sized chromosomes with submedian centromeres. The X chromosome resembles the longer chromosomes in this group, especially chromosome 6, from which it is difficult to distinguish. This large group is the one which presents major difficulty in identification of individual chromosomes. Group 13-15. INledium sized chromosomes with nearly terminal centromeres ("acrocentric" chromosomes). Chromosome 13 has a prominent satellite on the short arm. Chromosome 14 has a small satellite on the short arm. No satellite has been detected on chromosome 15. Group 16-18. Rather short chromosomes with approximately median (in chromosome 16) or sul>median centromeres. Group 19-20. Short chromosomes with approximately median centromeres. Group 21-22. Very short, acrocentric chromosomes. Chromosome 21 has a satellite on its short arm. The Y chromosome belongs to this group. Separations of the human chromosome pairs into the seven groups is not as difficult as designating the pairs within groups (Patau, 1960). The svstem is a notable ad


vance in summarizing visually the current information in the hope that availability of such a standard will promote further refinements, lessen misclassification, and contribute to a better understanding of the problems by cytologists and other workers in the field.

1. Xuclear Chromatin, Sex Chromatin

Sexual dimorphism in nuclei of man (Barr, 1949-59) and certain other mammals may be detected by the observable presence of nuclear chromatin adherent to the inner surfaces of the nuclear membrane. The material is about 1 /x in diameter. It frequently can be resolved into two components of equal size. It has an affinity for basic dyes and is Feulgen and methyl green positive. Nuclear chromatin can be recognized in 60 to 80 per cent of the somatic nuclei of females and not more than 10 per cent of males. It is known to be identifiable in the females of man, monkey, cat, dog, mink, marten, ferret, raccoon, skunk, coyote, wolf, bear, fox, goat, deer, swine, cattle, and opossum, but is not easily usable for sex differentiation in rabbit and rodents because these forms have multiple large particles of chromatin in their nuclei. The tests can be made quickly and easily on skin biopsy material or oral smears. Extensive utilization of the presence or absence of nuclear chromatin in cell samples of man has been made for assigning the presumed genetic sex to individuals who are phenotypically deviates from normal sex types. (See also chapters by Hampson and Hampson, and by Money.) Numerous studies on normal individuals seem to support the test's high accuracy. However, in certain cases involving sexual modification, questions have arisen which are only now being resolved. In male pseudohermaphroditism, sex, determined by nuclear chromatin, is male, thus agreeing with the major aspects of the phenotype. For female pseudohermaphroditism, individuals with adrenal hyperplasia or those without adrenal hyperplasia give the female nuclear chromatin test. For cases listed as true hermaphrodites Grumbach and Barr (1958) list 6 of the male type and 19 of the female type. For the syndrome of gonadal dysgenesis they list 90 as male and 12 as female among the proved cases and 15 more as female among those that are


56


BIOLOGIC BASIS OF SEX


suspected. In the syndrome of seminiferoustubule dysgenesis where there is tubular fibrosis, 9 are listed as male and 18 female. Where there is germinal aplasia, 15 are listed as male and 1 as female. The seeming difficulties in assigning a sex constitution to some of these types are now being dissipated through the study of the full chromosome complements which are responsible for these different disease conditions. As observations on different chromosome types have been extended, evidence has accumulated to show that the numbers of sex nuclear chromatins, for at least some of the nuclei making up the organism, often equals (n — 1) times the number of X chromosomes. The majority of male XY nuclei are chromatin negative as are most of the Turner XO type. Female nuclei XX have a single chromatin positive element as do the XXY and XXYY types. The XXX and XXXY have 14 and 40 per cent respectively with two Barr bodies in cases for which quantitative data are available. However, a child with 49 chromosomes, but whose cultured cell chromosomes appear as single heteropycnotic masses making identification of the individual chromosomes difficult, showed 50 per cent of the cell nuclei with three Barr elements (Fraccaro and Lindsten, 1960) . The chromosome constitution of these nuclei was interpreted as trisomic for 8, 11, and sex chromosomes. Sandberg, Crosswhite and Gordy (1960) report the case of a woman 21 years old having various somatic changes which does not fit this sequence. The chromosome number was 47 and the nuclei were considered trisomic for the sixth largest chromosome. Two chromatin positive bodies were ])rosent in the nuclei.

2. Chrotnosome Complement und Phenotijpe in Man

Experience of the past 50 years has emphasized that genes and trisomies or other types of aneuploid chromosome complexes may lead to the development of abnormal phenotypes expressing a variety of characteristics. Drosophila led the way in illustrating how the different gene or chromosome arrangements may affect sex expression. Investigations of human abnormal types, particularly those with altered sex differentiation, have reccntlv .^liown that man follow.-^


other species in this regard. The Y carries highly potent male influencing factors. Gene differences often lead to characteristic phenotypes of unique form.

