Chromosomes and Cell Division

Short version. Humans have 46 chromosomes — established by Tjio and Levan in 1956, not the 48 the field had taught for three decades. Chromosomes are linear DNA-protein structures with centromeres, telomeres, and characteristic banding; they replicate during S phase, segregate during mitosis, and undergo recombination and reductional division during meiosis. When segregation fails or structure is rearranged, the result is the cytogenetic syndromes that opened the modern era of medical genetics: trisomy 21 (Lejeune et al. 1959), the Philadelphia chromosome (Nowell & Hungerford 1960), Turner, Klinefelter, and the microdeletion syndromes that arrived later with higher-resolution techniques.

A quick history: 46, not 48

The modern era of human cytogenetics begins with a single 1956 paper. Tjio and Levan, working in Lund, established the human diploid chromosome number as 46 — correcting a count of 48 that had been accepted since 1923. Their methodological advance combined hypotonic swelling of cells with colchicine arrest at metaphase, producing well-spread chromosomes that could actually be counted. Within three years the technique had given the field its first cytogenetic disease association, when Lejeune, Gautier and Turpin (1959) identified an extra copy of chromosome 21 in children with Down syndrome. The next year Nowell and Hungerford (1960) described a small marker chromosome in chronic myeloid leukaemia — the Philadelphia chromosome — the first cancer-associated chromosomal abnormality.

For a decade, however, individual chromosomes could only be grouped by size and centromere position (the Denver classification, A through G). The next leap was banding. In 1970 Caspersson and colleagues introduced quinacrine fluorescence (Q-banding), demonstrating reproducible patterns of bright and dim bands along each chromosome. Giemsa banding (G-banding) followed shortly and remains the workhorse of modern cytogenetics. With banding, every chromosome could be uniquely identified, and structural rearrangements — translocations, inversions, deletions — became visible at megabase resolution. The International System for Human Cytogenomic Nomenclature (ISCN) codified the language used to describe what was seen, and continues to be revised; the current edition is ISCN 2024.

What a chromosome is

At metaphase, when chromosomes are at their most condensed, a typical human chromosome is a few micrometres long and contains a single linear DNA molecule of tens to hundreds of megabases, wrapped around histone octamers and folded into higher-order structures. Each chromosome has three structural landmarks: two telomeres (the protected, repeat-rich ends), a single centromere (the constriction where sister chromatids are held together and the kinetochore assembles), and the chromatin in between. The short arm is denoted "p" (petit) and the long arm "q". The autosomes are numbered 1 to 22 in approximate decreasing size; the sex chromosomes are X and Y.

The packaging is hierarchical. ~146 base pairs of DNA wrap around a histone octamer to form the nucleosome (the "beads on a string" 11 nm fibre); chromatin folds into 30 nm fibres, then into loops anchored to a protein scaffold, and finally into the condensed metaphase chromosome whose volume is roughly ten thousand times smaller than the linear DNA it contains. Centromere identity is specified epigenetically by the histone variant CENP-A, which replaces canonical H3 in centromeric nucleosomes and recruits the kinetochore. Telomeres are tandem TTAGGG repeats bound by the shelterin complex, which both protects the chromosome end from being read as a double-strand break and regulates the action of telomerase. The structural detail of all of this — centromeres, telomeres, banding, FISH, microarrays, the long-read assemblies that finally completed the human reference — is the subject of chromosome structure and mapping.

How cells divide

Cells make more cells by progressing through the cell cycle: G1 (growth), S (DNA synthesis), G2 (preparation), and M (mitosis). The transitions between phases are gated by cyclin-dependent kinase (CDK) activity, regulated by the rise and fall of cyclins and by checkpoint machinery that halts the cycle when DNA is damaged or unreplicated, or when chromosomes are not correctly attached to the spindle. The discovery of cyclins, CDKs, and the cell-cycle control system, recognised by the 2001 Nobel Prize in Physiology or Medicine, is associated with the work of Hartwell, Hunt, and Nurse on yeast and sea-urchin systems.

Mitosis — prophase, prometaphase, metaphase, anaphase, telophase — is the process by which a duplicated genome is partitioned equally into two daughter nuclei. The central mechanical event is the alignment of replicated chromosomes (paired sister chromatids joined at the centromere) at the metaphase plate, followed by their separation when sister chromatid cohesion is dissolved at anaphase. Meiosis is the specialised division that produces gametes: a single round of DNA replication is followed by two rounds of division, halving the chromosome number from 46 to 23. The defining events of meiosis I — pairing of homologous chromosomes, formation of the synaptonemal complex, programmed double-strand breaks initiated by the topoisomerase-like enzyme SPO11, repair of those breaks by recombination, and the segregation of homologues rather than sisters — are why offspring inherit chromosomes that are mosaics of their parents' chromosomes, not exact copies. The full mechanics of the cell cycle and the meiotic programme are covered in cell cycle, mitosis and meiosis.

