GENETIC ASPECTS OF SEXUAL DIFFERENTIATION

Meiosis, Which Occurs Only in Germ Cells, Gives Rise to Male and Female Gametes

Mitosis is the only kind of cell division that occurs in somatic cells. Mitosis results in the formation of two identical daughter cells (Fig. 52-1A), each having the same number of chromosomes (i.e., 46 in humans) and same DNA content as the original cell. Mitosis is a continuum consisting of five phases: prophase, prometaphase, metaphase, anaphase, and telophase. One reason for the genetic identity of the two daughter cells is that no exchange of genetic material occurs between homologous chromosomes, so sister chromatids (i.e., the two copies of the same DNA on a chromosome) are identical. A second reason for the genetic identity is that the sister chromatids of each chromosome split, one going to each daughter cell during anaphase of the single mitotic division. Meiosis occurs only in germ cells. In both sexes, the production of gametes necessitates that germ cells, after having undergone several mitotic divisions, undergo two meiotic divisions (see Fig. 52-1B) to reduce the number of chromosomes from the diploid number (46) to the haploid number (23). Because of this halving of the diploid number of chromosomes, meiosis is often referred to as a "reduction division." Meiosis is a continuum composed of two phases: the homologous chromosomes separate during meiosis I, and the chromatids separate during meiosis II. As cells enter meiosis I, the chromosomes duplicate so that the cells have 23 pairs of duplicated chromosomes (i.e., each chromosome has two chromatids). During prophase of this first meiotic division, homologous pairs of chromosomes-22 pairs of autosomal chromosomes (autosomes) plus a pair of sex chromosomes-exchange genetic material. This genetic exchange is the phenomenon of "crossing over" that is responsible for the "recombination" of genetic material between maternal and paternal chromosomes. At the completion of meiosis I, the daughter cells have a haploid number (23) of duplicated, crossed-over chromosomes. During meiosis II, no additional duplication of DNA takes place. The chromatids simply separate so that each of the daughter cells has a haploid number of unduplicated chromosomes. When two haploid gametes fuse, a mature oocyte from the mother and a mature spermatozoan from the father, a new individual is formed, a diploid zygote. Here we will illustrate meiosis by following the production of female gametes, or ova. The analogous process of producing males gametes, or spermatozoa, is discussed on p. 1131. In the female, oocyte maturation begins in the fetal ovary. The primordial germ cells migrate from the hind gut to the gonadal ridge. These primordial germ cells develop into oogonia, or immature germ cells, which in turn proliferate in the fetal ovary by mitotic division. By 6 to 7 weeks' intrauterine life, a total of approximately 10,000 oogonia are present. This figure is the result of migration and rapid mitotic division; up until this time, no atresia occurs (p. 1157). By about 8 weeks' gestation, approximately 600,000 oogonia are present, and they may enter prophase of the first meiosis and become primary oocytes. From this point on, the number of germ cells is determined by three ongoing processes: mitosis, meiosis, and atresia. The number of germ cells peaks at 6 to 7 million around 20 weeks' gestation, and about 2.5 million primary oocytes are present at birth. During prophase of the first meiosis, when the cells have a duplicated set of 23 chromosomes (22 duplicated pairs of autosomal chromosomes and one pair of duplicated X chromosomes), crossing over occurs. Meiosis is arrested in prophase I. Thus, the female germ cells are primary oocytes at birth, and they remain primary oocytes-arrested in prophase I of meiosis-until just before ovulation, many years later, when meiosis is completed and the first polar body is extruded (p. 1159). This prolonged state of meiotic arrest is known as the dictyotene stage.
The Genetic Sex of a Zygote Is Established at Fertilization, When an X-or Y-Bearing Sperm Fertilizes an Oocyte

The sex chromosomes that the parents contribute to the offspring determine the genotypic sex of that individual. The genotypic sex determines the gonadal sex, which in turn determines the phenotypic sex that becomes fully established at puberty. Thus, sex-determining mechanisms established at fertilization direct all later ontogenetic processes (processes that lead to the development of an organism) involved in male-female differentiation.
Figure 52-1 Meiosis and mitosis. A, In the process of mitosis, the two daughter cells are genetically identical to the mother cell. B, In the process of meiosis, the four daughter cells are haploid. Cell division I produces both recombination (i.e., crossing over of genetic material between homologous chromosomes) and the reduction to the haploid number of chromosomes. Cell division II separates the chromatids of each chromosome, just as in mitosis. Meiosis in Males versus Females
page 1106 page 1107

page 1107 page 1108

Figure 52-2 The location of the testis-determining region of the Y chromosome and an example of translocation. A, The normal human has 22 pairs of autosomal chromosomes (autosomes) as well as a pair of sex chromosomes. Females have two X chromosomes, whereas males have one X and one Y chromosome. B, The Y chromosome is much smaller than the X chromosome. Giemsa staining of the chromosome results in alternating light and dark bands, some of which are shown here. The short or "p" arm of the Y chromosome is located above the centromere, whereas the long or "q" arm is located below. The numbers to the left of the chromosome indicate the position of bands. The testis-determining factor (TDF) is the SRY gene. C, Crossing-over events between normal X and Y chromosomes of the father can generate an X chromatid that contains a substantial portion of the TDF region and a Y chromatid that lacks its TDF. The figure shows both an equal and an unequal recombination event. If a sperm cell bearing an X chromosome with a translocated TDF fertilizes an ovum, the result is a male with a 46, XX karyotype, because one of the X chromosomes contains the TDF. Conversely, if the sperm cell carries a Y chromosome lacking its TDF, the result can be a 46, XY individual that appears to be female.