3. Testicular Feminization

The testicular feminization syndrome illustrates one of these types. As described by Jacobs, Baikie, Court Brown, Forrest, Roy, Stewart and Lennox (1959), "In complete expression of this syndrome the external genitalia are female, pubic and axillary hair are absent or scanty, the habitus at puberty is typically female, and there is primary amenorrhoea. The testes can be found either within the abdomen, or in the inguinal canals, or in the labia majora, and as a rule the vagina is incompletely developed. An epididymis and vas deferens are commonly present on both sides, and there may be a rudimentary uterus and Fallopian tubes. The condition is familial and is transmitted through the maternal line." A sex-linked recessive, a sex-limited dominant, and chromosome irregularities of the affected persons have been postulated as mechanisms causing the apparent inheritance of this condition. Chromosome examinations of the cells of affected persons have shown 46 as the total number and X and Y as the sex complement. The karyotype analysis agrees with the Barr nuclear chromatin test in that the cells are chromatin-negative but both are at variance with the sex phenotypes in the sense that aside from suppressed testes the patients are so completely female. Genetically, Stewart (1959) has described two color-blind patients with the testicular feminization syndrome in the first five patients he reported. The limited data from these cases suggest that the genie basis for this condition is either independent or but loosely linked with color blindness. This evidence does not exclude sex-linkage but does make it less probable. The third hypothesis of autosomal inheritance may take one of several forms. A recessive gene which affects only the male phenotypes when in homozygous condition is apparently untenable because the matings from which these individuals come are of the outbreeding type and the ratios apparently do not differ from the one-to-one ratio expected of a heterozygous dominant instead of that re


FOUNDATIONS FOR SEX


57


quired for an autosomal recessive. The hypothesis advanced by Witschi, Nelson and Segal (1957), that the presence of an autosomal gene in the mother converts all her male offspring into phenotypes of more or less female constitution, in a manner comparable to that of the Ne gene in Drosophila (Gowen and Nelson, 1942) which causes the elimination of all the female type zygotes, is also made unlikely by the ratios of normal to testicular feminization phenotypes observed in the progenies of these affected mothers. The evidence favors a simple autosomal dominant, acting only in the male zygotes and perhaps balanced by some genes of the X chromosome, which have sufficient influence on the developing male zygote to guide it toward an intermediate to nearly female phenotype. The observations of Puck, Robinson and Tjio ( 1960) indicate that the action of a gene for this condition may not be entirely absent in the female, because in heterozygous condition in an XX individual it seemed to delay menarche as much as 8 years. If this delay be diagnostic for the heterozygote, it will further assist in the genetic analysis of this problem. Evidence on this point should be a part of the genetic studies.

Cases closely similar to those described by Jacobs, Baikie, Court Brown, Forrest, Roy, Stewart and Lennox (1959) are presented by Sternberg and Kloepfer (1960). The patients show no trace of masculinity. They are remarkably uniform in anatomic expression. Except for failure to menstruate due to lack of uteri they undergo normal female puberty. Cryptorchid testes, usually intra-abdominal, if removed precipitate menopause symptoms. Four unrelated cases were found in this one study with 7 additional cases traced through pedigree information. A total of 11 affected individuals was found in 6 sibships having 26 siblings of whom 5 were normal males. In each kindred the inheritance was compatible with that of a sex-linkecl recessive gene. A chromosomal study of a thyroid tissue culture from one case revealed 46 chromosomes with normal XY male configuration. The individuals observed were designated as simulant females."


4- Superfemale

The human superfemale has been recognized by Jacobs, Baikie, Court Brown, MacGregor, Maclean and Harnden (1959) in a girl of medium height and weight, breasts underdeveloped, genitalia infantile, vagina small, and uterocervical canal 6 cm. in length. Ovaries appeared postmenopausal with normal stroma, and as indicated by a biopsy specimen, deficient in follicle formation. Menstruation was thought to have begun at age 14, but was irregular, occurring every 3 to 4 months and lasting 3 days. The last spontaneous menstruation was at 19. Estrogen therapy caused some development of the breasts and external genitalia, vagina, and uterus with slight uterine bleeding. The patient's parents were above 40 years of age, mother 41, at time of her daughter's birth.

Examination of sternal marrow cultures showed 47 chromosomes in over 80 per cent of the cells examined. The extra chromosome was the X, the chromosomal type being XXX plus 22 pairs of autosomes. Buccal smears showed 47 per cent of nuclei contained a single chromatin body and 14 per cent contained 2 chromatin bodies as expected of a multiple XX or XXX genotype. In comparison, 25 smears from 20 normal women had 36 to 51 per cent chromatin positive cells but none of these contained 2 chromatin bodies. Two chromatin bodies were seen in some cells of the ovarian stromal tissue. The patient showed a lack of vigor, mentally was subnormal, was underdeveloped rather than overly developed in the phenotypic sexual characteristics. Examination of the patient's mother showed her to be XX plus 22 pairs of autosomes, the normal 46 chromosomes.

Other cases show that types with XXX plus 22 pairs of autosomes are of female l)henotype but may vary in fertility and development of the secondary sexual characteristics from nonfunctional to functional females bearing children ( Stewart and Sanderson, 1960; Eraser, Campbell, MacGillivray, Boyd and Lennox, 1960). The triplo X condition in man has a greater range of development and fertility than in Drosophila. In man ovaries may develop spontaneously. In Drosophila they require transplantation


58


BIOLOGIC BASIS OF SEX


to a diploid female host where they may attach to the oviducts and release eggs for fertilization (Beadle and Ephrussi, 1937).

