(August 2004)

Genetics and sex determination

Genetics is defined as the study of genes. Genes are composed of deoxyribonucleic acid (DNA) that can be passed down and inherited from one generation to the next. The information encoded in DNA is critical for determining the properties of a species1. DNA is divided into discrete molecules called chromosomes, each of which contain numerous genes.


Figure 1. Non-disjunction during meiosis II results in two normal gametes, one n+1 gamete, and one n-1 gamete.

A ‘normal’ human cell is diploid (2n) because it contains 2 copies of each of the 23 chromosomes. Included in these 46 chromosomes are sex chromosomes X and Y. A normal human male has one X- and one Y- chromosome. They are often denoted 46, XY male. A normal human female has two X chromosomes, and is denoted 46, XX female.

In mitosis, in order for the cell to divide, it must replicate its DNA to create identical copies for its daughter cells. An example of mitosis is the development of the multicellular organisms from a single celled zygote (fertilized egg) [1]. Meiosis is essential for humans to produce sex cells (like sperm in men and eggs in women). It consists of two nuclear divisions resulting in haploid cells (n), which contain single copies of chromosomes. Haploid cells from a female and a male can fuse together to create a zygote with a unique combination of chromosomes. As indicated above, sex chromosome combinations include XX or XY.

Sex determination is genetically programmed by the X- and Y- chromosomes and is defined at the time of testes or ovary formation in embryonic development [2]. Testes formation in men is regulated by the expression of genes on the Y chromosome. Ovary formation occurs if the Y chromosome is not present and this DNA is not expressed. In addition to aiding in the development of primary sex characteristics mentioned above (sex organs involved in reproduction), the production of hormones like estrogen in women and testosterone in men is key for the development of secondary sex characteristics. Secondary sex characteristics develop later in life and often emphasize the assignment of female or male sex. Examples of secondary sex characteristics in females include enlarged breasts, wide hips, less facial hair than men, and subcutaneous fat [3]. Examples of secondary sex characteristics in males include chest and facial hair, deep voices, and a relatively larger body size [3]. These sex characteristics are important for humans to define their biological sex.


Figure 2. Non-disjunction during meiosis I results in two n+1 gametes and two n-1 gametes.

Biological sex is identified based on the external genitalia (i.e. penis or vagina) and gonads (i.e. testes or ovaries) present in an individual. In contrast, gender identity refers to the self-identification in the brain of an individual as female or male. Most of the time sex and gender identity go hand in hand. However, unusual genetics may lead to biological sex ambiguities, discrepancies, and gender identity confusion [4].


Non-disjunction in meiosis I or meiosis II can lead to aneuploidy, an abnormal condition when an organism’s chromosome number differs from wild-type (normal). The result of non-disjunction in meiosis I is two gametes (sex cells) with an extra chromosome (n + 1) and two gametes missing a chromosome (n – 1). The result of non-disjunction in meiosis II is one gamete with an extra chromosome (n + 1), one gamete missing a chromosome (n – 1), and two gametes with the correct number of chromosomes (n). Fusion of abnormal sex cells from males and females can create aneuploidal zygotes 1. There are several genetic disorders that are associated with aneuploidy and I will use Turner’s syndrome and Klinefelter syndrome as examples to show how aneuploidy affects sex and gender identity.


Figure 3. Mosaicism occurs when tissues contain two genetically different cell lines.

Turner’s syndrome: Affected individuals with Turner’s syndrome (TS) are genetically 45, X as they are completely or partially lacking a partner sex chromosome [1]. Cells that are completely lacking a partner sex chromosome have evolved from spontaneous non-disjunction during meiosis. Mosaicism occurs in females with TS when their tissues contain at least 2 different cell lines that differ genetically, but are derived from a single zygote5. This is caused by a separate non-disjunction event occuring shortly after fertilization. 45,X/46,XX and 45X/46,XY are examples of mosaicisms, but there are other possibilities6. TS females have several distinguishing characteristics such as infertility (inability to have children), short stature, webbed skin behind the neck, low hairline, widely spaced nipples, small breast development, brown spots, small finger nails, and ovarian failure1. The most obvious characteristics that lead to diagnosis are short stature and infertility.

Klinefelter’s syndrome: Affected individuals with Klinefelter syndrome are genetically 47,XXY [1]. The second X chromosome is often X-inactivated, meaning that it no longer functions to express its genes. Klinefelter syndrome develops when there is spontaneous non-disjunction in meiosis. Non-disjunction could occur either maternally (in the mother’s gamete) or paternally (in the father’s gamete) to create a 47,XXY zygote. Paternal non-disjunction in meiosis I accounts for 53% of cases, and maternal non-disjunction in meiosis I accounts for 34% of cases. The remainder of cases occur in meiosis II. 15% of people with Klinefelter syndrome are 47,XXY/46,XY mosaics. Klinefelter’s syndrome is normally diagnosed during puberty [7]. Generally men with Klinefelter’s syndrome can lead normal lives. They have several distinguishing characteristics such as sterility, tall stature, long arms and legs, lanky build, feminized physique, little chest hair, female patterned pubic hair, testicular atrophy, hypogonadism, osteoporosis, reduced aggression, language deficits, and breast development [1]. The low level of testosterone accounts for the lack of development of male secondary sex characteristics.


At first glance sex identification appears simple. However, with closer examination it is clear that aneuploidy is always a possibility and can make sex identification ambiguous and complex. Perhaps further understanding of the biology of sexual differentiation will help our society realize that sex is not as clearcut as our ancestors would have us believe.


1. Griffiths AJF, Gelbart WM, Miller JH, Lewontin RC. Modern genetic analysis. W.H. Freeman and Company, New York 1999; p2, 91, 243

2. Cotinot C, Pailhoux E, Jaubert F, Fellous M. Molecular genetics of sex determination. Semin Reprod Med 2002; 20(3):157-166

3. Wikipedia. Secondary sex characteristics. Online. Internet. April 1, 2004. Available.

4. GIRES. Gender dysphoria. Online. Internet. April 1, 2004.

5. Nussbaum RL, McInnes RR, Willard HF. Thompson and Thompson genetics in medicine. W.B. Saunders Company, Philadelphia 2001; p75, 176

6. Ostberg JE, Conway GS. Adulthood in women with Turner syndrome. Horm Res 2003; 59: 211-221

7. Visootsak J, Aylstock M, Graham JM. Klinefelter syndrome and its variants: an update and review for the primary pediatrician. Clin Pediatr (Phila) 2001; 40(12): 639-651

8. Bradley SJ, Zucker KJ. Gender identity disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1997; 36:872-880

9. Batch J. Turner syndrome in childhood and adolescence. Best Practice & Research Clinical Endocrinology and Metabolism 2002; 16(3): 465-482

10. Muhs A, Lieberz K. Anorexia nervosa and Turner’s syndrome. Psychopathology 1993; 26: 29-40

11. El-Badri SM, Lewis MA. Anorexia nervosa associated with klinefelter’s syndrome. Comp Psych 1991; 32(4): 317-319

(Art by Jen Philpot)