sexology

GENETICS AND SEX

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The Sex Chromosomes
Sperm and Ovum Production
Chromosomes and Anomalous Sexual Development
Genetics and Anomalous Sexual Development

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Genetics, the science of heredity, seeks to explain how characteristics and traits are passed from one generation to the next. Chromosomes, the hereditary material studied by geneticists, are highly structured chains of DNA (deoxyribonucleic acid) with specific sequences of bases and amino acids. Functional units of these DNA chains are known as genes. Chromosomes and genes are the essential foundation of and mechanism for all structural growth and functioning of individual cells and organisms composed of cells. Chromosomes and their genes also allow a male and a female to transmit their characteristics and produce offspring like themselves. When sexually mature male and female individuals produce sperm and ova, the resulting gametes contain half the number of chromosomes in the adult body cells, so that fertilization, or union of the sperm and ovum, gives the resulting new organism the full chromosome complement of the adult parents.

Our sexuality includes all those aspects of our being—the biological, hormonal, neural, psychological, and social—that make us gendered persons, male or female. The relationship between genes and sex is twofold. At fertilization, when a sperm unites with an ovum, the combination of sex chromosomes (in humans, the X and Y chromosomes) determines the essential sexual character of the resulting embryo. Following fertilization, genes on the X and Y chromosomes regulate and direct the production of proteins and enzymes by other genes on the other chromosomes (known as autonomies) to produce the appropriate sexual anatomy, sexual differentiation, and sexual function, along with the other characteristics and functions of our bodies. The expression of the genes is affected by the ever-changing cellular, maternal uterine, hormonal, and outside environments.

The Sex Chromosomes

In genetics, sex chromosomes are distinguished from other chromosomes, the autosomes, because the former are different in males and females and contain genes related to primary sexual differentiation. Many, though not all, organisms possess specialized chromosomes that are associated with being either male or female. These specialized chromosomes segregate during production of the reproductive cells, the egg and sperm, so that at fertilization when the sperm and egg unite, each sex receives its own appropriate complement of sex-determining chromosomes.

In the animal kingdom, several different types of sex chromosomes exist. In the human male, the normal chromosome complement of somatic cells is 44 autosomes, or 22 pairs of body chromosomes, plus an X and a Y chromosome, for a total of 46 chromosomes in each cell nucleus. Having two complete homologous sets of autosomes and two sex chromosomes is referred to as the diploid condition. Human females have 44 autosomes arranged in 22 pairs plus two X chromosomes.

In humans, the X chromosome is much larger than the Y chromosome. The X chromosome contains many genes responsible for the development of the central nervous system, so at least one is essential for embryonic development and a viable organism. Other genes on the X chromosome are associated with clinically significant disorders such as hemophilia, Duchenne muscular dystrophy, and color blindness. Two X chromosomes are essential for the development of ovaries that can produce ova.

The smaller Y chromosome occurs in the human male. The crucial gene on the Y chromosome is known as the Testes Determining Factor gene (TDF). Active in the fifth week of gestation, this gene directs the commitment of the undifferentiated gonads to testicular development in weeks six through nine. If the embryo lacks the TDF gene, its development follows the inherent female path, with ovaries and female sexual anatomy starting to develop in week 12. When the isolated TDF is transplanted into very young mouse embryos, chromosomally female (XX) embryos develop into newborns with normal male anatomy and behavior.

Sperm and Ovum Production

Sexual reproduction, with the offspring developing from the union of a sperm and an egg (ovum), requires that the sperm and egg have exactly half the normal diploid complement of chromosomes that occur in the body cells of the parents. In the male gamete, or sperm, this haploid chromosome number includes 22 autosomes plus either an X or a Y chromosome. The normal egg or ovum has a haploid complement of one set of 22 autosomes and a single X.

To reduce the diploid chromosome number to the haploid status of the sperm or egg, primordial germ cells in the ovaries and testes undergo meiosis, a two-stage process of cell division. During the resting (interphase) stage before meiosis begins, the chromosomes of the primordial germ cell replicate. Homologous pairs of duplicated chromosomes then synapse, or pair up. A bipolar spindle forms as the paired chromosomes arrange themselves on an equatorial plate The spindle fibers then attach to the homologous chromosomes and separate them. At the end of this first stage, one duplicated chromosome from each homologous pair has migrated to one pole of the spindle, while its mate migrates to the opposing pole. In effect, the chromosome number in these intermediate germ cells is haploid.