These cases present confirmation of two facts already mentioned for Drosophila. They show that when the X chromosome has primarily sex determining genes, the organism generally becomes unbalanced when 3 of these X chromosomes are matched against two sets of autosomes. The resulting phenotypes are female but relatively undeveloped rather than overdeveloped. The second is that the connotations evoked by the prefix "super" are by no means applicable to this human type or to the Drosophila type.

The characteristics of the patient also suggest that the autosomes may be carrying sex genes opposing those of female tendencies as observed in both Drosophila and Rumex genie imbalance.

5. Klinefelter Syndrome

In the Klinefelter syndrome there is male differentiation of the reproductive tracts with small firm descended testes. Meiotic or mitotic divisions are rare, sperm are ordinarily not found in the semen. The type is eunuchoid in appearance with gynecomastia, high-pitched voice, and sparse facial hair growth. Seminiferous tubules showing an increased number of interstitial cells are atrophic and hyalinized. Urinary excretion of pituitary gonadotrophins is generally increased, whereas the level of 17-ketosteroids may be decreased. The nuclear chromatin is typically female. Of the dozen or more cases studied (Jacobs and Strong, 1959; Ford, Jones, Miller, Mittwoch, Penrose, Ridler and Sha])iro, 1959; Bergman and Reitalu quoted by Ford, 1960), only one, having but 5 metaphase figures, had less than 47 chromosomes in the somatic cells and XXY sex chromosomes. That case was thought to have typical female chromosomes XX + 22 AA. Two other cases were of particular interest as indicating further chromosome aberration. Ford, Jones, Miller, Mittwoch, Penrose, Ridler and Shapiro (1959) studied one patient who displayed both the Klinefelter and Mongoloid syndromes. The chromosome number was 48, the sex chromosomes being XXY and the 48tli chromosoinc being small acrocentric.


This individual had evidently developed from an egg carrying 2 chromosomal aberrations, one for the sex chromosomes and the second for one of the autosomes. The other case, Bergman and Reitalu as cited by Ford (1960), had 30 per cent of its cells with an additional acrocentric chromosome which had no close counterpart in the normal set.

Data where the Klinefelter syndrome occurs in families showing color blindness (Polani, Bishop, Ferguson-Smith, Lennox, Stewart and Prader, 1958; Nowakowski, Lenz and Parada, 1959; and Stern, 1959a) further test the XXY relationship and give information on the possible position of the color blindness locus with reference to the kinetochore. Polani, Bishop, FergusonSmith, Lennox, Stewart and Prader (1958) tested 72 sex chromatin-positive Klinefelter patients for their color vision and found that none was affected by red-green color blindness. Nowakowski, Lenz and Parada ( 1959) tested 34 cases and detected 3 affected persons, 2 of whom were deuteranomalous and one protanopic. Stern (1959a) l^oints out that these cases and their ratios are compatible with the interpretation of the Klinefelter syndrome as XXY. One of the deuteranomalous cases had a deuteranomalous mother and a father with normal color vision. This case could have originated from a nondisjunctional egg carrying 2 maternal X chromosomes fertilized by a sperm carrying a Y chromosome. The other two cases had normal fathers with heterozygous mothers. There are several explanations by which the color-blind Klinefelter progenies could be obtained. The heterozygotes might manifest the color-blind condition. The second hypothesis, which is favored, is that of crossing over between the kinetochore and the color-blind locus at the first meiotic division to form eggs each carrying 2 X chromosomes, one homozygous for color blindness, and the other for normal vision. An equational nondisjunction would form eggs homozygous for color blindness which on fertilization by the Y chromosomes of the male would give the necessary XXY constitution for the color-blind male which is Klinefelter in phenotype. A third possibiHty is that these exceptions may arise without crossing over as the result of


FOUNDATIONS FOR SEX


59


nondisjunction at the second meiotic division.

If the hypothesis of crossing over is accepted, the color-blind locus separates freely from its kinetochore and would suggest that the position of the locus is at some distance from the kinetochore of the X chromosome.

A disturbed balance between the X and the Y chromosomes alters the sexual type. A single Y chromosome, contributing factors important to male development, is able to alter the effects of two sets of female influencing X chromosomes. Yet two Y chromosomes in a complex of XXYY plus 44 autosomes seem to have little or no more influence than one Y (Muldal and Ockey, 1960). The locations of the sex-influencing genes in man are thus more like those of the plant Melandrium than of Drosophila in which the male-determining factors occur in the autosomes. The relative potencies of the male sex factors compared with those of the female, however, are much less than those in Melandrium.

