Beginner's guide to genetics: Sex and genetics

In the third part of our series, Adrián J González and colleagues explain the genetic bases of sexual development

Throughout history, humans have tried to discover differences between men and women, and how this determines the nature of sex. In the last century, scientists began to unlock the molecular and genetic mechanisms of sexual development. This process has not been so simple, however; sexual development consists of an orchestrated, ordered, and interrelated cascade of events.

The first step is the establishment of genetic sex (XX or XY). This results when a spermatozoid with an X or Y chromosome (genetic sex) fertilises an oocite, which carries an X chromosome. The second step is development of sex gonads. At the beginning of this step, regardless of genetic sex, embryos develop a bipotential primordium--a structure in the forming embryo that can turn into female or male gonad. This then differentiates to form the testis in XY embryos or the ovary in XX embryos, thereby defining gonadal sex. The last step is phenotypical sexual differentiation, when sexual external and internal genitalia develop due to hormones secreted by the gonad, resulting in the physical characteristics of each specific sex.

Finally, the gender of a person is the rearing assignated sex--the psychosocial implications of sex, which comprises determination and differentiation processes. Sex determination is the genetic events leading to male or female gonadal development; and sexual differentiation is the subsequent steps leading to functional sexuality and secondary sexual characteristics.

Gonadal sex differentiation

Formation of the genital and urinary systems are highly related. Both arise from the same structure--the intermediate lateral plate of the mesoderm. Before sex determination starts, bipotenial gonads are formed. On the 22nd day of intrauterine life, the primordial germ cells of extragonadal origin migrate from the yolk sac to the gonadal primordia, where they proliferate. At this stage, there are four cell lineages in the undifferentiated gonad--primordial germ cells (precursors of spermatozoa and ova), supporting somatic cells (Sertolli cells in males and granulosa cells in females), steroid cell precursors (Leydig and thecal cells in males and females, respectively), and connective tissue cells.

During the indifferent stage, both male and female embryos have two sets of paired ducts--the Müllerian (paramesonephric) and the Wolffian (mesonephric) ducts. Under the influence of the Y chromosome in males, testes develop, and Leydig cells produce testicular androgens inducing the Wolffian ducts to become the epidydimus, vas deferens, seminal vesicles, and ejaculatory ducts. Sertolli cells produce Müllerian inhibiting substance (or anti-Müllerian hormone), which causes the paramesonephric ducts to regress.

In females, in the absence of these two hormones, the Wolffian ducts degenerate and the Müllerian duct gives rise to the oviducts, uterus, and upper vagina.

Genes involved in sexual development

The genes involved in the genital ridge maintenance are WT1, SF1, and LIM1.

WT1

Located on chromosone 11p, this gene plays an essential role in urogenital tract development and has a specific pattern of expression in developing the kidney and gonads. In the testes, it is expressed in Sertolli cells and in ovaries in granulosa cells and is involved in the maturation of the primordial germ cells (precursors of spermatozoa and ova).

SF1

Located on 9q33, SF1 is an important hormone nuclear receptor required for early gonad formation. This gene acts as a transcription modulating factor (it turns other genes on or off), which participates in steroidogenesis and in male sexual development.

LIM1

This gene is located on chromosome 1. It is also involved in the early gonadal and kidney development.

Male gonadal development

A long time ago, the X and Y chromosomes were the same, but during evolution, the Y gained important genes needed for testicular development and spermatogenesis.

SRY

The most important of these genes, is SRY (the sex determining region on the Y chromosome), whose sole presence triggers the bipotential gonad to enter the male pathway. This transcription factor, located on Yp11.3, encodes the testis determining factor that regulates downstream genes in the testicular differentiation cascade.

SOX9

This autosomal gene, located on 17q24, is also necessary for testis differentiation, and activates the gene encoding Müllerian inhibiting substance.

Female pathway

In ovarian development, if the genital ridge is almost totally devoid of germ cells, differentiation of the supporting cell precursors does not proceed further, leaving a streak gonad containing only stromal tissue. The influence of germ cells on the somatic cell lineages in the fetal ovary is considerable, but genetic control of early ovarian development is still obscure. The idea that there is a lack of genes for ovarian determination and differentiation of female reproductive tract has begun to be dissmissed. WNT4 and DAX1 have a concerted role in both the control of female development and the prevention of testes formation.

