Genomic resource centre

Gender and Genetics

Genetic Components of Sex and Gender

Humans are born with 46 chromosomes in 23 pairs. The X and Y chromosomes determine a person’s sex. Most women are 46XX and most men are 46XY. Research suggests, however, that in a few births per thousand some individuals will be born with a single sex chromosome (45X or 45Y) (sex monosomies) and some with three or more sex chromosomes (47XXX, 47XYY or 47XXY, etc.) (sex polysomies). In addition, some males are born 46XX due to the translocation of a tiny section of the sex determining region of the Y chromosome. Similarly some females are also born 46XY due to mutations in the Y chromosome. Clearly, there are not only females who are XX and males who are XY, but rather, there is a range of chromosome complements, hormone balances, and phenotypic variations that determine sex.

The biological differences between men and women result from two processes: sex determination and differentiation.(3) The biological process of sex determination controls whether the male or female sexual differentiation pathway will be followed. The process of biological sex differentiation (development of a given sex) involves many genetically regulated, hierarchical developmental steps. More than 95% of the Y chromosome is male-specific (4) and a single copy of the Y chromosome is able to induce testicular differentiation of the embryonic gonad. The Y chromosome acts as a dominant inducer of male phenotype and individuals having four X chromosomes and one Y chromosome (49XXXXY) are phenotypically male. (5) When a Y chromosome is present, early embryonic testes develop around the 10th week of pregnancy. In the absence of both a Y chromosome and the influence of a testis-determining factor (TDF), ovaries develop.

Gender, typically described in terms of masculinity and femininity, is a social construction that varies across different cultures and over time. (6) There are a number of cultures, for example, in which greater gender diversity exists and sex and gender are not always neatly divided along binary lines such as male and female or homosexual and heterosexual. The Berdache in North America, the fa’afafine (Samoan for “the way of a woman”) in the Pacific, and the kathoey in Thailand are all examples of different gender categories that differ from the traditional Western division of people into males and females. Further, among certain North American native communities, gender is seen more in terms of a continuum than categories, with special acknowledgement of “two-spirited” people who encompass both masculine and feminine qualities and characteristics. It is apparent, then, that different cultures have taken different approaches to creating gender distinctions, with more or less recognition of fluidity and complexity of gender.

Sex Chromosome Abnormalities
Turner syndrome
XXX Females
Klinefelter Syndrome
XYY Males


Case Example 1: Genetics as an important determinant of biological sex
In 1959, chromosomal analysis of two human disorders, Turner syndrome and Klinefelter syndrome, demonstrated for the first time that genetic factors on the Y chromosomes of mammals are important determinants in male sex. (7) The sex determining region on the Y chromosome, referred to as the SRY, has a fundamental role in sex determination and is believed to be the switch that initiates testis development. It is, therefore, responsible for the initiation of male sex determination during embryo development. (8) SRY-box-related (SOX) genes have been identified on autosomes (9) and mutations in the SRY or SOX gene have been implicated in sex reversal. (10) In other words, individuals with SRY mutations should develop as females. (11) However, it is likely that there are other sex determining genes involved in phenotypic sex. (12) The DNA sequence of the human X chromosome and male-specific region of the Y chromosome have recently been published, enabling further research into sex-specific genes. (13)

Genetically Determined Disorders of Sexual Differentiation

Typical sexual development is the result of numerous genes, and mutation in any of these genes can result in partial or complete failure of sex differentiation. These include mutations or structural anomalies of the SRY region on the Y chromosome resulting in XY gonadal dysgenesis, XX males, or XY females; defects of androgen biosynthesis or androgen receptors, and others.

Hermaphroditism
Congenital Adrenal Hyperplasia
Androgen Insensitivity Syndrome

ELSI of Genetic Components of Sex and Gender

The issues of gender assignment, gender verification testing, and legal definitions of gender are especially pertinent to a discussion on the ELSI of gender and genetics. These practices, however, are misnomers as they actually refer to biological sex and not gender. Such a discrepancy is highlighted by the existence of intersex individuals whose psychosexual development and gender sometimes do not match the biological sex assigned to them as infants. In this report the term ‘sex’ will be used where the practice refers to biological sex and not the more social construct of ‘gender’.