6. Turner Syndrome

Turner's syndrome or ovarian agenesis further substantiates the female influence of the X chromosomes. The cases occur as the developmental expression of accidents in the meiotic or mitotic divisions of the chromosomes. These accidents lead to adults unbalanced for the female tendencies of the X chromosome. The gonads consist of connective tissue. The rest of the reproductive tract is female. Growth stimuli of puberty are lacking, resulting in greatly reduced female secondary sexual development. Patients are noticeably short and may be abnormal in bone growth. In its more extreme form, designated as Turner's syndrome, the individuals may show skin folds over the neck, congenital heart disease, and subnormal intellect, as well as other metabolic conditions. Earlier work (Barr, 1959; Ford, Jones, Polani, de Almeida and Briggs, 1959) shows that 80 per cent of the nuclear chromatin patterns are of the male type. Evidence from families having both this condition and color blindness suggested that at least some of the Turner cases would be found to have 45 chromosomes, the sex chromosome being a lone X (Polani, Lessof and Bishop, 1956). Work of Ford, Jones,


Polani, de Almeida and Briggs, (1959) has confirmed this hypothesis and added the fact that some of these individuals are also mosaics of cells having 45 and 46 chromosomes. The 45 chromosome cells had but one X, whereas the 46 had two X's. This finding may explain the female-chromatin cell type observed in about 20 per cent of the cases having the Turner syndrome. Such mosaics of different chromosome cell types could also be significant in reducing the severity of the Turner syndrome and in increasing the range of symptoms which characterize this chromosome-caused disease as contrasted with those characterizing Turner's disease. Further cases observed in other investigations, Fraccaro, Kaijser and Lindsten (1959), Tjio, Puck and Robinson (1959), Harnden, and Jacobs and Stewart cited by Ford (1960) have all shown 45 chromosome cells and a single X chromosome. As with the XXX plus 44 autosome super females, the Turner type, X plus 44 autosomes, also shows a rather wide range in development from sterility with extensive detrimental secondary effects to nearly normal in all respects. Bahner, Schwarz, Harnden, Jacobs, Hienz and Walter (1960) report a case which gave birth to a normal boy. Other cases have been described (Hoffenberg, Jackson and jVIuller, 1957; Stewart, 19601 in which menstruation was established over a period of years. The XO type in man and Melandrium is morphologically female. In Drosophila on the other hand, the XO type is phenotypically nearly a perfect male. It is further to be noted that the X chromosome of Drosophila appears to have a less pronounced female bias than that of man when balanced against its associated autosomes, inasmuch as the XO + 2A type in Drosophila is male as contrasted with the XO + 2A type in man which is female. At the same time it seems that the autosomes in the human may be influential in that the female gonadal development is suppressed instead of going to completion as it does in the XX type.

7. Hermaphrodites

Hermaphroditic phenotypes in man, to the number of at least 74 (Overzier, 1955), have been observed and recorded since 1900. Types with a urogenital sinus pre


60


BIOLOGIC BASIS OF SEX


dominated. The uteri were absent in some cases, even when complete external female genitalia were present. Ovotestes were found on the right side of the body in over half the cases; separate left ovaries or testes were about equally frequent ; in three cases separate testis and ovary were indicated. The left side of the body showed a different distribution of gonad types; about onefourth had ovotestes, another fourth ovaries, and one-twelfth testes. Unilateral distribution of gonad types was most frequent. The presence or absence of the prostate seemed to have significance because it is sometimes absent in purely female types. In recent literature similar cases have been called true hermaphrodites. This is an exaggeration in terms of long established practice in plants and animals where true hermaphroditism includes fully functioning gametes of each sex.

Hungerford, Donnelly, Nowell and Beck (1959» have reported on a case of a Negro in which the culture cells had the chromosome complement of a normal female 46, with XX sex chromosomes. Unfortunately, the possibility that this case may be a chromosome mosaic was not tested by karyotype samples from several parts of the body.

Harnden and Armstrong (1959) established separate skin cultures from both sides of the body of another hermaphroditic type. The majority of the cells were apparently of XX constitution with a total of 46 chromosomes. However, in one of the 4 cultures established, some 7 per cent of cells had an abnormal chromosome present, suggesting that the case might involve a reciprocal translocation between chromosomes 3 and 4 when the chromosomes were ordered according to size. All the other cell nuclei were normal. The fact that the majority of the cells in these two cases were XX and with 46 chromosomes seems to predicate against the view that either changes in chromosome number or structure of the fertilized egg are necessary for the initiation of hermaplu'odites.

Ferguson-Smith (1960) describes two cases of gynandromorphic type in which the reproductive organs on the left side were female and on the right side were male. The recognizable organs were Fallopian tube, ovary with primordial follicles only, imma


ture uterus in one case, none in the other, rudimentary prostate, small testis and epididymis, vas deferens, bifid scrotum, phallus, perineal urethra, pubic and axillary hair, breasts enlarging at 14 years. Testicular development with hyperplasia of Leydig cells, germinal aplasia, and hyalinization of the tubules was suggestive of the Klinefelter syndrome. Nuclear-chromatin was positive in both cases. Modal chromosome number was 46. The sex chromosomes were interpreted as XX. The 119 cell counts on one patient showed a rather wide range; 7 per cent had 44 chromosomes, 13 per cent had 45, 62 per cent had 46, and 18 per cent had 47 chromosomes. The extra chromosome within the cells containing 47 chromosomes was of medium size with submedian kinetochore as generally observed for chromosomes of group 3.