The process of fusion of a sperm and an ovum is referred to as fertilization, which is discussed in Chapter 55. Fusion of a sperm and egg-two haploid germ cells-results in a zygote, which is a diploid cell containing 46 chromosomes (Fig. 52-2A), 22 pairs of somatic chromosomes (autosomes) and a single pair of sex chromosomes. In the female, these sex chromosomes are both X chromosomes, whereas males have one X and one Y. When the karyotypes of normal females and males are compared, two differences are apparent: (1) among the 23 pairs of chromosomes in the female, 8 pairs-including the two X chromosomes-are of similar size, whereas males have only 7 such pairs. (2) Instead of a second X chromosome, males have a Y chromosome that is small and acrocentric (i.e., the centromere is located at one end of the chromosome). This chromosome is the only such chromosome that is not present in the female. In the offspring, 23 of the chromosomes-including 1 of the sex chromosomes-are from the mother, and 23-including the other sex chromosome-come from the father. Thus, the potential offspring has a unique complement of chromosomes differing from those of both the mother and father. The ovum provided by the mother (XX) always provides an X chromosome. Because the male is the heterogenetic (XY) sex, half the spermatozoa are X bearing whereas the other half are Y bearing. Thus, the type of sperm that fertilizes the ovum determines the sex of the zygote. X-bearing sperm produce XX zygotes that develop into females with a 46, XX karyotype, whereas Y-bearing sperm produce XY zygotes that develop into males with a 46, XY karyotype. Thus, the genetic sex of an individual is determined at the time of fertilization. The Y chromosome appears to be the fundamental determinant of sexual development. When a Y chromosome is present, the individual develops as a male; when the Y chromosome is absent, the individual develops as a female. In embryos with abnormal sex chromosome complexes, the number of X chromosomes is apparently of little significance.

Two Intact X Chromosomes Are Required for Differentiation of the Indifferent Gonad as a Normal Ovary
page 1108 page 1109

GONADAL DYSGENESIS

The best known example of gonadal dysgenesis is a syndrome referred to as Turner syndrome, a disorder of the female sex characterized by short stature, primary amenorrhea, sexual infantilism, and a number of other congenital abnormalities. The cells in these individuals have a total number of 45 chromosomes and a normal karyotype, except that they lack a second sex chromosome. The karyotype is 45, XO. Examination of the gonads of individuals with Turner syndrome reveals so-called streak gonads, firm, flat, glistening streaks lying below the fallopian tubes. These glands generally do not show evidence of either germinal or secretory elements but, instead, are largely composed of connective tissue arranged in whorls suggestive of ovarian stroma. Individuals with Turner syndrome have normal female differentiation of both the internal and external genitalia, although these genitalia are usually small and immature for the patient's age. Partial deletion of the X chromosome may also result in the full Turner phenotype, particularly if the entire short arm of the X chromosome is missing. The so-called ring chromosome is an example of an abnormality of the second sex chromosome. A ring chromosome is a small round or oval chromosome that often appears as a single black dot without a central hole. It forms as a result of a deletion and subsequent joining of the two free ends of the chromosome. Formation of a ring chromosome is, in effect, a deletion of the X chromosome and produces the same characteristics as gonadal dysgenesis. The aforementioned defects result from disordered meiosis. A central genetic lesion is an abnormality of the second sex chromosome in some or all of the cells of the person. In at least half of affected individuals, this abnormality appears to be total absence of the second X chromosome. In others, the lesion is structural, as shown by the presence of ring chromosomes that have lost some genetic material. In at least a third of cases, these lesions appear as parts of a mosaicism; that is, some of the germ cells carry the aberrant or absent chromosome, whereas the rest are normal. The primary sex organs of an individual are the gonads. Gene complexes on sex chromosomes determine whether the indifferent gonad differentiates into a testis or an ovary. As discussed later, the Y chromosome exerts a powerful testis-determining effect on the indifferent gonad. The primary sex cords differentiate into seminiferous tubules under the influence of the Y chromosome. In the absence of a Y chromosome, the indifferent gonad develops into an ovary. The differentiated gonads in turn determine the sexual differentiation of the genital ducts and external genitalia. The indifferent gonad is composed of an outer cortex and an inner medulla. In embryos with an XX sex chromosome complement, the cortex develops into an ovary and the medulla regresses. On the other hand, in embryos with an XY chromosome complex, the medulla differentiates into a testis and the cortex regresses. Loss of a sex chromosome causes abnormal gonadal differentiation or gonadal dysgenesis. Loss of one of the X chromosomes of the XX pair results in an individual with an XO sex chromosome constitution and ovarian dysgenesis (see the box titled Gonadal Dysgenesis). Thus, two X chromosomes are necessary for normal ovarian development. In an XO individual, the gonads appear only as streaks on the pelvic sidewall in the adult. Because these streak gonads of XO individuals may contain germ cells, germ cell migration apparently can occur during development. The absence of only some genetic material from one X chromosome in an XX individual-for example, as might occur as a result of breakage or deletion-may also cause abnormal sexual differentiation.
The Testis-Determining Gene Is Located on the Y Chromosome

