Chromosomal inheritance & nondisjunction

The chromosome theory of inheritance

In 1902, Theodor Boveri showed that sea urchin embryos develop properly only if they have a full set of chromosomes, and Walter Sutton, studying sperm formation in grasshoppers, saw that chromosomes come in matched pairs that separate in meiosis. Chromosomes behave just like Mendel's "factors": they come in pairs, the pairs separate into gametes, and different pairs sort independently. This led to the chromosome theory of inheritance: genes are located on chromosomes, and the way chromosomes move in meiosis explains Mendel's laws.

Morgan's white-eyed fly in 1910 tied one gene to one chromosome, the X. Bridges's exceptional flies then showed that when the chromosomes misbehave, the genes misbehave in exactly the same way. It follows that anything that changes the number or structure of chromosomes can change what an organism inherits.

Reading a karyotype

A karyotype is a picture of all of a cell's chromosomes. Cells are stopped in metaphase, when chromosomes are most condensed, stained so that each shows a pattern of light and dark bands, and then arranged in homologous pairs, roughly from largest (chromosome 1) to smallest.

Each chromosome is identified by its size, its banding pattern and the position of its centromere. The short arm is called p and the long arm q. A human karyotype has 22 pairs of autosomes plus two sex chromosomes: XX in females and XY in males.

Karyotypes are written in a short code: the total chromosome count, then the sex chromosomes, then any change. A typical male is 46,XY. A girl with Down syndrome is 47,XX,+21, meaning 47 chromosomes including an extra chromosome 21.

Nondisjunction: when chromosomes fail to separate

Nondisjunction is when chromosomes that should separate in meiosis go to the same pole instead. Where it happens changes the result.

1. 1In meiosis I, a pair of homologues fails to separate. Both go into one cell and none into the other.
2. 2Meiosis II then runs normally in both cells.
3. 3Result: all four gametes are abnormal. Two carry both homologues (n + 1) and two carry neither (n − 1).

1. 1In meiosis II, meiosis I goes normally, but in one of the two cells a pair of sister chromatids fails to separate.
2. 2Result: two gametes are normal (n), from the cell that divided properly. Of the other two, one gets both chromatids (n + 1) and one gets none (n − 1).

When an n + 1 gamete joins a normal one, the embryo has three copies of that chromosome, a trisomy (2n + 1). An n − 1 gamete gives a monosomy (2n − 1). Any cell with a missing or extra chromosome is aneuploid.

Down syndrome and other aneuploidies

Most aneuploid embryos don't survive. Losing an autosome entirely is lethal in humans. Some trisomies of small chromosomes, including 13, 18 and 21, can survive to birth, and trisomy 21 is the most common in live births, causing Down syndrome. Its cause was found in 1959 in Raymond Turpin's lab in Paris, in work published by Jérôme Lejeune, Marthe Gautier and Turpin. Gautier later argued that her role in the discovery had been downplayed.

About 94% of cases are a full extra chromosome 21 from nondisjunction. Around 88% of these extra chromosomes come from the mother, and most from her meiosis I. The risk rises steeply with maternal age: roughly 1 in 1,400 pregnancies at age 20 and 1 in 84 at age 40.

About 4% of cases are different: the extra chromosome 21 material is stuck to another chromosome in a Robertsonian translocation, where the long arms of two chromosomes fuse. A parent can carry this rearrangement in a balanced form, with 45 chromosomes and no symptoms, and have a much higher chance of a child with Down syndrome at any age. The remaining ~2% are mosaic, with only some cells trisomic, usually because the error happened after fertilisation.

Why extra or missing sex chromosomes are more survivable

Aneuploidies of the X and Y are far milder than autosomal ones. Examples include Turner syndrome (45,X), females with short stature and usually infertility, and the only full monosomy people survive (though most 45,X embryos still miscarry); Klinefelter syndrome (47,XXY), males with small testes and reduced fertility; and triple X (47,XXX), females who often have no obvious symptoms, though some are tall or have learning difficulties.