When cell division goes wrong

Errors in chromosome segregation produce aneuploidy — cells with too many or too few chromosomes. Most autosomal aneuploidies are incompatible with development; the survivable trisomies are 21, 18, and 13. Trisomy 21 (Down syndrome) was the first chromosomal disease described, and remains the most common viable autosomal aneuploidy in liveborn infants. Sex-chromosome aneuploidies — 45,X (Turner syndrome), 47,XXY (Klinefelter syndrome), 47,XYY, 47,XXX — are individually rarer but collectively common, and produce milder, more variable phenotypes. The strong dependence of trisomy frequency on maternal age, established empirically over decades and reviewed by Hassold and Hunt (2001), traces back to the long arrest of human oocytes in prophase I and the consequent ageing of meiotic spindle and cohesion machinery.

Structural rearrangements — reciprocal and Robertsonian translocations, inversions, deletions, duplications, isochromosomes, ring chromosomes — arise from mis-repaired double-strand breaks, ectopic recombination between repeats, and replication errors. A balanced rearrangement, in which all genetic material is present but rearranged, may be phenotypically silent in the carrier but generate unbalanced gametes. The Philadelphia chromosome, t(9;22)(q34;q11), is the canonical somatic example: the resulting BCR-ABL1 fusion drives chronic myeloid leukaemia and was the first chromosomal abnormality with a known oncogenic mechanism. Submicroscopic copy-number variants — the 22q11.2 deletion, the 7q11.23 deletion underlying Williams-Beuren syndrome, the 15q11-q13 region behind Prader-Willi and Angelman syndromes — opened up after chromosomal microarray (aCGH; SNP arrays) entered routine use in the 2000s, and were associated systematically with disease by Cooper et al. (2011). Non-invasive prenatal testing of cell-free fetal DNA in maternal plasma, demonstrated at scale by Bianchi et al. (2014), has since become the routine antenatal screen for the common autosomal aneuploidies. The full catalogue of mechanisms and named syndromes is the subject of chromosomal abnormalities.

Why this matters for pedigree work

Pedigree analysis is the diagrammatic record of inherited variation across a family, and the units of that inheritance are chromosomes. Mendel's laws of segregation and independent assortment are statements about meiosis. Linkage between traits is a consequence of physical proximity on the same chromosome; recombination is the reason linkage decays with distance. Sex-linked inheritance follows the X and Y; mitochondrial inheritance bypasses the nuclear chromosomes entirely. When a pedigree shows a cytogenetic abnormality — a balanced translocation segregating in a family, an unbalanced product producing affected offspring, a Robertsonian translocation explaining recurrent loss — the inheritance pattern in the pedigree and the chromosomal mechanism are two views of the same phenomenon. Educational pedigree drawing tools that record the ISCN-format karyotype alongside the pedigree symbols, such as ISCN-aware pedigree notation and the karyogram viewer, sit at this junction.

How this pillar is organised

The three subtopic pages take each branch in detail:

Chromosome structure and mapping — centromeres, telomeres, the packaging hierarchy, the cytogenetic and molecular techniques used to read chromosomes (G-banding, FISH, spectral karyotyping, aCGH, SNP arrays, long-read assemblies), and the ISCN nomenclature.
Cell cycle, mitosis and meiosis — cyclin-CDK regulation, the four checkpoints, mitotic mechanics, the meiotic programme, SPO11-induced double-strand breaks, recombination hotspots and PRDM9, and the origin of non-disjunction.
Chromosomal abnormalities — numerical aneuploidies and the maternal age effect, structural rearrangements (reciprocal and Robertsonian translocations, inversions, deletions, duplications, isochromosomes, ring chromosomes), microdeletion syndromes, and the cytogenetic and microarray techniques used to detect them.

Foundational references

Tjio JH, Levan A. The chromosome number of man. Hereditas 1956;42:1.
Lejeune J, Gautier M, Turpin R. Etude des chromosomes somatiques de neuf enfants mongoliens. Comptes rendus hebdomadaires des seances de l'Academie des sciences 1959;248:1721.
Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.
Caspersson T, Zech L, Johansson C, Modest EJ. Identification of human chromosomes by DNA-binding fluorescent agents. Experimental Cell Research 1970;60:315.
Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Reviews Genetics 2001;2:280.
Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nature Genetics 2011;43:838.
Bianchi DW, Parker RL, Wentworth J et al. DNA sequencing versus standard prenatal aneuploidy screening. New England Journal of Medicine 2014;370:799.
ISCN 2024: An International System for Human Cytogenomic Nomenclature. Karger.