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Molecular Biology

Chromosome Structure

If DNA is the instruction manual, Chromosome Structure is how that manual is organized, packaged, and managed within the cell. Proper structure is essential not just for fitting the immense length of DNA into a tiny nucleus, but also for regulating gene access, ensuring accurate replication, and guaranteeing correct segregation during cell division

Think of it like organizing a massive library: you can’t just have loose pages everywhere; you need books (chromatin fibers) shelved and cataloged (organized into chromosomes) for the library (the cell) to function

The Basic Idea: DNA Packaging

A single human cell contains about 2 meters (over 6 feet!) of DNA. Fitting this into a nucleus only about 6 micrometers in diameter requires incredible compaction. This is achieved by wrapping DNA around proteins. The complex of DNA and its associated proteins is called chromatin. Chromosomes are the highly condensed structures formed from chromatin, especially visible during cell division

Prokaryotic vs. Eukaryotic Chromosomes

There’s a fundamental difference:

  • Prokaryotic Chromosomes (e.g., Bacteria)
    • Location: Reside in the cytoplasm in a region called the nucleoid (not membrane-bound)
    • Structure: Typically a single, circular DNA molecule
    • Packaging: DNA is associated with nucleoid-associated proteins (NAPs) – not histones. These proteins help organize the DNA into loops and domains, achieving compaction through supercoiling
    • Plasmids: Prokaryotes often also contain smaller, independent circular DNA molecules called plasmids, which carry non-essential genes (like antibiotic resistance)
  • Eukaryotic Chromosomes (e.g., Humans)
    • Location: Contained within the membrane-bound nucleus
    • Structure: Multiple, linear DNA molecules. Each species has a characteristic number (e.g., humans have 46)
    • Packaging: DNA is tightly complexed with a family of proteins called histones, forming chromatin, which undergoes several levels of hierarchical folding

Eukaryotic Chromosome Structure: Levels of Compaction

This is a step-wise process:

  1. DNA Double Helix The basic molecule (approx. 2 nm diameter)
  2. Nucleosomes (“Beads on a String”) The fundamental unit of chromatin. DNA wraps approximately 1.7 times (about 147 base pairs) around a core octamer of histone proteins (two each of H2A, H2B, H3, and H4). Histones are rich in basic amino acids (lysine, arginine), giving them a positive charge that strongly interacts with the negatively charged phosphate backbone of DNA. Short stretches of “linker DNA” connect adjacent nucleosomes. This structure is about 11 nm in diameter
  3. 30 nm Chromatin Fiber (Solenoid/Zigzag) Nucleosomes coil or fold upon themselves, likely stabilized by interactions involving Histone H1 (which binds to the linker DNA and the nucleosome core). This compacts the DNA further into a fiber approximately 30 nm wide
  4. Looped Domains The 30 nm fiber is further organized into loops, ranging from tens to hundreds of kilobases long. These loops are anchored to a nuclear scaffold or matrix composed of non-histone proteins. This level helps organize the genome into functional domains. (Approx. 300-700 nm diameter)
  5. Metaphase Chromosome The highest level of compaction, achieved only when the cell prepares to divide (mitosis or meiosis). The looped domains coil and fold extensively, resulting in the classic, highly condensed structure visible under a light microscope (approx. 1400 nm diameter). At this stage, the chromosome typically consists of two identical sister chromatids joined at the centromere (having been replicated during the S phase)

Key Features of a Eukaryotic Metaphase Chromosome

  • Sister Chromatids: Two identical copies of a chromosome resulting from DNA replication, joined together
  • Centromere: A constricted region where the two sister chromatids are most closely attached. It serves as the assembly site for the kinetochore, a protein complex that attaches to microtubules of the spindle apparatus, ensuring proper chromosome segregation during cell division
    • Location defines morphology
      • Metacentric: Centromere near the middle
      • Submetacentric: Centromere off-center, creating one shorter (p arm) and one longer (q arm) arm
      • Acrocentric: Centromere very near one end, resulting in a very short p arm (often containing non-essential repetitive sequences, satellite DNA) and a long q arm. (Humans have acrocentric chromosomes 13, 14, 15, 21, 22)
      • Telocentric: Centromere at the very end (not typically found in humans)
  • Telomeres: Specialized structures at the ends of linear eukaryotic chromosomes
    • Structure: Consist of repetitive nucleotide sequences (e.g., TTAGGG in humans) and associated proteins. They form protective “caps.”
    • Functions
      1. Protect the ends from being recognized as DNA breaks and degraded or fused
      2. Solve the “end replication problem” Standard DNA polymerase cannot fully replicate the very tips of linear chromosomes. The enzyme telomerase (a reverse transcriptase carrying its own RNA template) adds repeats to the telomeres, preventing progressive shortening with each cell division in germ cells and stem cells. Most somatic cells have low telomerase activity, leading to telomere shortening with age
  • Arms: The portions of the chromatid extending from the centromere
    • p arm: Short arm (“p” for petit)
    • q arm: Long arm (“q” follows “p”)