Gender Assignment of Intersex Infants and Children
Legal Definitions of Gender

Sex Chromosome Abnormalities

Chromosomes are the structures that carry genes which in turn transmit hereditary characteristics from parents to offspring. Humans have 23 pairs of chromosomes, one half of each pair inherited from each parent. The Y chromosome is small, carries few genes, and has abundant repetitive sequence, while the X chromosome is more autosome-like in form and content. (14)Despite being relatively gene-poor overall due to reduced recombination, the X and Y sex chromosomes are enriched for genes that relate to sexual development. (15)

Aneuploidy is the condition of having less than (monosomy) or more than (polysomy) the normal diploid number of chromosomes. Aneuploidy occurs in at least 5% of all pregnancies and is the most commonly recognized chromosome abnormality in humans. (16) Divergence from the normal number of X and Y chromosomes, called sex chromosome aneuploidy (SCA), accounts for approximately half of all chromosomal anomalies in humans with a total frequency of 1:400. (17) Sex chromosome physical abnormalities are able to be diagnosed prenatally via amniocentesis and chorionic villi sampling (CVS). Prenatal diagnosis of SCA is increasing because of the widespread use of these technologies. (18)

The high frequency of individuals with SCA is due to the fact that their effects are generally not as severe as autosomal abnormalities and are rarely lethal. Indeed, most cases of SCA are compatible with normal life expectancy and often go undiagnosed. (19) Still, it is estimated that1 in 3 miscarriages is due to aneuploidy affecting the foetus. (20) The induced abortion rate for SCA has steadily decreased from 100% in the 1970s to 69% in the 1980s and 49% in the 1990s. (21) It has been suggested that this decrease is directly the result of improved knowledge of the conditions associated with SCA combined with the influence of genetic counseling. (22)

Turner syndrome

This disorder, also referred to as monosomy X (45X) occurs in individuals that have one X chromosome, no Y chromosome, and are phenotypically female. Although 45X is a frequent chromosomal anomaly, Turner syndrome is rare with a live-birth frequency of 1:3000, (23) as only 1 in 40 affected zygotes develops to term. (24) Affected individuals experience abnormal growth patterns, are short in stature, generally lack prominent female secondary sexual characteristics and are sterile. In some instances of Turner syndrome, there is slight mental retardation.

XXX Females

Women with three X chromosomes (47XXX) experience normal development of sexual traits and are fertile. Affected individuals are usually taller than average and have slender builds. The frequency of women obtaining an extra X chromosome is approximately 1:1000. There is no severe phenotype associated with three X chromosomes in women. (25) These women may have slight learning difficulties.

Klinefelter Syndrome

Klinefelter syndrome (47XXY or XY/XXY mosaic) with male phenotype is the most pervasive sex chromosomal anomaly (26) affecting approximately 1:600 males. (27) Males with Klinefelter syndrome carry two or more X chromosomes which results in abnormal development of the testis, leading to hypogonadism and infertility. (28) Affected individuals are often tall and produce relatively small amounts of testosterone. As a result of this hormone imbalance, affected males have incompletely developed secondary male sex characteristics.

XYY Males

Men inheriting an additional Y chromosome are usually taller than average and are prone to acne because they produce higher than average levels of testosterone. Affected males are typically fertile and many are unaware that they have a chromosomal abnormality. The frequency of males born with an additional Y chromosome is approximately 1:1000.

Hermaphroditism

‘True’ hermaphroditism is a genetic condition in which affected individuals have both mature ovarian and testicular tissue. (29) There are no published population-wide estimates of the frequency of true hermaphrodites. (30) The autosomal inheritance of this condition suggests that genes controlling sexual development and differentiation are not limited to the sex chromosomes.(31) Blackless et al. suggest that such familial inheritance “opens the possibility that, as with other inherited forms of sexual ambiguity, there may be pockets, perhaps even large geographical regions, with relatively high frequencies of true hermaphroditism.” (32)

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is an inherited autosomal recessive condition that can affect both boys and girls. It is the most common cause of intersexuality in females with 46XX, where untreated girls develop an outwardly male appearance. This disorder, also called adrenogenital syndrome (AGS), results from a genetically caused deficiency of cortisol, a steroid hormone produced by the adrenal cortex. The disorder occurs with a frequency of 1:5000 and results in incomplete female sex differentiation and increased androgenic effects due to a compensatory increase in adrenocortical hormone (ACTH). (33)

Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome (AIS) is an X-linked recessive disorder in which affected individuals have external female genitalia and breast development despite being genetically male (46XY). Tissues of affected individuals are unresponsive to male hormones (androgens) yet respond to estrogens.