During the second stage, two new spindles form at each of the two poles of the original spindle. The twinned chromosomes do not replicate themselves a second time. Instead, they arrange themselves on new equatorial plates, and the duplicated strands of each chromosome are pulled apart by the new spindle fibers. After these DNA strands migrate to opposite poles in each of the two intermediate daughter cells, four daughter cells are produced, each with a haploid chromosome complement.

In production of the egg or ovum, meiosis results in three polar bodies that disintegrate and die producing a single ovum. In sperm production, the result is four functional sperm, from a single spermatogonial cell.

Fertilization, the union of the egg and sperm, restores the diploid chromosome complement and gives the offspring the same chromosomal makeup as its parents.

Sometimes, during production of the egg or sperm, two paired or replicated chromosomes may fail to separate. As a result of this nondisjunction, one germ cell ends up with both chromosomes of a homologous pair, while the other daughter cell is missing that chromosome. Fertilization of a sperm or egg with an extra chromosome can result in Down's syndrome (trisomy 21 or 47, 21+) and Klinefelter's syndrome (47, XXY). Fertilization of a sperm or egg with a missing chromosome can result in Turner's syndrome (45, XO). Nondisjunction of a sex chromosome during cell division in the first few days after fertilization can result in a chromosome mosaic condition that may affect sexual differentiation.

An interesting aspect of the sex chromosomes results from the fact that females have two X chromosomes and males only one X. This gives females a double dose of the X chromosome genes and their products. Female body cells compensate for this phenomenon by partially inactivating one X chromosome in a so-called sex chromatin or Barr body on the nuclear membrane of somatic cells. Thus, in normal female body cells, one X chromosome remains active and functional, and the second X chromosome is partially inactivated. In cells with abnormal chromosome complements, such as 47, XXY and multiple X, the number of Barr bodies is always one fewer than the number of X chromosomes in the cell. The presence or absence of Barr bodies in somatic cells obtained by buccal smear, amniocentesis, or chorionic villi sampling is used in ascertaining chromosomal sex status. Individuals with Turner's syndrome (45, X0) and 46, XY males lack a Barr body; 47, XXY individuals with Klinefelter's syndrome have one Barr body.

Chromosomes and Anomalous Sexual Development

The sexual development of a fetus may deviate from the male or female path either because of an abnormal sex chromosome complement or because of a mutated gene. A missing X chromosome in a Turner's syndrome female and the addition of an X chromosome in a Klinefelter's syndrome male provide the more common examples of sex chromosome variations. The mutation of a single gene can result in conditions known as androgen insensitivity, congenital virilizing adrenal hyperplasia (CVAH), and DHT deficiency syndrome.

A female with Turner's syndrome (or ovarian agenesis) has a normal complement of 22 pairs of autosomes or body-regulating chromosomes, but only one X chromosome instead of the usual XX Hence the genetic notation 45, XO. These individuals develop a female body type with undeveloped, nonfunctioning ovaries, persistent juvenile genitals, and other symptoms Although the second X chromosome in a normal 46, XX female is partially inactivated, this second X chromosome is essential for ovarian development Approximately one in 4,000 newborns has Turner's syndrome. This is lower than expected because many fetuses with this condition miscarry.

Although females with Turner's syndrome lack the second X chromosome, they may appear reasonably normal anatomically until puberty, when a lack of estrogen production in the nonfunctional streak ovaries results in a lack of sexual maturation and secondary sex characteristics. Other symptoms may include webbed skin on the back of the neck, low nape hairline, retarded growth, obesity, spinal deformities, triangular-shaped face, prominent ears, small jaw, hearing defects, and myopia. Swollen tissue and dwarfism are common. Language, motor, and learning deficits are often reported, along with a retarded spatial-nonverbal IQ. Right brain hemisphere impairment may result in low self-esteem, reduced self-confidence, and lack of social adept-ness. Reduced spatial and face-interpreting skills may cause adolescent emotional and social problems.

About one in 500 newborn males has Klinefelter's syndrome, characterized by very small, sterile testes. The cells of individuals with this condition have a full set of 22 paired body chromosomes, the usual X and Y chromosomes, and at least one extra X chromosome. Roughly 80 percent are 47, XXY. Much rarer are 48, XXXY and mosaics, with different genotypes in two cell lines and two or more X chromosomes and one or two Y chromosomes. While the condition is often diagnosed in childhood because of the very small testes, diagnosis is more common in adolescence, since clinical symptoms appear mostly after puberty.

