Sex determination of a person occurs in terms of the XY-mechanism (this heterogametic sex is male) and includes three stages: chromosomal, gonadal, and phenotypic.
The presence or absence of Y-chromosome is crucial for determining the sex. In the absence of the Y-chromosome, there occurs differentiation of gonads into ovaries and, as a result, a female organism develops. The physiological basis of sex determination mechanism is bisexuality of embryonic gonads. In such gonads Mullerian duct and Wolff channel are simultaneously present; they are the beginning of the genital tract of a male and a female respectively. Primary sex determination begins with the appearance of specialized cell lines in gonads called Sertoli cells. The purpose of the paper is to analyze primary and secondary sex determination and aberrations that lead to intersex conditions.
Central Dogma of Molecular Biology Overview
The central dogma of molecular biology is the generalization observed in nature’s general rule of realization of genetic information. The dogma states that information is transmitted from nucleic acid to protein, but not in the reverse direction. The rule was formulated by Francis Crick in 1958 and brought into line with the accumulated data in 1970. The transition of genetic information from DNA to RNA and then – from RNA to a protein is universal for any and all cellular organisms and underlies macromolecule biosynthesis. The replication of the genome corresponds to the information transfer of DNA → DNA. In nature, there are also passages RNA → RNA and RNA → DNA (e.g. some viruses), and changing the conformation of proteins transferred from molecule to molecule.
Overview of Sex Determination in Humans
Sex determination is a process of the development of phenotypic structures that results from the exposure to the hormones produced in accordance with the development of the gonads. The development of sex differences, or sexual differentiation, includes the development of the genitalia and internal reproductive tract, mammary glands, as well as hair on the body, all playing a crucial role in gender identity.
Formation of sex differences begins with the formation of gonosoms (sex chromosomes). During the formation of phenotypic differences between male and female, organisms of undifferentiated zygote meet complex mechanisms. The organism is female if it has two X-chromosomes, and male if it contains one Y-chromosome and one X-chromosome. In the early stages of embryonic development of the human body, all have the same internal structure. The presence of SRY gene on the Y-chromosome causes the development of the testes in the male body and the subsequent production of hormones. Thus, sex determination is a complex mechanism with many factors involved.
Primary and Secondary Sex Determination
Genetic sex is determined at the time of fertilization and is driven by heterogametic nature of male. The formation of two types of spermatozoon provides a numerical equality of the sexes in the next generation. However, the actual sex ratio in the population changes with age. Therefore, they distinguish the primary, secondary, and tertiary sex ratio.
The general scheme of the primary sex determination is as follows: there is a specific signal switching on a particular gene in the early stages of embryonic development. This gene, in turn, stimulates the growth and differentiation of gonads in a certain direction, and the operation of the latter determines the development of sexual characteristics.
The biological basis of genetic sex determination mechanism is bisexuality of embryonic gonads (bisexuality in this case means equal probability of the primary gonads to develop into testes or ovaries). The obligatory condition for the normal development of the reproductive system is the presence of functionally active receptors for sex hormones. Mutations in the genes that encode these receptors lead to the same consequences as the absence of the hormone in the body. For example, mutations in the androgen receptor gene (localized on X chromosome, p 11-12) lead to the emergence of testicular feminization syndrome. In summary, the formation of the sex and the normal development of the reproductive system result from the presence of Y-chromosome in the cells of the embryo, the formation of hormones that affect the reproductive organs, and the presence of functionally active receptors, through which hormones realize their action. The formation of sexual characteristics stems from the genes located in different chromosomes (autosomes and sex), so the knowledge of the functional activity of these genes helps to explain discrepancies of genetic and phenotypic sex, as well as the emergence of human hermaphroditism. The main causes of these disorders are either chromosomal mutation (deletion or translocation site Y-chromosome with SRY gene) or mutations in the genes coding for hormones and hormone receptors. Secondary sex determination is responsible for the appearance of the external genitalia and secondary sex characteristics and relates to primary sex determination.
Intersexuality is the variations of the sexual characteristics in humans and animals that do not fit into the traditional binary representation of male and female bodies. They include variations of the genitals, gonads, or chromosomes. There is Zygote (genetically caused) intersexuality as a result of the deviation from the norm set of sex chromosomes and genes at the moment of fertilization when connecting gametes in the zygote. The forms of intersexuality, the so-called pseudohermaphroditism in humans, can also be the result of disruption of the normal number of sex chromosomes. Another form of intersex conditions is hormonal intersexuality.
