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
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whereas males have one X and one Y. XX karyotype.
. In embryos with abnormal sex chromosome complexes. XX karyotype.. The Y chromosome appears to be the fundamental determinant of sexual development. whereas Y-bearing sperm produce XY zygotes that develop into males with a 46. which is discussed in Chapter 55. the genetic sex of an individual is determined at the time of fertilization. 23 of the chromosomes-including 1 of the sex chromosomes-are from the mother. 52-2A). the type of sperm that fertilizes the ovum determines the sex of the zygote. these sex chromosomes are both X chromosomes. Thus. The short or "p" arm of the Y chromosome is located above the centromere. The Y chromosome is much smaller than the X chromosome. two differences are apparent: (1) among the 23 pairs of chromosomes in the female.e. 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. whereas males have only 7½ such pairs. 8 pairs-including the two X chromosomes-are of similar size. This chromosome is the only such chromosome that is not present in the female. Females have two X chromosomes. The ovum provided by the mother (XX) always provides an X chromosome. some of which are shown here. the number of X chromosomes is apparently of little significance. Fusion of a sperm and egg-two haploid germ cells-results in a zygote. In the offspring. if the sperm cell carries a Y chromosome lacking its TDF. whereas males have one X and one Y chromosome. Giemsa staining of the chromosome results in alternating light and dark bands. the individual develops as a male. C. XY karyotype. whereas the long or "q" arm is located below. A. because one of the X chromosomes contains the TDF. when the Y chromosome is absent. In the female. males have a Y chromosome that is small and acrocentric (i. When a Y chromosome is present. and 23-including the other sex chromosome-come from the father. The testis-determining factor (TDF) is the SRY gene. B. The numbers to the left of the chromosome indicate the position of bands. the result can be a 46.page 1107 page 1108
Figure 52-2 The location of the testis-determining region of the Y chromosome and an example of translocation. The normal human has 22 pairs of autosomal chromosomes (autosomes) as well as a pair of sex chromosomes. half the spermatozoa are X bearing whereas the other half are Y bearing. Thus. Because the male is the heterogenetic (XY) sex. which is a diploid cell containing 46 chromosomes (Fig. XY individual that appears to be female. If a sperm cell bearing an X chromosome with a translocated TDF fertilizes an ovum. X-bearing sperm produce XX zygotes that develop into females with a 46. When the karyotypes of normal females and males are compared. Thus. the result is a male with a 46. the individual develops as a female.
The process of fusion of a sperm and an ovum is referred to as fertilization. The figure shows both an equal and an unequal recombination event. Conversely. the centromere is located at one end of the chromosome). the potential offspring has a unique complement of chromosomes differing from those of both the mother and father. (2) Instead of a second X chromosome. 22 pairs of somatic chromosomes (autosomes) and a single pair of sex chromosomes.
Because these streak gonads of XO individuals may contain germ cells. germ cell migration apparently can occur during development. In embryos with an XX sex chromosome complement. This so-called testis-determining factor (TDF) has been mapped to the short arm of the Y chromosome and. and a number of other congenital abnormalities. Thus. whereas the rest are normal. A central genetic lesion is an abnormality of the second sex chromosome in some or all of the cells of the person. Individuals with Turner syndrome have normal female differentiation of both the internal and external genitalia. Formation of a ring chromosome is. are largely composed of connective tissue arranged in whorls suggestive of ovarian stroma. In the absence of a Y chromosome. As discussed later. with rare exception (see later). The cells in these individuals have a total number of 45 chromosomes and a normal karyotype. These glands generally do not show evidence of either germinal or secretory elements but. The absence of only some genetic material from one X chromosome in an XX individual-for example. Loss of a sex chromosome causes abnormal gonadal differentiation or gonadal dysgenesis. Examination of the gonads of individuals with Turner syndrome reveals so-called streak gonads. as shown by the presence of ring chromosomes that have lost some genetic material. the gonads appear only as streaks on the pelvic sidewall in the adult. two X chromosomes are necessary for normal ovarian development. primary amenorrhea. a disorder of the female sex characterized by short stature. sexual infantilism. the medulla differentiates into a testis and the cortex regresses. it stands to reason that the gene that determines organogenesis of the testis is normally located on the Y chromosome. the cortex develops into an ovary and the medulla regresses. In others. turns out to be a single
The Testis-Determining Gene Is Located on the Y Chromosome
It has been clearly established that a Y chromosome (see Fig. flat. in effect. XO. some of the germ cells carry the aberrant or absent chromosome. The so-called ring chromosome is an example of an abnormality of the second sex chromosome. this abnormality appears to be total absence of the second X chromosome. the Y chromosome exerts a powerful testis-determining effect on the indifferent gonad.Two Intact X Chromosomes Are Required for Differentiation of the Indifferent Gonad as a Normal Ovary