There are two reasons. First, the Y chromosome carries very few genes, so an extra Y changes little. Second, mammals already have a built-in system for coping with different X numbers. In each cell of an early female embryo of placental mammals such as humans, one X is chosen at random and shut down for good, condensing into a small dark lump called a Barr body. This is X inactivation, proposed by Mary Lyon in 1961. The rule is that all X chromosomes but one are inactivated, so an XXY or XXX cell still has just one active X.

Then why do these conditions have any symptoms at all? About 12–20% of genes on the inactive X escape inactivation and stay switched on. So a 45,X woman has too few doses of those genes, and a 47,XXY man has too many. No such system exists for autosomes, so an extra chromosome 21 unbalances hundreds of genes.

Changes to chromosome structure

Chromosomes can also break and rejoin wrongly. There are four main kinds of change:

• Deletion: a segment is lost, removing one copy of its genes. Losing part of the short arm of chromosome 5 causes cri-du-chat syndrome, named after the baby's high-pitched cry.
• Duplication: a segment is present twice, adding an extra dose of its genes.
• Inversion: a segment flips 180° and reinserts. No genes are lost, but their order changes. In someone who carries one inverted and one normal copy, crossovers inside the inverted region produce faulty chromatids, so recombinants between those genes are rarely recovered. A pericentric inversion includes the centromere; a paracentric one doesn't.
• Translocation: a segment moves to a different, non-homologous chromosome. In a reciprocal translocation two chromosomes swap pieces, and a carrier may be healthy but make unbalanced gametes. A translocation can also join genes into a harmful new combination, as happens in chronic myelogenous leukaemia.

Deletions and duplications change gene dosage. Inversions and translocations change which genes sit next to each other, which alters linkage and can break a gene at the join.

Key terms

Chromosome theory of inheritance

Genes sit on chromosomes, and chromosome behaviour in meiosis explains the patterns of inheritance.

Karyotype

An ordered picture of a cell's chromosomes, used to check their number and structure.

Nondisjunction

Failure of homologues (meiosis I) or sister chromatids (meiosis II) to separate.

Aneuploidy

Having a missing or extra chromosome, such as trisomy (2n + 1) or monosomy (2n − 1).

Gene dosage

The number of copies of a gene, which affects how much of its product is made.

X inactivation / Barr body

Silencing of all X chromosomes but one in each mammalian cell / the condensed inactive X.

Robertsonian translocation

Fusion of the long arms of two chromosomes, which can carry extra chromosome 21 material.

Deletion, duplication, inversion, translocation

A segment lost, repeated, flipped, or moved to a non-homologous chromosome.

Check yourself

Try answering in your head before you open each answer.

• 1.How many Barr bodies would you expect in the cells of a 47,XXX woman, a 47,XXY man and a 45,X woman?Show answerHide

  Two, one and none. All X chromosomes but one are inactivated, so the number of Barr bodies is the number of X chromosomes minus one.

• 2.A healthy woman has 45 chromosomes, one of which is a fusion of chromosomes 14 and 21. She has had a child with Down syndrome at age 25. Explain how, and why her risk is not mainly about her age.Show answerHide

  She carries a balanced Robertsonian translocation: her genes are all present in the normal dose. But in meiosis the fused chromosome and her free chromosome 21 can go to the same egg, which then carries two doses of chromosome 21 material. With the father's 21, the child has three. The risk comes from how her chromosomes are built, so it doesn't depend on her age the way nondisjunction does.

• 3.Genetic markers show that a child with trisomy 21 has two copies of chromosome 21 from the mother that are identical near the centromere. In which division did nondisjunction probably happen?Show answerHide

  Maternal meiosis II. Identical copies near the centromere means sister chromatids of one homologue ended up in the same egg. If meiosis I had failed, the egg would carry both of the mother's different homologues.