Gene Organisation and Chromosomes

Viral and Bacterial Genomes

Relatively small genomes that typically consist of a single nucleic acid molecule (DNA or RNA) and are largely devoid of associated packaging proteins.

Human Genome Packaging Problem

The physical requirement to compress approximately $2.2\,\text{m}$ ($2{,}200{,}000\,\mu\text{m}$) of linear diploid DNA ($3.2 \times 10^9\,\text{base pairs}$ with $3.4\,\text{\AA}$ base pair spacing) into a cell nucleus with a diameter of approximately $10\,\mu\text{m}$.

Histones

Small, highly basic eukaryotic packaging proteins composed of approximately $25\%$ basic amino acid residues (arginine and lysine) that associate with DNA to mediate chromatin condensation.

Core Histones

The four classes of histone proteins—$H2A$, $H2B$, $H3$, and $H4$—that assemble into an octameric protein core to organize DNA.

Histone H1

A linker histone protein that associates with linker DNA outside the nucleosome core particle to assist in folding the $10\,\text{nm}$ fiber into higher-order structures.

Nucleosome

The fundamental structural repeating unit of chromatin, consisting of an octamer of core histone proteins ($H2A$, $H2B$, $H3$, $H4$) wrapped by approximately $146$ base pairs of DNA to form a $10\,\text{nm}$ 'beads on a string' fiber.

Solenoid

The supercoiled chromatin structure forming a $30\,\text{nm}$ fiber, produced by the helical coiling of the continuous nucleosome strand and stabilized by histone $H1$.

Orders of Chromatin Structure

The progressive levels of DNA compaction in eukaryotic cells: naked DNA ($2\,\text{nm}$), nucleosomes ($10\,\text{nm}$ fiber), solenoid ($30\,\text{nm}$ fiber), looped chromatin domains ($300\,\text{nm}$), chromatids ($700\,\text{nm}$), and mitotic metaphase chromosomes ($1400\,\text{nm}$).

Euchromatin

A loosely packed, uncoiled form of chromatin that is transcriptionally active and characterized by high levels of histone acetylation and unmethylated histones.

Heterochromatin

A densely packed, condensed form of chromatin that is transcriptionally repressed and characterized by a low degree of histone acetylation and high levels of histone and DNA methylation.

Histone Acetylation

An epigenetic modification added by writer enzymes that relaxes chromatin into an open, transcriptionally active state, which is reversed by deacetylase eraser enzymes.

Histone Deacetylase (HDAC) Inhibitors

Therapeutic compounds, including antiepileptic drugs such as valproic acid (VPA) and topiramate (TPM), that inhibit HDAC enzymes to promote histone hyperacetylation and chromatin relaxation.

3-Deazaneplanocin A (DZNep)

An investigational epigenetic reversal agent that reverses histone methylation by decreasing trimethylation of histone $H3$ lysine 27 ($H3K27$) to presensitize cancer cells to nucleoside analogs like gemcitabine.

Chromosome

A macromolecular complex consisting of a single long linear DNA molecule containing numerous genes packaged with proteins, visible as an individual condensed entity during mitosis.

Sister Chromatids

Two identical copies of a replicated chromosome joined together at the centromere prior to separation during mitotic anaphase.

Centromere

The primary constriction of a chromosome that joins sister chromatids together, serves as the assembly site for kinetochore proteins, and divides the chromosome into short and long arms.

p Arm and q Arm

The structural arms of a chromosome defined by the position of the centromere, where $p$ denotes the short arm and $q$ denotes the long arm.

Replication Origins

Specific chromosomal nucleotide sequence locations where the DNA double helix unwinds and replication initiates.

Telomeres

Specialized nucleoprotein cap structures located at the physical ends of linear eukaryotic chromosomes composed of repetitive non-coding DNA sequences.

End-Replication Problem

The progressive loss of terminal DNA sequences occurring with each round of cell division caused by the inability of DNA polymerase to replicate the lagging strand at chromosome ends.

Telomerase

A ribonucleoprotein enzyme active in stem cells and cancer cells that synthesizes telomeric tandem repeats onto chromosome ends, counteracting replication-associated shortening.

Karyotype

The complete chromosomal complement of an individual or cell, systematically aligned and displayed in homologous pairs arranged by size.

Homologous Chromosomes

Chromosome pairs that are identical in size, morphology, and gene locus composition, with one homologue inherited from each parent.

G-Banding

A cytogenetic staining method employing Giemsa stain in which adenine- and thymine-rich, gene-poor heterochromatic regions stain darkly to yield distinctive diagnostic banding patterns.

Fluorescence In Situ Hybridisation (FISH)

A molecular cytogenetic technique utilizing fluorescently labeled DNA probes ($10\text{--}100\,\text{kb}$ long) to detect and localize specific complementary DNA sequences on chromosomes.

Autosomes

The 22 numbered, non-sex chromosome pairs in human cells that are shared identically between males and females.

Numerical Aberrations

Chromosomal anomalies caused by improper chromosome segregation during cell division that result in cells carrying an abnormal chromosome count.

Structural Aberrations

Chromosomal mutations resulting from the breakage and abnormal rejoining of chromosomal segments, including deletions, duplications, inversions, ring formations, and translocations.

Trisomy 21 (Down Syndrome)

A numerical chromosomal abnormality caused by the presence of three copies of chromosome 21, resulting in hypotonia, characteristic facial dysmorphisms, and intellectual disability.