Turner’s syndrome is a genomic disease, accompanied by the characteristic abnormalities of physical development, such as short stature and sexual infantilism. It is monosomy for X-chromosome (XO). Failures in the development of gonads in people with Turner syndrome are a consequence of the absence or structural defects of one sex chromosome (X-chromosome). In Turner syndrome, the sex glands are usually undifferentiated connective tissue bands that do not contain the elements of the gonads.
In embryo, primary embryonic germ cells are laid in almost the normal amount, but in the second half of pregnancy their rapid involution (reverse development) takes place, and at the time of a child’s birth, there is a reduced number of follicles in the ovary in comparison with the norm, or they may be completely absent. This leads to a pronounced lack of female sex hormones and sexual underdevelopment, the majority of patients having primary amenorrhea (absence of menstruation) and infertility.
Genetic features of this syndrome have a variety of cytogenetic variants and combinations (mosaicism). There are several types of polysomy on chromosomes X and Y in males: 47, XXY; 47, XYY; 48, XXXY; 48, XYYY; 48 XXYY; 49 XXXXY; 49 XXXYY. The most common karyotype in Kleinfelter syndrome is 47, XXY.
During adolescence, boys are very tall and slightly disproportional, the most common indicator of the syndrome being breast enlargement, although in some cases this feature may be absent. A typical manifestation of Kleinfelter syndrome may be the presence of small dense testes. This sign is pathognomonic for this disease as it almost never occurs in other forms of hypogonadism; however, not all patients with this syndrome have that feature. Some, but not all patients with Kleinfelter’s syndrome, have reduced intelligence and limited verbal and cognitive abilities.
Androgen Insensitivity Syndrome (AIS)
AIS is a congenital endocrine disorder of sexual development, caused by a mutation of the gene responsible for the androgen receptor. Such disorders vary depending on the structure and abnormal sensitivity receptor. The clinical phenotypes of such individuals range from a normal male body with a mild disorder of spermatogenesis to an entirely female body, despite the presence of Y-chromosome. An individual with complete androgen insensitivity syndrome has a feminine appearance, development of breasts and vagina, despite 46XY karyotype and undescended testicle. Therefore, the genotype is male, but the person develops female characteristics in body structure.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of diseases inherited in an autosomal recessive way and characterized by the disruption in the production of cortisol by the adrenal glands. Genes associated with adrenal hyperplasia encode enzymes involved in steroidogenesis (chain reactions for conversion of cholesterol to steroids). Manifestations of hyperplasia vary depending on the gene affected that is, from the changes that are incompatible with life in hindering synthesis cholesterol desmolase to subtle manifestations in some mutations of 21-hydroxylase. Therefore, CAH affects the hormonal levels.
5-alpha Reductase Deficiency
The 5-alpha-reductase deficiency is autosomal recessive intersex condition that results from a mutation of the enzyme SRD5A2, isoform 5-alpha-reductase. The 5-alpha-reductase deficiency affects only genetic males, that is, the Y-chromosome carriers. At the moment, there is no evidence as to the role of the substance in the development of women.
Those exposed to a shortage of 5-alpha-reductase may have male, intermediate, or female external genitalia. They are born with male genital gland, including testicles and Wolffian channels, but usually other primary sexual characteristics typical of females. As a result, they are often raised as girls, although having male gender identity. Usually, people with this syndrome are capable of producing viable sperm; urethra may be connected with the phallus; ejaculation and erection are possible. There are fertility problems caused by the underdevelopment of seminal vesicles and prostate.
In sum, sex determination in human biology is the development of sex differences in humans. The most important factor in sex determination is the period of embryonic development associated with chromosome Y. The genetic specifications lead to the development of different gonads and, consequently, secretion levels of different hormones. Theoretically, environmental factors may also play a role. Primary and secondary sex determination differ in that the first one is under the impact of genetic factors while the second one is the development of secondary organs. The sex ratio falls into two groups: primary (the sex ratio in the zygote after fertilization) and secondary (the sex ratio at birth). Intersex conditions result either from chromosome aberrations and changes in the number of sex chromosomes or mutations that lead to hormone insensitivity.