Chromosome Structure

Human chromosomes are organized structures of DNA wound around histone proteins into chromatin. The 46 human chromosomes (22 pairs of autosomes plus XX or XY) are classified by centromere position and visualized through banding techniques. Understanding chromosome structure is essential for interpreting karyotypes, identifying structural abnormalities, and understanding gene regulation.

• Centromere: The constricted region where sister chromatids are joined and the kinetochore assembles for spindle attachment. Centromere position defines chromosome morphology: metacentric (center), submetacentric (off-center), acrocentric (near the end, with short arm satellite stalks).
• Telomeres: Protective repetitive sequences (TTAGGG in humans) at chromosome ends that prevent degradation and end-to-end fusion. Telomeres shorten with each cell division; critically short telomeres trigger senescence. Telomerase (TERT/TERC) maintains telomere length in germ cells and stem cells.
• Acrocentric chromosomes: Chromosomes 13, 14, 15, 21, and 22. Their short arms contain nucleolar organizing regions (NORs) with ribosomal RNA gene clusters. Acrocentric chromosomes are uniquely prone to Robertsonian translocations because loss of short-arm material is generally tolerated.
• Nucleolar organizing regions (NORs): Located on the short arms of all five acrocentric chromosomes. Contain tandem repeats of rDNA (ribosomal RNA genes). Silver staining (AgNOR) identifies active NORs. NOR material can be lost or rearranged without major phenotypic consequence because rRNA genes are highly redundant.
• Euchromatin: Loosely packed chromatin that is gene-rich and transcriptionally active. Located predominantly in R-bands (light bands on G-banding). Most pathogenic genes reside in euchromatic regions.
• Heterochromatin: Densely packed, transcriptionally silent chromatin. Constitutive heterochromatin is permanently condensed (centromeres, telomeres, Y long arm). Facultative heterochromatin can switch between active and inactive states (e.g., the inactive X chromosome / Barr body).
• G-banding (Giemsa banding): The standard karyotype technique. Trypsin treatment followed by Giemsa staining produces a pattern of dark (AT-rich, gene-poor, late-replicating) and light (GC-rich, gene-rich, early-replicating) bands. Standard resolution is 400-550 bands per haploid set; high-resolution can reach 850+.
• Other banding techniques: Q-banding (quinacrine, fluorescent, same pattern as G-banding), R-banding (reverse of G-banding, stains GC-rich regions dark), C-banding (highlights constitutive heterochromatin at centromeres), NOR staining (silver stain for active ribosomal genes).
• Chromosome nomenclature: Short arm = p (petit), long arm = q (queue). Bands are numbered from centromere outward. Example: 17p13.1 = chromosome 17, short arm, region 1, band 3, sub-band 1.

• Telomere biology disorders: Mutations in telomere maintenance genes (TERT, TERC, DKC1, RTEL1) cause dyskeratosis congenita, pulmonary fibrosis, and bone marrow failure. Short telomeres are a hallmark diagnostic finding.
• Pericentromeric and subtelomeric rearrangements: These regions are enriched in segmental duplications (low-copy repeats) that predispose to recurrent deletions and duplications via non-allelic homologous recombination (NAHR). Many recurrent microdeletion syndromes map to these regions.
• Acrocentric associations: Acrocentric chromosomes can associate at their NORs during cell division, predisposing to Robertsonian translocations. rob(13;14) is the most common Robertsonian translocation in the general population (~1/1,300).
• Heteromorphisms (normal variants): Variation in centromeric heterochromatin size, NOR stalk length, and Y long arm length are common and clinically insignificant but can complicate karyotype interpretation.