Chapter #4 Sex Determination and Chromosomes

4.1 Mechanisms of Sex Determination Among Various Species

• Definition of Sex Determination: The biological process by which an individual develops into either a female or male. In many species, this process is governed by distinct sex chromosomes found in males and females.

  • Example in Humans: In humans, sex determination relies on the presence of X and Y chromosomes.

  • Alternate Mechanisms: Other than chromosomal mechanisms, sex determination can be influenced by environmental factors such as temperature, as well as behavioral interactions.

X-Y Sex Determination

• Characteristics:

  • Present in mammals, including humans.

  • The male is designated as X-Y, making it the heterogametic sex.

  • Produces two types of sperm: one carrying an X chromosome and the other carrying a Y chromosome, each plus 22 autosomes.

  • The female is represented as X-X, known as the homogametic sex.

  • All eggs carry an X chromosome plus 22 autosomes.

  • Sex Determination Mechanism: The sex of the zygote is determined by the sperm: X sperm leads to female (XX) and Y sperm leads to male (XY).

• Function of the Y Chromosome: The Y chromosome plays a critical role in promoting male development.

  • Key Gene: A single gene on the Y chromosome, known as SRY (Sex-determining Region Y), is crucial for male development.

  • Evidence of SRY Gene Function: The presence of XXY individuals, who are males, and X0 individuals, who are females, suggests that two X chromosomes do not independently determine female characteristics.

X-0 Sex Determination

• Characteristics:

  • Found in various insect species, including grasshoppers.

  • The male is defined as X-0, possessing only one X chromosome.

  • Other insects exhibit XY male systems, such as Drosophila.

  • The female is represented as X-X.

  • Sex Determination Mechanism: In this system, irrespective of the presence of XY males, the sex determination is based on the ratio of X chromosomes to autosomes, defined as follows:

  • 1 X to 2n autosomes results in male.

  • 2 X to 2n autosomes results in female.

Z-W Sex Determination

• Characteristics:

  • Observed in birds and certain fish species.

  • Males exhibit a Z-Z configuration (homogametic), whereas females have a Z-W configuration (heterogametic).

Haplodiploid Sex Determination

• Characteristics:

  • This method determines sex based on the number of chromosome sets.

  • Found in bees, wasps, and ants.

  • Example - Honeybee: Males, known as drones, develop from unfertilized eggs (haploid - unpaired set of 16 chromosomes), while females including workers and queens develop from fertilized eggs (diploid - paired set of 32 chromosomes). Hence, females result from sexual reproduction.

Temperature-Dependent Sex Determination

• Characteristics:

  • Present in some reptiles and fish.

  • Example - American Alligator:

  • Eggs incubated at temperatures 34°C or higher develop into males.

  • Eggs incubated at temperatures 30°C or below develop into females.

  • Eggs incubated between 30°C and 34°C can develop into either sex.

  • Both male and female alligators possess the same chromosomal composition.

Behavioral Sex Determination

• Characteristics:

  • Includes protandrous hermaphrodites that can switch from male to female.

  • Example - Clownfish (Amphiprion):

  • In an anemone habitat, typically consists of one female, one male, and several juvenile fish. If the female dies, the male transitions to take her role, and one juvenile matures into a male.

  • Both male and female clownfish have identical chromosomal compositions.

4.2 Dosage Compensation and X-Chromosome Inactivation in Mammals

• Concepts to Address:

  • Mechanisms of dosage compensation in different animal species.

  • Details of X-chromosome inactivation processes in mammals.

  • Effects of X-chromosome inactivation on the phenotype of female mammals.

Dosage Compensation

• Definition: Dosage compensation is the mechanism that ensures equal levels of expression of X-linked genes between both sexes, despite female mammals having two X chromosomes compared to one in males.

  • Differences manifest in various species.

  • In Drosophila (fruit flies), males increase their expression of X-linked genes by doubling the output of X-linked genes.

  • In C. elegans (a nematode), females reduce their X-linked gene expression to 50% of that in males.

  • X-Chromosome Inactivation (XCI): A mechanism employed by mammals whereby one of the two X chromosomes in females is inactivated.

  • In male birds (ZZ) and female birds (ZW), some Z-linked genes may be dosage-compensated, whereas many are not.

Table 4.1 - Mechanisms of Dosage Compensation Among Different Species

X-Chromosome Inactivation

• Historical Context: Proposed by Mary Lyon in 1961, the hypothesis states that female mammals randomly inactivate one X chromosome in each somatic cell early in development, which remains throughout the organism's life.

  • This process is known as the Lyon Hypothesis.

  • Observational Evidence: Barr and Bertram discovered a condensed structure in somatic cell nuclei identified as a Barr body, indicating the inactivated X chromosome.

  • Phenotypic Effects: The variegation observed in female mammals, particularly in calico cats, demonstrates the cellular consequences of X-chromosome inactivation.