It is surprising that the male differentiation in these four and other hermaphroditic cases (Table 1.5) is as complete as it is. Other observations show that the Y chromosome contains factors of strong male potency, yet in its absence the hermaphrodites develop an easily recognized male system. It is not complete but the degree of gonadal differentiation is as great as that observed in the XXY 4- 2A Klinefelter types. The bilateral sex differentiation in hermaphrodites would seem to require other conditions than those heretofore considered.

Another case of hermaphroditism is that presented by Hirschhorn, Decker and Cooper (1960). The patient's j:)henotype was intersexual with phallus, hypospadias, vagina, uterus. Fallopian tubes, two slightly differentiated gonads in the position of ovaries. The child was 4 months old. Culture of bone marrow cells showed that the individual was a mosaic of two types. About 60 per cent of the cells had 45 chromosomes of XO karyotype, and 40 per cent had 46 chromosomes with a karyotA'^pe XY. The Y chromosome when present was larger than Y chromosomes of normal individuals. The change in size may be related to the association of the XO and XY cells and be similar etiologically to the case discussed by yivtz (1959) in Sciara triploids.

There are mosaics in Drosophila formed from the loss by the female in some cells of one of lioi- X chromosomes, as for instance


FOUNDATIONS FOR SEX


61


in ring chromosome types, which may display primary and secondary hermaphroditic development. For this to happen the altered nuclei apparently find their way into the region of the egg cytoplasm which is to differentiate into the reproductive tract. As seen in the adults, organ tissue of one chromosome type is cell for cell sharply differentiated from that of the other chromosome type with regard to sex. These observations indicate that for these mosaics the basic chromosome structure of the cell itself determines its development. In fact most mosaics of this species show this cell-restricted differentiation. Several problems arise when these well tested observations are considered in comparison with those now arising in the chromosome mosaics of the sex types in man. It would seem unlikely that the bone marrow cells or for that matter any somatic cells not a part of the reproductive tract would operate to modify the adult sex or a part thereof. Rather the developmental secjuence should start from cell differences within the early developing reproductive tract. Circulatory cells or substances would be of dubious direct significance from another viewpoint. All cells of the body would ultimately be about equally affected by any cells or elements circulating in the blood. With strong male elements and strong female elements the result expected would be a reduction in sex development of either sex instead of the sharply differentiated organ systems which are observed. This raises the question, are the chromosomally differentiated cell sex mosaics primary to or secondarily derived from the tissues of the ultimate hermaphrodites? Study of the cell structure of the sex organs themselves as well as much other information will be necessary to clear up this problem.

There are, however, other types of controlled sex development, as by various genes, which lead to the presence of both male and female sexual systems. Genes for these phenotypes are relatively rare, but once found are transmitted as commonly expected. The inherited hermaphroditic cases in Drosophila are certainly relevant to the testicular feminization syndrome in man. Are they equally pertinent to the highly sporadic hermaphroditic forms just


considered for man? If so, they indicate a genie basis for these types which would probably be beyond the range of the microscope to detect. The low frequency of true hermaphrodites in the human, together with lack of information on possible inheritance mitigates against the genie explanation ; although genie predisposition acting in conjunction with rare environmental events as occurs in our Balb/Gw mice (Hollander, Go wen and Stadler, 1956 ) could explain the rare hermaphrodites observed in that particular line of mice and a limited number of its descendants.

8. XX XY + U Autosome Type

The XXXY -I- 44 autosome type in the human has been studied by Ferguson-Smith, Johnson and Handmaker (1960) and Ferguson-Smith, Johnston and Weinberg (1960). The two cases described were characterized by primary amentia, microorchidism and by two sex chromatin bodies in intermitotic nuclei. The patients were similar in having disproportionately long legs; facial, axillary, and abdominal hair scant; pubic hair present; penes and scrota medium to well developed ; small testes and prostates; vasa deferentia and epididymides normally developed on both sides of the body and no abnormally developed Miillerian derivatives. Testes findings were like those in Klinefelter cases with chromatinpositive nuclei, small testes with nearly complete atrophy, and hyalinization of seminiferous tubules and islands of abnormal and pigmented Leydig cells in the hyalinized areas. The few seminiferous tubules present were lined with Sertoli cells but were without germinal cells. Nuclear chromatin was of female type. About twofifths of the nuclei had double and twofifths single sex chromatin. The modal chromosome count for bone marrow cells was 48, 75 per cent of the cells having this number. Chromosome counts spread from 45 to 49. This type, XXXY plus 44 autosomes, may be looked upon as a superfemale plus a Y or a Klinefelter plus an X chromosome. In either case the male potency of the genes in the Y chromosome is able to dominate the female tendencies of XXX to develop nearly complete male phenotypes.

Both cases had severe mental defects but


TABLE 1.5 Chromosome kinds and numbers for different recognized sex types in man


External Type


Male

Female

Female (rare hemophilic)

Eunuchoid female Female


Female Female Female


Female Female


Male . Male. Male.


Male. Male.


Male . . . Female. Female .


Female . Female .


Male. Male.


