HMG 35110B: Human Chromosomes

• Principle of Medical Genetics (HMG 35110B)

Human Chromosomes

• Chromosomes consist of DNA and protein within the nucleus.
• A diploid human cell contains 46 chromosomes
• A haploid human cell contains 23 chromosomes.
• Chromosomes have two arms.

Chromosome Structure

• A chromosome comprises two arms separated by a centromere.
• The kinetochore is the region of spindle fiber attachment.
• Telomeres are the ends of the chromosome arms.
• Each arm is divided into two parts known as chromatids.

Chromosome Types

• Chromosomes are categorized by the location of their centromere.
• Types include Metacentric, Submetacentric, Acrocentric, and Telocentric chromosomes.
• Telocentric chromosomes are not found in humans.
• Metacentric designation has a middle centromere location and a metaphase shape with sister chromatids.
• Submetacentric designation has a centromere location between the middle and end with p and q arms.
• Acrocentric designation has a centromere at close to the end.
• Telocentric centromere location is at the end.

Telomeres

• Telomeres are regions of repetitive DNA at the ends of chromosomes.
• Telomeres act as protective "caps" for chromosomes; protect chromosomes from degradation and loss during cell division.
• Telomeres carry the TTAGGG repeat sequence.
• Telomere shortening can cause chromosomal instability, cancer, senescence (aging), and cell death.
• Telomerase helps maintain telomere length by adding DNA.
• Dysfunctional telomeres can lead to age-related diseases.
• Telomere length is used as a biomarker for cellular aging.

Centromeres

• Centromeres play a crucial role in chromosome segregation during cell division.
• Centromeres serve as the attachment site for spindle microtubules.
• Centromere structure is highly conserved across eukaryotes.

Kinetochore

• Kinetochores are protein structures that assemble at the centromere.
• Kinetochores provide an attachment site for spindle microtubules during cell division.
• Kinetochores are complex structures made up of over 100 proteins.
• Abnormal kinetochore function can lead to chromosome mis-segregation.

Human Chromosome Size

• Chromosome 1 is the longest.
• The number of genes is 1 is the most genes.
• Chromosome Y is the shortest; also contains the least genes.
• The human genome is about 3.2 billion base pairs.
• Human somatic cells contain two copies of the genome, totaling about 6.4 billion base pairs.
• The human genome includes approximately 20,000-25,000 protein-coding genes, about 1-2% of the total genome.
• The majority of the genome is non-coding DNA.

Chromosome Number Maintenance

• Genomic stability relies on maintaining chromosome number.
• Chromosomal duplication is required to maintain chromosome number across generations.
• Chromosomal duplication occurs during cell division.
• Meiosis reduces the chromosome number by half to restore the original diploid number.

Role of Y Chromosome

• The Y chromosome plays a crucial role in determining sex and human development.
• In early embryonic development, gonads are undifferentiated and can develop into testes or ovaries.
• The presence of the Y chromosome determines if the key SRY gene (Sex-determining Region Y), also known as TDF (Testis Determining Factor) is present.
• The SRY gene triggers development of testes; testes produce androgens, which stimulate male internal and external genitalia development.
• Chromosome Y is approximately 1/3 the size of chromosome X and contains ~55 genes (compared to ~900 in chromosome X).
• Chromosome Y functions in male sex determination and spermatogenesis.
• Deletions in AZF regions can cause male infertility (azoospermia or oligospermia).
• Mutations in the SRY gene can cause Disorders of Sex Development (DSD).
• Structural abnormalities in the Y chromosome can cause Turner Syndrome, Klinefelter Syndrome (XXY), and other chromosomal disorders.
• In nonobstructive azoospermia, the normal range of sperm is 20-40 million/mL.
• Azoospermia is when no sperm is detectable in semen.
• Severe oligospermia: sperm count is <5 million/mL.

Cell Cycle and Division

• The events from one division to the next constitute the cell cycle.
• The cell cycle includes interphase (initial stage) and cell division.
• The cell cycle consists of two phases: interphase and cell division.
• There are two types of cell division: mitosis and meiosis.

Interphase

• G1 Phase: RNA and protein synthesis.
• G0 Phase: The cell decides whether to proceed.
• S Phase: DNA replication.
• G2 Phase: Cell growth and preparation for mitosis, with a double check for DNA error.
• Cells require more time to grow and double their mass of protein and the repair of the duplicate chromosome in the Gap phase.

Mitosis

• The stages of this cell division include Prophase, Prometaphase, Metaphase, Anaphase and Telophase
• Prophase includes chromosomal condensation, centrosome movement to opposite cell poles.
• Prometaphase: involves nuclear envelope dissolving as well as attachment to spindle fibers.
• Metaphase includes aligning chromosomes the equator.
• Anaphase includes the centromere of each chromosome splitting, allowing sister chromatids to separate and pull away.
• Telophase divides the sets of chromosomes and arrives at opposite poles. Nuclear envelop begins to reassemble.
• Cytokinesis includes cytoplasmic division with the help of actin and myosin, eventually leading to two cells.

Meiosis

• Meiosis includes one round of DNA replication followed by two rounds of chromosome segregation and cell division.
• Genetic recombination occurs in Prophase I (crossing over).
• In males, pairing occurs between homologous segments X and Y.

Effect of Recombination

• Chromosomes inherited by a child from a parent is never an exact copy of the parent chromosome
• In Metaphase I, pairs of homologous chromosomes move to the equator.
• In Metaphase I The pairs are held in the centre of the cell by the spindle fibers.
• In Anaphase I chromosomes are pulled to the opposite pole as spindle fibres contract
• Telophase occurs reaching each opposite pole.
• Two haploid cells are formed during Cytokinesis.
• In Meiosis II Nuclear membrane disappears again as the centrioles move to opposite pole
• The chromosomes with 2 sister chromatids line up along the equator (metaphase plate) of the cell
• In Anaphase II, centromere divides as sister chromatids are pulled to either pole as spindle fibres contract
• The chromatids reach either pole and the nuclear membrane reforms and nucleolus reappears.
• Four haploid daughter cells are produced.