Genetics Lecture 6: Sex Determination and Sex Chromosome Inheritance

Chapter 7: Sex Determination and Sex Chromosomes

Introduction

This chapter explores the genetic mechanisms underlying sex determination, the structure and function of sex chromosomes, and the inheritance patterns of sex-linked traits. It covers both human and non-human systems, with a focus on X-linked and Y-linked inheritance, dosage compensation, and the influence of sex on gene expression.

Sex Determination Systems

Genotypic and Phenotypic Sex

• Genotypic sex: Refers to an individual's sex as determined by their chromosome composition (e.g., XX or XY in humans).

• Phenotypic sex: Refers to the observable characteristics, including internal and external genitalia, secondary sex characteristics, and behavior, influenced by hormones.

• In mammals, the XY pair determines sex, but some sex-determining genes are located on autosomes.

Sex Chromosome Systems in Different Organisms

• Humans: XX = female, XY = male (heterogametic sex is male).

• Birds: ZW = female, ZZ = male (heterogametic sex is female).

• Haplo-diploidy: In bees, wasps, and ants, females are diploid (from fertilized eggs), males are haploid (from unfertilized eggs).

• XX-X0 system: In some insects (e.g., grasshoppers), females are XX, males are X0 (only one X chromosome).

Hermaphroditism and Environmental Sex Determination

• Hermaphrodites: Organisms with both ovaries and testes. Can be simultaneous (e.g., earthworms) or sequential (e.g., some fish).

• Temperature-dependent sex determination: In some reptiles, sex is determined by incubation temperature during embryonic development.

Y-Linked Inheritance

Characteristics of Y-Linked Inheritance

• Present only in males; passed from father to son (holandric inheritance).

• The Y chromosome contains relatively few genes (~350), with about 70 encoding proteins, many related to male fertility.

• Most of the Y chromosome does not recombine with the X chromosome.

• Pseudoautosomal regions (PARs): Regions of homology with the X chromosome that allow pairing and recombination during meiosis.

• Three major regions on the Y chromosome:

  • Testis-determining factor (TDF)

  • Gonadoblastoma locus on Y chromosome (GBY)

  • Azoospermia factor (AZF)

X and Y Chromosome Pairing

• The X and Y chromosomes pair during meiosis via their pseudoautosomal regions (PAR1 and PAR2).

• Genes in these regions follow autosomal inheritance patterns.

• There is also an X-chromosome-transposed region (XTR or PAR3).

Protein-Coding Genes in the Male-Specific Region of the Y Chromosome (MSY)

The MSY contains genes critical for male development and fertility. The table below summarizes key MSY genes, their domains, and expression patterns.

Gene	Functional Domain	Expression
BPY2, 2B, 2C	Winged HTH-like domain	Testis specific
CDY1, 1B, 2A, 2B	CHROMO domain	Testis specific
DAZ 1, 2, 3, 4	RRM, DEAD-like helicase	Predominantly testis
HSFY1, 2	PID zinc finger, jumonji domain	Ubiquitous
PRY, PRY2	SR/RA binding domain	Testis, heart, lung
RBMY1A1, 1B, 1C, 1D, 1E, 1FJ	RRM	Testis specific
RPS4Y1, RPS4Y2	WD40 repeats (WD40)	Ubiquitous
SRY	HMG domain	Predominantly testis
VCY, VCY1B	Zinc fingers (ZF, C2H2)	Predominantly testis

Genetic Disorders of Sex Determination

SRY Gene and Swyer Syndrome

• SRY gene: The sex-determining region of the Y chromosome; encodes a protein that triggers male development.

• Swyer syndrome (XY gonadal dysgenesis): Individuals have an XY karyotype but develop as females due to mutations in SRY or other genes. They have female genitalia but nonfunctional gonads ("gonadal streaks").

• Other genes involved in sex determination include MAP3K1, NROB1 (DAX1), DHH, DMRT1, CBX2, SF-1, and others.

Androgen Insensitivity Syndrome (AIS)

• Caused by mutations in the androgen receptor (AR) gene (over 400 known mutations).

• X-linked recessive inheritance.

• Individuals have XY chromosomes and produce testosterone, but cells cannot respond to the hormone, leading to female or ambiguous phenotypes.

X-Linked Inheritance

General Features

• The X chromosome is large and contains many genes, most unrelated to sex determination.

• Males are hemizygous for X-linked genes (only one X chromosome), while females can be homozygous or heterozygous.

• Inheritance patterns differ between males and females due to the presence of only one X in males.

Examples of X-Linked Inheritance

• White-eye in Drosophila: The gene for eye color is on the X chromosome. Reciprocal crosses show different results depending on the sex of the parent carrying the mutation.

• Color blindness: X-linked recessive trait; red-green color blindness is due to mutations affecting photopigments.

• Hemophilia: X-linked recessive disorder affecting blood clotting factors (e.g., Hemophilia A, B, C).

Pedigree Analysis and Criss-Cross Inheritance

• Pedigree analysis is used to study inheritance patterns in families, especially for X-linked traits.

• X-linked recessive traits often show a "criss-cross" pattern: affected males inherit the trait from carrier mothers, and affected females must have an affected father and a carrier or affected mother.

Dosage Compensation

Mechanisms of Dosage Compensation

• Ensures equal expression of X-linked genes in males (one X) and females (two Xs).

• Mammals: One X chromosome in females is inactivated (Lyonization), forming a Barr body. In placental mammals, inactivation is random; in marsupials, the paternal X is always inactivated.

• Drosophila: Males double the transcription of their single X chromosome.

• C. elegans: Both X chromosomes in hermaphrodites are transcribed at half the rate.

X-Inactivation and Barr Bodies

• The inactive X chromosome is condensed into a Barr body, visible in the nucleus.

• The X-inactivation center (XIC) controls inactivation, with the XIST gene producing a non-coding RNA that coats and silences the X chromosome.

Sex-Limited and Sex-Influenced Traits

Sex-Limited Traits

• Autosomal genes expressed in only one sex, often due to hormonal differences (e.g., milk production in females, beards in males).

Sex-Influenced Traits

• Autosomal traits expressed in both sexes but with different phenotypic expression (e.g., pattern baldness is dominant in men, recessive in women).

• Example: Heterozygous men (b+/b) show baldness, while heterozygous women do not; homozygous individuals (b/b) of either sex are bald.