Hermaphrodite


Hermaphrodite. Intersex


Numbers of Chromosomes


chromosoil rearrange


1 + X fragment

1 2 2


2 2 Interpreted a.s XX trisomic for Sand 11 or as XXXX 4X + Yl


3X+ Yj 1 3 3


2l /mosaic


Missing or Extra Chromosomes


? Chr mosome 3

orT(X;A)


Small autosome

? Large chromosome or

T(X;A)


X or Y

(X or Y) +21


46,47,48 cliromosomes X, Y X or Y -fA set


Sex Chromatm


Negative Positive

Negative Negative Positive


Negative Positive Negative

Negative


Negative Negative


Negative ±

Negative Positive Positive


Triple positi


Negative Double posit Double posit

Negative

Double posit Negative


Negative Negative


Designating Term


Normal male Normal female


Pure gonadal dysgenesis CJonadal dysgenesis


Testicular feiuinizati

Turner

Turner type female


Tinner? gave birth to boy Turner


Turner

Klinefelter

Klinefelter mongoloid


Klinefelter Klinefelter


Klinefelter


Klinefelter Sujierfemale

Superfemale gave birtli to children

Testicular deficiency


Precocious puberty


Triploid


Hermaphrodite or intersex dei)cnding on definition


Investigators*


2 3, 4, 5,


5, 12, 13, 14, 40, 41

41


16, 17, 18, 40, 41

19


40

23, 40

24, 25

41

26


29, 30, 31,. 32, 33 35, 39, 40

34

41


Tjio and Levan, 1956.

Nilsson, Bergman, Reitalu and Waldenstrom, 1959. Harnden and Stewart, 1959. Stewart, 1960b. Stewart, 1960a.

Elliott, Sandler and Rabinowitz, 1959.

Jacobs, Baikie, Court Brown, Forrest, Roy, Stewart and Lennox, 1959. Stewart, 1959

Lubs, Vilar and Bergenstal, 1959. Sternberg and Kloepfer, 1960. Puck, Robinson and Tjio, 1960. Ford, Jones, Polani, de Almeida and Briggs, 1959. Fraccaro, Kaijser and Lindsten, 1959. Fraccaro, Kaijser and Lindsten, 1960a.


15. Bahner, Schwarz, Harnden, Jacobs, Hienz and Walter, 1960.

16. Jacobs and Strong, 1959.

17. Bergman, Reitalu, Nowakowski and Lenz, 1960.

18. Nelson, Ferrari and Bottura, 1960.

19. Ford, Jones, Miller, Mittwoch, Penrose, Hidlor and Shapiro,

1959.

20. Ford, Polani, Briggs and Bishor), 1959.

21. Crooke and Hayward, 1960.

22. Muldal and Ockey, 1960.

23. Jacobs, Baikie, Court Broun, MacCJregor, Maclean and

Harnden, 1959.

24. Eraser, Campbell, .MacCiillivray, Boyd and Lennox, 1960.

25. Stewart and Sanderson, 1960.

26. Jacobs, Harnden, Court Brown, Cohl.stein, Close, Mac Gregor, Maclean and Strong, 1960.


62


FOUNDATIONS FOR SEX


63


27. Ferguson-Smith, Johnston and Handiiiaker, 196(

28. Book and Santesson, 1960.

29. Harnden and Armstrong, 1959.

30. Hungerford, Donnelly, Nowell and Beck, 1959.

31. Ferguson-Smith, Johnston and Weinberg, 1960.

32. deAssis, Epps, Bottura and Ferrari, 1960.

33. Gordon, O'Gorman, Dewhurst and Blank, 1960

34. Hirschhorn, Decker and Cooper, 1960.

35. Sasaki and Makino, 1960.


36. Bloise, Bottura, deAssis, and Ferrari, 1960,

37. Fraccaro, Kaijser and Lindsten, 1960c. 37a. Fraccaro and Lindsten, 1960.

38. Fraccaro, Ikkos, Lindsten, Luft and Kaijser, 1960.

39. Harnden, 1960.

40. Ferguson-Smith and Johnston, 1960.

41. Sandberg, Koepf, Crosswhite and Hauschka, 1960.

42. Hayward, 1960.


it should be remembered that they were sought in institutions for which this is a criterion of admittance. Their mental ability was distinctly less than that of Klinefelter XXY cases which have come under study. The pattern of the XXXY effects on the reproductive tract, however, was comparable with that observed in the XXY genotypes. The effects of one Y chromosome were balanced by either two or three X chromosomes to give nearly equal phenotypic effects.

9. XXY + 66 Autosome Type

XXY + 66 autosome type was established by Book and Santesson (1960) for an infant boy having several somatic anomalies which may or may not be relevant to the sex type. Externally the genitalia were normal for a male of his age, penis and scrotum with testes present in the scrotum. Again the Y chromosome demonstrates its male potencies over two X's even in the presence of three sets of autosomes. The case is of particular significance since further development may indicate what male potencies an extra set of autosomes may possess.

10. Summary of Types

Other types of sex modifying chromosomal combinations and their contained genes have been observed particularly as mosaics or as chromosomal fragments added or substracted from the normal genomes. No doubt other types will be discovered during the mushroom growth of this period. Time can only test the soundness of the observations for the field of human chromosomal genetics and cytology is difficult at best requiring special aptitudes and experience. Mistakes, no doubt, will be made. The status of the subject is summarized in Table 1.5.

