Table of Contents
Humans have two types of sex chromosomes: the X chromosome and the Y chromosome. The combination of these chromosomes in an individual’s karyotype determines their genotypic sex.
Human Sex Chromosome System (XX/XY)
Humans use an XX/XY system:
- Genotypic female: $46,XX$
- Two X chromosomes.
- Genotypic male: $46,XY$
- One X and one Y chromosome.
Autosomes (chromosomes 1–22) are the same in both sexes; only the 23rd pair (sex chromosomes) differs.
Inheritance of Sex Chromosomes
Gametes and Their Sex Chromosomes
- Egg cells (ova): always carry one X chromosome (22 autosomes + X).
- Sperm cells: half carry an X, half carry a Y (22 autosomes + X or 22 autosomes + Y).
Thus, the genetic contribution:
- Mother: always provides an X.
- Father: provides either X or Y, determining the child’s genotypic sex.
Punnett Scheme for Sex Determination
If we cross the parental genotypes:
- Mother: $X$
- Father: $X$ or $Y$
Possible combinations:
- $X$ (egg) + $X$ (sperm) $\rightarrow XX$ (genotypic female)
- $X$ (egg) + $Y$ (sperm) $\rightarrow XY$ (genotypic male)
Under idealized conditions, the probability for each conception is:
- $\approx 50\%$ $XX$ (genotypic female)
- $\approx 50\%$ $XY$ (genotypic male)
Real populations can show slight deviations from exactly 1:1 due to biological and environmental factors, but the mechanism is the same.
Structure and Special Features of X and Y Chromosomes
X Chromosome
- Large chromosome with many genes (over 1,000).
- Contains genes essential for basic cellular functions, not only sex-specific traits.
- Present in both $XX$ and $XY$ individuals.
Y Chromosome
- Much smaller than the X.
- Contains relatively few genes.
- Carries genes that are crucial for male sex determination and spermatogenesis.
- Present only in $XY$ individuals.
Pseudoautosomal Regions (PAR)
X and Y chromosomes are largely different, but they share small homologous segments at their ends:
- PAR1 and PAR2 (pseudoautosomal regions).
- Genes here are present on both X and Y and can undergo homologous pairing and recombination in meiosis.
- Genes in PAR regions are usually not sex-limited in expression because both sexes have copies (on X; males also on Y).
The SRY Gene and Testis Determination
The central genetic switch for male development in humans is the SRY gene.
Location and Function of SRY
- Located on the short arm of the Y chromosome (Yp).
- Name: Sex-determining Region on Y.
- Encodes a transcription factor that activates a cascade of genes leading to:
- Development of undifferentiated gonads into testes.
- Production of testosterone and other testicular hormones.
- Differentiation of internal and external male genitalia.
Presence or Absence of SRY
- SRY present and functional (usually $XY$)
→ Gonads develop into testes, initiating male sexual differentiation. - SRY absent (usually $XX$)
→ Gonads develop into ovaries, leading to female sexual differentiation.
Therefore, genotypic sex in humans is typically determined by:
- Presence of Y with a functional SRY → genotypic male.
- Absence of Y (no SRY) → genotypic female.
Timing and Principle of Sex Determination
Early Embryonic Stage
- Initially, embryonic gonads are bipotential (undifferentiated): they can become either testes or ovaries.
- The genetic constitution (presence or absence of SRY) directs this development at an early embryonic stage.
Primary vs. Secondary Sex Characteristics
- Primary sex characteristics: gonads and internal/external genitalia. These are directly influenced by genotypic sex via SRY and downstream genes.
- Secondary sex characteristics (e.g., body hair distribution, voice pitch, breast development) are hormonally influenced and are consequences of the primary sex differentiation. Their detailed regulation belongs to other chapters.
X-Linked Inheritance and Sex Determination Context
While sex determination itself depends on X/Y combination and SRY, the unequal distribution of X and Y also has consequences for inheritance patterns:
- $XX$ individuals have two X chromosomes:
- Can be homozygous or heterozygous for X-linked alleles.
- $XY$ individuals have only one X chromosome:
- Are hemizygous for X-linked genes: any recessive allele on X will be expressed because there is no second X copy to mask it.
This genetic asymmetry underlies typical X-linked inheritance patterns (covered in detail in other chapters) and explains why certain traits or disorders occur more frequently in one genotypic sex than the other.
Variations in Genotypic Sex Determination
Most humans fit clearly into $46,XX$ or $46,XY$, but variations occur due to changes in chromosome number, structure, or gene location. These illustrate that genotypic sex is rooted in chromosomal and gene-level mechanisms, not only in external appearance.
Examples of Chromosomal Variants Affecting Sex Determination
(Phenotypic details and clinical features are discussed elsewhere; here the focus is on genotypic mechanisms.)
- Turner syndrome ($45,X$ or $45,X0$)
- Only one X chromosome, no second sex chromosome and no Y.
- Genotypic sex: typically classified as female because of absence of Y/SRY.
- Shows that two sex chromosomes are not strictly required for female genotypic sex but absence of Y is critical.
- Klinefelter syndrome ($47,XXY$ and related variants)
- At least one Y and at least two X chromosomes.
- Genotypic sex: male, because SRY is present on the Y.
- Demonstrates that the presence of Y (with SRY) overrides extra X in determining genotypic sex.
- $47,XYY$
- One X, two Y chromosomes.
- Genotypic sex: male, due to presence of Y (typically SRY-positive).
- $47,XXX$ (Triple X)
- Three X chromosomes, no Y.
- Genotypic sex: female, as Y is absent.
SRY Translocations and Discordance Between Chromosomes and Sex
Occasionally, SRY can move due to chromosomal rearrangements:
- SRY-positive $46,XX$ individuals
- SRY gene is translocated onto an X chromosome or an autosome.
- Despite the XX karyotype, SRY can drive testis development.
- Genotypic sex (by presence of SRY) → male, though “chromosomal sex” is XX.
- SRY-negative $46,XY$ individuals
- The Y chromosome may have lost the SRY region.
- Without SRY, gonadal development follows the typical ovarian pathway.
- Genotypic sex based on gonadal determination → female, though the karyotype is XY.
These cases show that, in humans, SRY function is more decisive for primary sex determination than the mere presence of a morphologically recognizable Y chromosome.
Summary of the Genetic Logic
- Fertilization:
- Egg ($X$) + sperm ($X$ or $Y$) → $XX$ or $XY$.
- Chromosomal composition:
- $XX$ → usually no Y, no SRY → ovarian pathway.
- $XY$ → Y present, SRY usually present → testicular pathway.
- Genotypic sex:
- Determined by the combination of sex chromosomes and key genes (primarily SRY).
- Shapes the development of primary sex characteristics and underlies sex-specific patterns of inheritance for X-linked and Y-linked genes.
While later hormonal influences and environmental factors affect phenotypic sex and sexual development, genotypic sex determination in humans is ultimately a chromosomal and gene-based process, primarily governed by whether a functional SRY gene is present.