Abnormal development of the testes and sterility with no sperm production result when elastic connective tissue replaces the germinal cells in the testes. An affected male is still capable of erection and coitus, although secondary erectile dysfunction may result from response to lowered libido and gynecomastia, or female breast development. Other symptoms include eunuchoid body with poor male secondary sex characteristics, which give a feminine appearance. In half the cases, the gynecoid impression is accented by gynecomastia. Penile size is usually normal, although pubic hair may be sparse and female in pattern. The axillary and facial hair is also usually sparse. Klinefelter's males are tall and slim, with long arms and legs.

Some experts report that most Klinefelter's individuals are retarded, some severely, while others report that a majority have normal intellectual development. Social adjustment may be poor, in part in response to the tall, eunuchoid body and gynecomastia. Personality and character-trait disturbances, emotional and behavioral troubles, alcoholism, minor criminality, and outright psychosis are common, but their frequencies are not documented.

Individuals can have either Turner's or Klinefelter's syndrome because of a mosaicism in their sex chromosomes, with different combinations of sex chromosomes in two or more cell lines. Also, two embryonic masses, one with 46, XX and the other with 46, XY, may fuse as they move through the Fallopian tube prior to implantation. In these individuals, symptoms vary depending on which cells in the body have the XX and which the XY chromosome complement, Fertilization of one ovum by two sperm and other variations can also result in genetic and sexual mosaicism.

Genetics and Anomalous Sexual Development

Some fetuses have a defective recessive gene on the X chromosome that prevents the normal production of receptors that are necessary for testosterone and its derivatives to enter body cells. Affected individuals have a male chromosome complement (46, XY), testes, and a male balance of hormones. However, the cells of their bodies cannot react to the masculinizing message of testosterone circulating in the blood. This condition is known as testicular feminization or androgen insensitivity syndrome.

Since the circulating testosterone cannot enter its normal target cells, the body is not masculinized but follows the inherent female path. In the androgen insensitivity syndrome, testosterone cannot cause the Wolffian ducts to develop into the internal male system. However, the Mullerian inhibiting hormone prevents female development of the Mullerian ducts. The external genitals differentiate as female, except for a short, blind vagina that is usually not deep enough to allow for coitus unless dilated or surgically lengthened during adolescence. At birth, such individuals appear to be anatomically normal females and are so assigned and raised by their parents. Affected individuals have no menstrual cycle and are infertile. Breast and secondary sex characteristic development is normal for a female because of estrogens from the testes and adrenal glands. However, lactation is not possible.

Another genetic variation that alters the path of sexual development is congenital virilizing adrenal hyperplasia. CVAH can occur in either a male or a female, leading to a pseudohermaphrodite condition. An affected newborn female has virilized, ambiguous genitals. Affected males experience premature puberty.

The immediate result of the genetic mutation behind CVAH is varying degrees of deficiency in the adrenal cortical enzymes—cortisol and aldosterone—needed for synthesis of various steroid sex hormones. The reduced sex hormone output triggers an increase in adrenocorticotropic hormone production, which in turn causes overdevelopment of the adrenal glands and overproduction of androgens. Adrenal malfunction begins before birth and continues unless treated. When left untreated, the severe form is lethal. Treatment can prevent premature death and postnatal virilization, although prenatally virilized females require plastic surgery.

A third genetic mutation that alters sexual development is dihydrotestosterone (DHT) deficiency, or 5-alpha-reductase deficiency. This form of pseudohermaphroditism results from a genetic mutation that creates a deficiency of the enzyme needed to convert testosterone into DHT. DHT is responsible for the masculniization of the external genitals from a bipotential set of primordia.

Affected individuals have 46, XY and testes. The newborn has ambiguous external sexual anatomy with a clitoral-like phallus and more or less fused, scrotal-like labia. Internal duct differentiation is usually male. The affected infant is usually gender-assigned and raised as a female However, at puberty, the surge of testosterone in such individuals may be sufficient to trigger partial virilization, with the clitoral-like phallus developing into a small penis; weak male secondary sex characteristics also develop.

In the small rural village of Salinas in the Dominican Republic, where most cases have been reported, the "conversion" of a daughter into a son is acceptable because of the strong patriarchal tradition. The affected children are subject to some ridicule, however, being referred to as quevote ("penis at 12") or machihembra ("first woman, then man"). When the condition occurs in more developed countries, the usual result is much more negative, with severe psychological trauma.

In cases where DHT-deficient children have been clinically and socially raised and conditioned as girls from birth onward with surgical feminization, they become women with a heterosexual orientation as a female, despite chromosomal and gonadal status as male. The extent and success of pubertal psychosexual adjustment, shifting from a female to a male gender identity, is widely disputed and debated.

In summary, the X and Y sex chromosomes and the Testes Determining Factor gene initiate and direct all sexual development, with some latitude of variant developments.