11. Types Unrelated to Sex

Other cases not related to sex or only secondarily so were scrutinized during the


course of these studies. The information gained from them is valuable as it strengthens our respect for the mechanisms involved. The sex types which are dependent on loss or gain of the X and/or Y chromosomes belong to the larger category of monosomies or trisomies. Numbers of autosomal monosomic and trisomic syndromes have also been identified in the course of these investigations. Similarly, not all cases that have been studied have turned out to be associated with chromosomal changes. This in itself is important since it lends confidence in those that have, as well as redirects research effort toward the search for other causes than chromosomal misbehavior. The first trisomic in man was identified through the study of Mongolism. The condition affects a number of primary characteristics but not those of sex, for males and females occur in about equal numbers. The broad spectrum of these effects points to a loss of balance for an equally extensive group of genes in the two sexes. The common association of characteristics making up these Mongoloids, together with their sporadic appearance and their change in frequency with maternal age, all suggest the findings which Lejeune, Gautier and Turpin (1959a, b) and Lejeune, Turi)in and Gautier (1959a, b) were able to demonstrate so successfully. They established that the tissue culture cells of Mongoloid imbeciles had 47 chromosomes and that the extra chromosome was in the small acrocentric group. Lejeune, Gautier and Turpin (1959a, b) have now confirmed these observations on not less than nine cases. Jacobs, Baikie, Court Brown and Strong (1959), Book, Fraccaro and Lindsten (1959) and Fraccaro (cited by Ford, 1960) as well as later observers have substantiated the results on more than ten other cases. The well known maternal age effect, whereby women over 40 have a chance of having IMongoloid offspring 10 to 40 times as frequently as those of the younger ages, would seem to point to non


64


BIOLOGIC BASIS OF SEX


disjunction in oogenesis as the most important cause of this condition. Some women who have had previous JMongoloid progeny have an increased risk of having others. This is an important consideration in that genetic factors may materially assist in bringing about nondisjunction in man as they are known to do in Drosophila (Gowen and Gowen, 1922; Gowen, 1928). The products of the nondisjunctions approach those expected on random distribution of the chromosomes (Gowen, 1933) so that occasionally more than one type of chromosome disjunction will appear in a given individual. Such a case is that illustrated by Ford, Jones, Miller, Mittwoch, Penrose, R idler and Shapiro (1959) in which the nondisjunctional type included not only that for the chromosome important to Mongolism but also the sex chromosomes significant in determining the Klinefelter condition. This individual showed 48 chromosomes, 22 pairs of normal autosomes, 3 sex chromosomes XXY, and a small acrocentric chromosome matching a pair of chromosomes, the 21st, within the smallest chromosomes of the human idiogram. The analysis of Mongolism showed the way for the separation of the various human sex types through chromosome analyses.

Chromosome translocations furnish another means of establishing an anomaly that may then continue on an hereditary basis as either the male or female may transmit the rearranged chromosomes. Polani, Briggs, Ford, Clarke and Berg (1960), Fraccaro, Kaijser and Lindsten (1960b), Penrose, Ellis and Delhanty (1960) and Carter, Hamerton, Polani, Gunalp and Weller (1960) have studied Mongoloid cases which they interpreted in this manner. In some cases the rearranged chromosomes have been transmitted for three generations. Several of the translocations were considered to include chromosomes 15 and 21.

Another trisomic autosomal type was rc])ortcd by Patau, Smith, Therman, Inhorn and Wagner (1960). The patient was female and had 47 chromosomes. The extra chromosome was a medium-sized acrocentric autosome belonging to the D group. Despite extensive malformations affecting several organs the patient lived more than a year. Another female iiortraying the same


syndrome has since been found, so other cases may be expected. Among the characteristics are mental retardation, minor motor seizures, deafness, apparent micro or anophthalmia, horizontal palmar creases, trigger thumbs, Polydactyly, cleft i)alate, and hemangiomata.

The third trisomic type was also reported by Patau, Smith, Therman, Inhorn and Wagner (1960). Six individuals have been observed. The characters affected are mental retardation, hypertonicity (5 patients), small mandible, malformed ears, flexion of fingers, index finger overlaps third, big toe dorsiflexed (at least 4), hernia and/or diaphragm eventration, heart anomaly (at least 4), and renal anomaly (3). The sexes were two males and four females. The extra chromosome was in the E group and was diagnosed as number 18. Edwards, Harnden, Cameron, Crosse and Wolff (1960) have described a similar case but they consider the trisomic to be number 17. Ultimate comparisons of these types no doubt will decide if this is a 4th trisomic or if all the cases belong in the same group.

The Sturge-Weber syndrome apparently is caused by another trisomic. Locomotor and mental abilities are retarded. Hayward and Bower (1960) interpret the 3 chromosomes responsible as the smallest autosomes, number 22, of the human group.