Wisniewski et al. assessed the physical and psychosexual status of 14 women with complete androgen insensitivity syndrome (CAIS) by questionnaire as well as medical examination in order to determine the participants' knowledge of their disorder as well as their opinion of medical and surgical treatment. (34) Most of the women questioned expressed satisfaction with their psychosexual development and sexual function. All of the women who participated in the study were satisfied at having been raised as females, and none of the participants desired gender reassignment. (35)

Gender Assignment of Intersex Infants and Children

Intersex is defined as a congenital anomaly of the reproductive and sexual system. An estimate about the birth prevalence of intersex is difficult to make because there are no concrete parameters to the definition of intersex. The Intersex Initiative, a North-American based organization, estimates that one in 2,000 children, or five children per day in the United States, are born visibly intersex. (36) This estimate sits within range; from genital anomalies, such as hypospadias, with a birth prevalence of around 1:300 to complex genital anomalies in which sex assignment is difficult, with a birth prevalence of about 1:4500. (37) Many intersex children have undergone medical intervention for health reasons as well as for sociological and ideological reasons. An important consideration with respect to sex assignment is the ethics of surgically altering the genitalia of intersex children to “normalize” them.

Clitoral surgery for intersex conditions was promoted by Hugh Hampton Young in the United States in the late 1930s. Subsequently, a standardized intersex management strategy was developed by psychologists at Johns Hopkins University (USA) based on the idea that infants are gender neutral at birth. (38) Minto et al. note that “the theory of psychosexual neutrality at birth has now been replaced by a model of complex interaction between prenatal and postnatal factors that lead to the development of gender and, later, sexual identity”. (39) However, currently in the United States and many Western European countries, the most likely clinical recommendation to the parents of intersex infants is to raise them as females, often involving surgery to feminize the appearance of the genitalia. (40)

Minto et al. conducted a study aiming to assess the effects of feminizing intersex surgery on adult sexual function in individuals with ambiguous genitalia. As part of this study, they noted a number of ethical issues in relation to this surgery, including that:

  • there is no evidence that feminizing genital surgery leads to improved psychosocial outcomes;
  • feminizing genital surgery cannot guarantee that adult gender identity will develop as female; and that
  • adult sexual function might be altered by removal of clitoral or phallic tissue. (41)

Developmental biology suggests that a strict belief in absolute sexual dimorphism is incorrect. (42) Instead, Blackless et al. suggest two overlapping bell-shaped curves to conceptualize sexual variations across populations. Qualitative variation in chromosome complement, genital morphology and hormonal activity falls under the area of overlap. (43) Such an opinion challenges the need for medical intervention in cases of intersexuality.

Legal Definitions of Gender

An example of the implications of legal definitions of sexual affiliation

In addition to social implications, sex and gender categorization has important political and legal implications as well. The identification of an individual as either biologically male or female can have legal ramifications for marriage licenses, spousal support and eligibility for parenthood. The issue of sexual classification, however, is complicated by factors such as chromosomal complement, external genitalia, gender identification and surgical alteration.

In the United States, as in most countries, there is an absence of controlling legislation that defines exactly how a person’s gender is determined. (44) The following example demonstrates some of the complexities this may raise. In 1999, the Texas Court of Appeals considered the validity of a marriage between a man and a person born genetically as a man, but surgically altered to have the physical characteristics of a woman. (45) As in most American states, Texas family law prohibits same-sex marriages, and the United States Congress has passed the Defense of Marriage Act that, for federal purposes, defines marriage as a “legal union between one man and one woman”. (46)

Despite the fact that medical experts gave testimony to the effect that the individual in question was psychologically and psychiatrically female before and after the sex reassignment surgery, the court held that chromosome complement, and not sex reassignment surgery, outward gender characteristics, nor psychosocial self-identification, determine a person’s gender. The court invalidated the marriage on the grounds that the transsexual woman was legally a man. (47)

This case is one example of how the legal system in one country has dealt with the complexities of defining sex and gender and the implications of defining gender and sex. Clearly, there are many other potential legal implications of such definitions and the complicated issues they raise are many.