It has been clearly established that a Y chromosome (see Fig. 52-2B), with rare exception (see later), is necessary for normal testicular development. Thus, it stands to reason that the gene that determines organogenesis of the testis is normally located on the Y chromosome. This so-called testis-determining factor (TDF) has been mapped to the short arm of the Y chromosome and, indeed, turns out to be a single

gene called SRY (for "sex-determining region Y"). The SRY gene encodes a transcription factor that belongs to the high-mobility group (HMG) superfamily of transcription factors. The family to which SRY belongs is evolutionarily ancient. One portion of SRY, the 80-amino-acid HMG box, which actually binds to the DNA-is highly conserved among members of the family. Rarely, the TDF may also be found translocated on other chromosomes. One example is an XX male (see Fig. 52-2C), an individual whose sex chromosome complement is XX but whose phenotype is male. During normal male meiosis, human X and Y chromosomes pair and recombine at the distal end of their short arms. It appears that most XX males arise as a result of an aberrant exchange of genetic material between X and Y chromosomes in the father; in such cases, the TDF is transferred from a Y chromatid to an X chromatid. If the sperm cell that fertilizes the ovum contains such an X chromosome with a TDF, the resultant individual will be an XX male.
Phenotypic Differentiation Is Modulated by Endocrine and Paracrine Messengers

Just as an individual's genes determine whether the indifferent gonad develops into an ovary or a testis, so does the sex of the gonad dictate the gonad's endocrine and paracrine functions. Normally, chemical messengers-both endocrine and paracrine-produced by the gonad determine the primary and secondary sexual phenotypes of the individual. However, if the gonads fail to produce the proper messengers, if other organs (e.g., the adrenal glands) produce abnormal levels of sex steroids, or if the mother is exposed to chemical agents (e.g., synthetic progestins, testosterone) during pregnancy, sexual development of the fetus may deviate from that programmed by the genotype. Therefore, genetic determination of sexual differentiation is not irrevocable; numerous internal and external influences during development may modify or completely reverse the phenotype of the individual, whatever the genotypic sex.
page 1109 page 1110

DISCORDANCE BETWEEN GENOTYPE AND GONADAL PHENOTYPE

A group of patients have been reported who have no recognizable Y chromosome but do have testes. Some of these individuals are 46, XX and are true hermaphrodites; that is, they possess both male and female sex organs. Other patients have mixed gonadal dysgenesis-a testis plus a streak ovary-and a 45, XO karyotype. Some are pseudohermaphrodites; that is, affected individuals have only one type of gonadal tissue, but morphologic characteristics of both sexes. All these patterns can result from mosaicisms (e.g., 46, XY/46, XX) or from translocation of the SRY gene (Fig. 52-2C)-which normally resides on the Y chromosome-to either an X chromosome or an autosome. A "normal" testis in the absence of a Y chromosome has never been reported. Another group of individuals with a sex chromosome complex of 46, XY have pure gonadal dys-genesis-streak gonads, but no somatic features of XO. In the past it has been assumed that these individuals possess an abnormal Y chromosome. Perhaps the SRY gene is absent or its expression is somehow blocked. An abnormal chemical environment can affect sexual differentiation at the level of either the genital ducts or the development of secondary sex characteristics. Higher vertebrates, including humans, have evolved highly elaborate systems of glands and ducts for transporting gametes. This system of glands and conduits collectively comprises the accessory sex organs. Together with the gonads, these accessory sex organs constitute the primary sex characteristics. The gonads produce and secrete hormones that condition and develop these accessory sex organs and, to a large extent, influence phenotypic sexual differentiation; that is, they induce either "maleness" or "femaleness" and influence the psychobiologic phenomena involved in sex behavior. Secondary sex characteristics are external specializations that are not essential for the production and movement of gametes; instead, they are primarily concerned with sex behavior and with the birth and nutrition of offspring. Examples include the development of pubic hair and breasts. Not only do the sex steroids produced by the gonads affect the accessory sex organs, they also modulate the physiologic state of the secondary sex characteristics toward "maleness" in the case of the testes and "femaleness" in the case of the ovaries.
Printed from STUDENT CONSULT: Medical Physiology (on 28 August 2006) 2006 Elsevier