X-Chromosome Inactivation Process

• Visual Explanation: The process can be illustrated through a graphical representation showing the color alleles (white fur and black fur) transitioning to a mouse with patches of black and white fur after random X-chromosome inactivation occurs during early development.

Mammals Maintain One Active X Chromosome

• Regardless of deviations from typical chromosomal configurations, individual humans maintain only one active X chromosome in somatic cells. Examples include:

  • Klinefelter syndrome (XXY): Results in one Barr body; presence of additional X chromosomes.

  • Turner syndrome (X0): Results in no Barr bodies; has only one X chromosome.

  • Triple X syndrome (XXX): Results in two Barr bodies.

X-Inactivation Center and Xist

• Mechanism of Counting X Chromosomes: The regulation of X chromosome inactivation is linked to a specific region known as the X-inactivation center (Xic), which contains the X-inactive specific transcript (Xist) gene.

  • The Xist gene produces an RNA molecule that coats the condensed X chromosome in the Barr body, leading to the inactivation of that chromosome by recruiting proteins that promote its compaction.

Phases of X-Chromosome Inactivation

1. Initiation: The selection of the X chromosome for inactivation occurs.

2. Spreading: Includes expression of Xist on the targeted chromosome, leading to its coating by Xist transcripts.

3. Maintenance: The inactivated state is preserved during mitosis and persists in descendant cells.

4.3 Properties of the X and Y Chromosomes in Mammals

Characteristics of X and Y Chromosomes

• Certain genes are unique to either the X or Y chromosome, categorized as:

  • X-Linked Genes: Those located solely on the X chromosome.

  • Y-Linked or Holandric Genes: Those exclusively found on the Y chromosome.

• These inheritance patterns differ from those of autosomal genes.

• Pseudoautosomal Genes: Located on both X and Y chromosomes, exhibiting inheritance patterns similar to autosomal genes.

  • Example Gene: Mic2 demonstrates pseudoautosomal inheritance.

• Homologous Regions: Some regions of X and Y chromosomes share homology, which assists in the pairing of the two during meiosis I.

4.4 Transmission Patterns for X-Linked Genes

Inheritance Patterns of X-Linked Genes

• The inheritance patterns of X-linked genes diverge from those of autosomal genes and are specifically termed X-linked inheritance.

  • Males inherit their X chromosome only from their mothers, while females inherit their X chromosomes from both parents.

  • Males are considered to be hemizygous concerning X-linked genes as they possess only one X chromosome (as opposed to homozygous or heterozygous).

Morgan’s Experiments with Drosophila

• In the early 1900s, geneticist Thomas Hunt Morgan confirmed the existence of specific gene locations on chromosomes.

  • He induced mutations in the eye color of Drosophila melanogaster, with the white-eyed phenotype identified as a mutant allele.

  • Experimental Crosses: He bred the white-eyed flies with red-eyed flies to study the inheritance pattern of the trait.

Detailed Cross Analysis in Morgan's Experiment

Test Cross Results

• In a test cross, a white-eyed male was crossed with F1 generation females, yielding diverse offspring ratios, similar to the overall patterns observed previously, confirming X-linked trait behaviors in Drosophila.

Human Inheritance Patterns

• Unlike Mendel’s controlled crosses with pea plants, human genetic traits cannot be curated in similar ways; results must be inferred from analyzing family pedigrees.

Pedigree Analysis

1. Purpose: Pedigree analysis reveals the inheritance pattern of genes affecting human genetic diseases. Individuals may possess a normal allele (wild-type) or a disease-causing mutant allele.

2. Patterns of Inheritance: Genetic diseases can demonstrate simple Mendelian inheritance, following dominant or recessive patterns.

   • Dominant Pattern: An affected individual typically has an affected parent.

   • Recessive Pattern: Two unaffected heterozygous parents can produce approximately 25% affected offspring.

Example - Cystic Fibrosis (CF)

• Nature of Disorder: Cystic fibrosis is an autosomal recessive disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

  • Pathophysiology: Mutant CFTR protein causes ion imbalances, resulting in dysfunction across various body systems including the pancreas, skin, intestine, and respiratory tract, leading to the buildup of sticky mucus in the lungs which complicates breathing.

Pedigree Identification of X-Linked Genes

• Example - Duchenne Muscular Dystrophy (DMD): The gene responsible for Duchenne muscular dystrophy is located on the X chromosome and encodes the dystrophin protein crucial for muscle structure. The disease exhibits an X-linked recessive inheritance pattern, causing rare incidence in females, who can only act as carriers.

Reciprocal Crosses in Research

• Definition of Reciprocal Cross: This involves conducting two different crosses wherein the traits' sex carriers are interchanged to deduce inheritance behavior, elucidating the X-linked nature of certain genes in various species, including dogs and humans.