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The best known example of gonadal dysgenesis is a syndrome referred to as Turner syndrome. that is. 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). In at least half of affected individuals. except that they lack a second sex chromosome. a deletion of the X chromosome and produces the same characteristics as gonadal dysgenesis. particularly if the entire short arm of the X chromosome is missing. is necessary for normal testicular development. the lesion is structural. the indifferent gonad develops into an ovary. 52-2B). The karyotype is 45. The indifferent gonad is composed of an outer cortex and an inner medulla. The primary sex cords differentiate into seminiferous tubules under the influence of the Y chromosome. indeed. A ring chromosome is a small round or oval chromosome that often appears as a single black dot without a central hole. The aforementioned defects result from disordered meiosis. The primary sex organs of an individual are the gonads. Thus. firm. as might occur as a result of breakage or deletion-may also cause abnormal sexual differentiation. In at least a third of cases. It forms as a result of a deletion and subsequent joining of the two free ends of the chromosome. glistening streaks lying below the fallopian tubes. instead. Gene complexes on sex chromosomes determine whether the indifferent gonad differentiates into a testis or an ovary. Partial deletion of the X chromosome may also result in the full Turner phenotype. although these genitalia are usually small and immature for the patient's age. In an XO individual. in embryos with an XY chromosome complex. these lesions appear as parts of a mosaicism. On the other hand. The differentiated gonads in turn determine the sexual differentiation of the genital ducts and external genitalia.
the adrenal glands) produce abnormal levels of sex steroids. During normal male meiosis. Secondary sex characteristics are external specializations that are not essential for the production and movement of gametes. This system of glands and conduits collectively comprises the accessory sex organs. 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.gene called SRY (for "sex-determining region Y"). the TDF may also be found translocated on other chromosomes. Some are pseudohermaphrodites. to a large extent. or if the mother is exposed to chemical agents (e. XX) or from translocation of the SRY gene (Fig. In the past it has been assumed that these individuals possess an abnormal Y chromosome. Rarely. synthetic progestins.g. these accessory sex organs constitute the primary sex characteristics. which actually binds to the DNA-is highly conserved among members of the family.g. the 80-amino-acid HMG box. Some of these individuals are 46. genetic determination of sexual differentiation is not irrevocable.. whatever the genotypic sex. However. 52-2C)-which normally resides on the Y chromosome-to either an X chromosome or an autosome. but morphologic characteristics of both sexes. Not only do the sex steroids produced by the gonads affect the accessory sex organs. 52-2C). If the sperm cell that fertilizes the ovum contains such an X chromosome with a TDF. XX and are true hermaphrodites. they induce either "maleness" or "femaleness" and influence the psychobiologic phenomena involved in sex behavior.
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DISCORDANCE BETWEEN GENOTYPE AND GONADAL PHENOTYPE
A group of patients have been reported who have no recognizable Y chromosome but do have testes. Therefore.
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. The gonads produce and secrete hormones that condition and develop these accessory sex organs and. they possess both male and female sex organs. Normally. testosterone) during pregnancy. including humans. Other patients have mixed gonadal dysgenesis-a testis plus a streak ovary-and a 45. that is. Together with the gonads. in such cases. One example is an XX male (see Fig. the resultant individual will be an XX male. Perhaps the SRY gene is absent or its expression is somehow blocked. human X and Y chromosomes pair and recombine at the distal end of their short arms.. A "normal" testis in the absence of a Y chromosome has never been reported. influence phenotypic sexual differentiation. Examples include the development of pubic hair and breasts. affected individuals have only one type of gonadal tissue. XY/46. if other organs (e. The SRY gene encodes a transcription factor that belongs to the high-mobility group (HMG) superfamily of transcription factors. they are primarily concerned with sex behavior and with the birth and nutrition of offspring. sexual development of the fetus may deviate from that programmed by the genotype. that is. that is. an individual whose sex chromosome complement is XX but whose phenotype is male. 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. One portion of SRY.
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. have evolved highly elaborate systems of glands and ducts for transporting gametes. XY have pure gonadal dys-genesis-streak gonads. Another group of individuals with a sex chromosome complex of 46. if the gonads fail to produce the proper messengers.. XO karyotype. the TDF is transferred from a Y chromatid to an X chromatid. The family to which SRY belongs is evolutionarily ancient. All these patterns can result from mosaicisms (e.g. 46. instead. 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. but no somatic features of XO. chemical messengers-both endocrine and paracrine-produced by the gonad determine the primary and secondary sexual phenotypes of the individual. so does the sex of the gonad dictate the gonad's endocrine and paracrine functions. numerous internal and external influences during development may modify or completely reverse the phenotype of the individual.