DAX1

DAX1 (Xp21.3) is a member of the nuclear receptor superfamily (family of genes that synthesise nuclear receptors) and is expressed in the adrenal cortex, gonads, hypothalamus, and pituitary gland. Since in 46, XY individuals, deletions in DAX1 do not affect male development, while duplications do, this suggests that additional doses of DAX1 in some way disrupt testis determination. This gene, therefore, would be an ovarian determining gene.

WNT4

WNT4 (1p35) encodes one member of a large family of locally acting growth factors that are involved in intracellular signalling. It has been proposed that this has a role in the development of kidney, Müllerian ducts, and female germ cells.

Phenotypical sex differentiation

At age 9 weeks in both sexes, the external genitalia consist of two sets of genital folds (outer and inner) and a prominent genital tubercle. These structures are rich in androgen and 5 * reductase receptors, therefore are highly sensitive to dihydrotestosterone, a 5 * reduced form of testosterone. In male embryos, this hormonal stimulation leads to the fusion process of the genital folds, giving rise to the scrotum and the genital tubercle growth, forming the penis.

In female embryos, testosterone and dihydrotestosterone are not present in sufficient quantities to masculinise the external genitalia, and the genital folds remain separate, forming the labia minora and majora. The genital tubercle remains small and becomes the clitoris.

Anomalies of sexual differentiation

Anomalies in sexual differentiation are a specific group of disorders resulting from defects at any step of this process. These alterations can be classified as chromosomal, gonadal, and phenotypical anomalies.

Sex chromosome anomalies

Numeric and structural sex chromosome aberrations include a wide phenotypical variability, without ambiguous genitalia, but are common causes of infertlity, such as Turner's syndrome and Klinefelter's syndrome.

Klinefelter's syndrome has an incidence of 1 in 500 newborn boys. People with Klinefelter's syndrome have a 47 XXY kariotype, as a result of a nondisjuction during meiosis, mainly during oogenesis in the mother. People with Klinefelter's syndrome have small testes, infertility (azoospermia), eunochoid proportions, poor virilisation, increased gonadotropines (lutenising hormone and follicle stimulating hormone) and low concentrations of testosterone.

Turner's syndrome is caused by a total or partial absence of one member of the sexual chromosome pair and it affects 1 in 2500 females. The karyotype is 45 X in almost 50% of patients with Turner's syndrome, about a quarter have 46 XX/45 X mosaicism and the rest have some structural abnormality of the X chromosome.

Characteristics of Turner's syndrome include small stature, bilateral streak gonads (infertility), primary amenorrhea, short stature, and multiple congenital anomalies in a phenotypical female.

Gonadal anomalies

Sex reversal is the discordance between genotypic sex and gonadal sex of an individual. It is complete when 46 XX males and 46 XY females showing complete gonadal dysgenesis. It is partial or incomplete sex reversal and affects individuals with 46 XY partial gonad dysgenesis, and 46 XY or 46 XX true hermaphroditism.

Depending on whether the 46 XY gonadal dysgenesis is complete or partial, it can be characterised by complete female external genitalia, Müllerian structures, and streak ovaries, or for the later partial masculinisation of external genitalia such an enlarged clitoris with labia resembling a scrotum. It has also been described as a mixture of Müllerian and Wolffian ducts with partial testes differentiation within streak ovaries.

True hermaphrodites have both ovarian and testicular tissues, either as a combined structure (ovotestis) or as a testis on one side and an ovary in the other side of the body. The ready ascertainment of individuals with sex reversal provides a basis for gene identification (table).

Phenotypical anomalies

Anomalies in phenotypical differentiation are characterised by the discrepancy between genetic and gonadal sex with the physical characteristics of the external genitalia. It is classified in two major groups--male and female pseudohermaphroditism. An person with male pseudohermaphroditism has a 46 XY chromosomic complement, bilateral testicular development, and ambiguous or feminine characteristics.

On the other hand, female patients with pseudohermaphroditism are characterised by a 46 XX karyotype, bilateral ovaries, and several grades of external genitalia virilisation as a result of circulating androgens during intrauterine life. The degree of masculinisation is related to hormonal concentration and to the embryonic development stage when exposure occurred (box). In the near future, the convergence of molecular genetics and studies in other sexual dimorphic organisms will elucidate the remaining steps of the sexual development network and should provide further insights on the nature of sex.

Adrián J González interim, medial genetics
Email: grangeroloco@hotmail.com

Luis R Macias second year resident

Regina Gómez-Palacio second year resident

Osvaldo M Mutchinick chief, Department of Genetics, National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Mexico


studentBMJ 2004;12:393-436 November ISSN 0966-6494

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