chromosome structure and organisation, including the role of histone proteins, sex chromosomes and autosomes, homologous pairs and karyotypes as a visual representation of chromosomes used to identify chromosomal abnormalities

What this dot point is asking

VCAA wants the structure of chromosomes (DNA + histones), the distinction between autosomes and sex chromosomes, the meaning of a homologous pair, and the use of a karyotype to identify chromosomal abnormalities.

The answer

Chromosome structure

A chromosome is one continuous DNA molecule packed with proteins, found in the nucleus of a eukaryotic cell. If stretched out, the DNA in a single human chromosome would be several centimetres long; it has to be packed thousands-of-times tighter to fit into a nucleus a few micrometres across.

Packaging happens through several levels:

1. Double helix. Two complementary DNA strands wound together (about 2 nm wide).
2. Nucleosomes. DNA wraps about 1.65 times around a core of 8 histone proteins (two each of H2A, H2B, H3 and H4). This forms the "beads on a string" of chromatin (about 11 nm wide).
3. 30-nm fibre. Linker histone H1 helps the nucleosomes coil into a denser fibre.
4. Loops and scaffolds. The fibre is organised into loops on a non-histone protein scaffold.
5. Condensed chromosome. During mitosis and meiosis, the chromatin condenses into the X-shaped chromosomes visible under a light microscope (about 700 nm wide).

In interphase, chromosomes are dispersed as chromatin, accessible for transcription and replication. During cell division, they condense into visible chromosomes that can be separated mechanically by the spindle.

After S-phase DNA replication, each chromosome consists of two identical sister chromatids joined at the centromere. The centromere is the attachment point for spindle fibres in mitosis and meiosis.

Autosomes and sex chromosomes

Human cells contain 46 chromosomes organised as 23 pairs.

• Autosomes: pairs 1 to 22 (44 chromosomes). These carry most of the genes and look identical in males and females.
• Sex chromosomes: pair 23. In humans, XX in females and XY in males. The X chromosome is large and contains around 800 genes. The Y chromosome is small (around 50 genes) and carries the SRY gene that triggers male development.

Other species have different sex-determination systems: birds use ZW (males ZZ, females ZW); some reptiles use temperature; bees use haploid-diploid.

Homologous chromosomes

A homologous pair is the two chromosomes in one pair (such as the two copies of chromosome 7, or X and X in a female). They:

• Are the same size and shape.
• Carry the same genes at the same loci.
• May carry the same allele or different alleles at each locus.
• Came one from each parent (one maternal, one paternal).

The two X chromosomes in a female are fully homologous. The X and Y in a male are not fully homologous: they pair only at the small pseudoautosomal regions. This is why sex-linked inheritance has different rules.

Diploid (2n) means having two copies of each chromosome (one homologous pair per gene). Haploid (n) means having one copy of each chromosome. Human somatic cells are diploid; gametes (sperm and egg) are haploid.

Karyotypes

A karyotype is a visual display of all the chromosomes in a cell, arranged by size, banding pattern and centromere position. To prepare one:

1. Cells are collected (typically white blood cells, or fetal cells from amniocentesis or chorionic villus sampling).
2. Cells are encouraged to divide; division is stopped at metaphase, when chromosomes are most condensed and visible.
3. Cells are spread on a slide, stained (commonly with Giemsa for G-banding), photographed.
4. The chromosomes are sorted by image: largest (chromosome 1) to smallest (chromosome 22), then the sex chromosomes.

The output is the familiar paired-up display.

What a karyotype can detect

• Sex. XX = female, XY = male.
• Numerical abnormalities (aneuploidy): the wrong number of one chromosome, almost always from non-disjunction in meiosis. Examples:
  • Down syndrome: trisomy 21 (three copies of chromosome 21), incidence about 1 in 700 births; risk rises with maternal age.
  • Edwards syndrome: trisomy 18.
  • Patau syndrome: trisomy 13.
  • Turner syndrome: XO (a single X, no second sex chromosome). Female phenotype with infertility and shorter stature.
  • Klinefelter syndrome: XXY. Male phenotype with reduced fertility.
  • Triple X: XXX.
• Structural abnormalities:
  • Deletions: a piece of chromosome is missing.
  • Duplications: an extra copy of a region.
  • Inversions: a section flipped end-to-end.
  • Translocations: a piece swapped between two non-homologous chromosomes (such as the Philadelphia chromosome in chronic myeloid leukaemia).

Karyotype notation

The convention: total chromosome number, comma, sex chromosomes, comma, any abnormalities.

• Normal female: 46, XX.
• Normal male: 46, XY.
• Down syndrome female: 47, XX, +21.
• Turner syndrome: 45, X.

Examples in context

Example 1. Down syndrome screening in Victorian maternity hospitals. Victorian maternity hospitals such as the Mercy Hospital for Women offer non-invasive prenatal testing (NIPT) and karyotyping for trisomy 21. A normal human karyotype shows 23 homologous pairs of chromosomes - 22 autosomal pairs and one sex pair (XX or XY). In Down syndrome the karyotype shows three copies of chromosome 21, a result of non-disjunction in meiosis I or II. The karyotype is prepared from a chorionic villus sample, with chromosomes arrested in metaphase by colchicine, stained with Giemsa for banding, then arranged by size. NIPT instead sequences fetal DNA fragments in the maternal blood. The karyotype remains the gold-standard confirmatory test.

Example 2. Klinefelter syndrome diagnosis at Monash Medical Centre. A teenage boy with delayed puberty and tall stature is referred to Monash Medical Centre endocrinology. His karyotype shows 47,XXY - one extra X chromosome attached to the normal X and Y sex pair. The extra X comes from non-disjunction in either parent's meiosis. Klinefelter syndrome affects 1 in 600 males and is associated with infertility and low testosterone. Histone proteins package the extra X into a Barr body (a darkly stained inactive X) visible on a buccal smear. Treatment is hormone replacement; the diagnosis reframes the patient's symptoms as a chromosomal rather than a hormonal disorder.

Try this

Q1. Describe the structure of a chromosome, including the role of histone proteins, with reference to nucleosomes. [3 marks]

• Cue. DNA double helix wraps twice around an octamer of histones (H2A, H2B, H3, H4) forming a nucleosome (the "beads on a string"); coiled further into 30 nm fibre and loops; condensed into the chromosome during mitosis.

Q2. A karyotype shows 47 chromosomes with three copies of chromosome 21. State the name of the condition, the type of mutation, and the probable cause. [3 marks]

• Cue. Down syndrome (trisomy 21); non-disjunction during meiosis I or II in egg or sperm formation.

Q3. Refer to sex determination in mammals. (a) Distinguish autosomes from sex chromosomes. (b) Explain how X inactivation produces a Barr body in XX cells. (c) Predict the karyotype of a person with Turner syndrome and explain the structural consequence. [2+2+2 marks]

• Cue. (a) Autosomes (1-22) carry non-sex genes; sex chromosomes (X and Y) determine sex. (b) One X is randomly inactivated in each cell to balance gene dosage; condenses to a Barr body. (c) 45,X (monosomy X); short stature, no functional ovaries.