Chromatin States and Gene Activity

Chromatin isn’t uniformly packed; its structure relates directly to gene activity:

  • Euchromatin: Less condensed, appears lighter in micrographs. Contains most of the actively transcribed genes. Corresponds generally to the “beads on a string” or 30 nm fiber state, allowing transcription machinery access
  • Heterochromatin: Highly condensed, appears darker. Generally transcriptionally inactive. Contains fewer genes, often repetitive sequences
    • Constitutive Heterochromatin: Always condensed in all cell types (e.g., centromeric and telomeric regions)
    • Facultative Heterochromatin: Can vary in condensation state depending on cell type or developmental stage. Contains genes that are silenced through condensation (e.g., the inactive X chromosome forming a Barr body in mammalian females)

Epigenetics Connection Modifications to histones (acetylation, methylation, phosphorylation) and DNA (methylation) play a huge role in dynamically regulating chromatin structure, switching between euchromatin and heterochromatin states to control gene expression without changing the underlying DNA sequence

Chromosome Number and Karyotype

  • Ploidy: Refers to the number of sets of chromosomes. Human somatic cells are diploid (2n), having two sets (one maternal, one paternal) for a total of 46 chromosomes (22 pairs of autosomes + 1 pair of sex chromosomes, XX or XY). Gametes (sperm/egg) are haploid (n), with one set (23 chromosomes)
  • Karyotype: The complete set of chromosomes in a cell, organized and displayed systematically (usually in pairs, ordered by decreasing size and centromere position). Visualizing the karyotype, often using G-banding (staining that produces characteristic light and dark bands), is a fundamental cytogenetic technique

Clinical Laboratory Relevance

Chromosome structure and number are fundamental to health. Cytogenetics labs analyze chromosomes to detect abnormalities:

  • Numerical Abnormalities (Aneuploidy): Gain or loss of whole chromosomes
    • Trisomy: Three copies of a chromosome (e.g., Trisomy 21 - Down syndrome)
    • Monosomy: One copy of a chromosome (e.g., Monosomy X - Turner syndrome)
  • Structural Abnormalities: Changes in the structure of one or more chromosomes
    • Deletions: Loss of a chromosomal segment
    • Duplications: Repetition of a chromosomal segment
    • Inversions: A segment is flipped and reinserted
    • Translocations: Exchange of segments between non-homologous chromosomes (e.g., the Philadelphia chromosome t(9;22) in Chronic Myeloid Leukemia - CML)
  • Techniques
    • Karyotyping: Detects large numerical and structural changes. Used in prenatal diagnosis, diagnosing developmental disorders, infertility workups, and cancer characterization
    • Fluorescence In Situ Hybridization (FISH): Uses fluorescently labeled DNA probes to detect the presence, absence, or location of specific sequences or chromosome segments. More targeted than karyotyping, can detect smaller changes (microdeletions/duplications) or specific translocations
    • Chromosomal Microarray Analysis (CMA): High-resolution technique to detect copy number variations (CNVs - small deletions and duplications) across the entire genome. Often the first-tier test for developmental delay/intellectual disability
  • Cancer: Chromosomal abnormalities (both numerical and structural) are hallmarks of most cancers, driving tumor development and progression. Cytogenetics is crucial for cancer diagnosis, prognosis, and monitoring
  • Telomere Biology: Telomere length and telomerase activity are implicated in aging and cancer, although routine clinical testing is less common

Key Terms

  • Chromosome: Organized structure of DNA and proteins carrying genetic information
  • Chromatin: Complex of DNA and associated proteins (primarily histones in eukaryotes)
  • Histones: Basic proteins (H1, H2A, H2B, H3, H4) crucial for DNA packaging into nucleosomes in eukaryotes
  • Nucleosome: Fundamental unit of chromatin; DNA wrapped around a histone octamer
  • Centromere: Constricted region of a chromosome; site of kinetochore formation
  • Telomere: Protective structure at the end of a linear eukaryotic chromosome
  • Sister Chromatids: Two identical copies of a replicated chromosome joined at the centromere
  • p arm / q arm: Short and long arms of a chromosome, respectively
  • Euchromatin: Less condensed, transcriptionally active chromatin
  • Heterochromatin: Highly condensed, transcriptionally inactive chromatin
  • Karyotype: An individual’s complete set of chromosomes, arranged systematically
  • Aneuploidy: Abnormal number of chromosomes
  • Translocation: Exchange of segments between non-homologous chromosomes
  • FISH (Fluorescence In Situ Hybridization): Technique using fluorescent probes to visualize specific DNA sequences on chromosomes
  • CMA (Chromosomal Microarray Analysis): Technique to detect genome-wide copy number variations