Trisomic frequencies should be matched by equal numbers of monosomies. Turpin, Lejeune, Lafourcade and Gautier (1959) have reported polydysspondylism in a child with low intelligence, dwarfing, and multil)le malformations of spine and sella turcica. The somatic cell chromosome count was only 45 but one of the smallest acrocentric chromosomes appeared to have been translocated, the greatest part of this chromosome being observed on the short arm of one of the 3 longer acrocentric chromosomes. Th(> condition appears to be unique and not likely to be found in other unrelated famiVws. However, the phenotyj^ic effects were so severe that all members of the proband's family would seemingly be worthy of careful sur\'('y for their chromosome characteristics.

The comi)lex pattern of multiple anomalies renders each syndrome distinct from the othei's. Chromosome losses or gains from


FOUNDATIONS FOR SEX


Go


the normal diploid would be expected to lead to the complex changes. Mongolism is influenced by age of the mother and probably to some extent by her inheritance. It is to be expected that the other trisomies may show parallel relations. Other trisomies may be expected although, as the chromosomes increase in size, a group of them will have less opportunity to survive because of loss of balance with the rest of the diploid set. Thus far most of these conditions affect the sex phenotypes. This is in accord with the results in Drosophila. Changes in the balance of the X chromosomes are less often lethal than the gain or loss of an autosome. Other animals show like effects. In plants, loss or gain of a chromosome, although generally detrimental, often causes less severe restrictions on life. Harmful effects are observed but do not cause early deaths. This may be because many aneuploids are within what are presumably polyploid plant species.

Ford (1960) has collected the data on 13 different phenotypes that could come under suspicion of chromosomal etiology as examined by a number of workers. Careful cytologic examination of patients suffering from one or another of these diseases has shown that the idiograms were normal in both number and structure of the chromosomes. The disease conditions were: acrocephalosyndactyly, arachnodactyly

(Marfan's syndrome), chondrodystrophy, Crouzon's disease, epiloia, gargoylism, Gaucher's disease, hypopituitary dwarfism, juvenile amaurotic idiocy, Laurence-MoonBiedl syndrome. Little's disease, osteogenesis imperfecta, phenylketonuria, and anencephalic types. To this list Sandberg, Koepf , Crosswhite and Hauschka (1960) have now been added neurofibromatosis, Lowe's syndrome, and pseudohypoparathyroidism.

F. SEX RATIO IN MAN

Sex ratio studies on human and other animal populations have always been large in volume. The period since 1938 is no exception. Geissler's (1889) data on family sex ratios, containing more than four million births, have been reviewed and questions raised by several later analysts. Edwards (1958) has reanalyzed the clata from this population and considered these points and


reviewed the problems in the light of the following questions: (1) Does the sex ratio vary between families of the same size? (2) Do parents capable of producing only unisexual families exist? (3) Can the residual deviations in the data be satisfactorily explained? Probability analyses were based on Skellam's modified binomial distribution, a special case of the hypergeometrical. The following conclusions were drawn. The probability of a birth being male varies between families of the same size among a complete cross-section of this 19th century German population. There is no evidence for the existence of parents capable of producing only unisexual families. With the assumption that proportions of males vary within families, the apparent anomalies in the data appear to be explicable. These studies have a bearing on the variances observed in further work dealing with family differences such as that of Cohen and Glass ( 1959) on the relation of ABO blood groups to the sex ratio and that of Novitski and Kimball (1958) on birth order, parental age, and sex of offspring. Novitski and Kimball's data are of basic significance, for the interpretations are based on a large volume of material covering a one-year period in which improved statistical techniques were utilized in the data collection, in showing that within these data sex ratio variation showed relatively little dependence on age of mother, whereas it did show dependence on age of father, birth order, and interactions between them. These observations have direct bearing on the larger geographic differences observed in sex ratios as discussed by Russell (1936) and have recently been brought to the fore through the studies of Kang and Cho (1959a, b). If these data stand the tests for biases, they are of significance in showing Korea to have one of the highest secondary sex ratios of any region, 113.5 males to 100 females, as contrasted with the American ratio of about 106 males to 100 females. Of similar interest is the lower rate of twin births, 0.7 per cent in Korea vs. about 1 per cent in Caucasian populations and the fact that nearly twothirds of these tW'in births in Korean peoples are identical, whereas those in the Caucasian groups are only about half that number. The reasons for these differences must


66


BIOLOGIC BASIS OF SEX


lie in the relations of the human X and Y chromosomes and autosomes and the balance of their contained genes. Little or nothing is known about how these factors operate in the given situations.

Acknowledgment. In formulating and organizing the material on which this paper is based I have been fortunate in the helpful discussions and analytical advice contributed so generously by Doctors H. L. Cai'son, K. W. Cooper, H. V. Grouse, C. W. Metz, S. B. Pipkin, W. C. Rothenbuhler, and H. D. Stalker, and others having primary research interests in this field. To them, and particularly to my research associates Doctors S. T. C. Fung and Janice Stadler, our secretary Gladys M. Dicke and to my wife, ]\Iarie S. Gowen, I tender grateful acknowledgment for their contributions to the manuscript. Direct reference is made to some 300 investigations in the body of the paper but the actual number, many of which could equally well have been incorporated, that furnished background to these advances is much larger, more than 1600. To this vast effort toward understanding the foundations for sex we are all indebted.

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