Independent assortment
At metaphase I each bivalent orients at random, independently of the others. Shuffle the plate and count how many different combinations of maternal and paternal chromosomes the gametes can receive.
The human karyotype
A karyogram arranges the 46 metaphase chromosomes in pairs by size and centromere position. Click any chromosome for its notable genes; load an abnormal karyotype to see what nondisjunction produces.
From DNA to chromosome
About 2 metres of DNA fits into a nucleus 6 µm across. Zoom out through each level of packaging, from the double helix to a metaphase chromosome.
Nondisjunction in humans
Choose the parent, the chromosome and the division in which separation fails. See the four products of meiosis and what happens when each is fertilised by a normal gamete.
Key facts to remember
- Human somatic cells: 46 chromosomes (22 pairs of autosomes + XX or XY). Gametes: 23. Karyotype notation: total, sex chromosomes, then the change, e.g. 47,XX,+21.
- Mitosis gives 2 identical diploid cells; meiosis gives 4 varied haploid gametes. Homologues separate in anaphase I, sister chromatids in anaphase II.
- Nondisjunction in meiosis I makes all four gametes aneuploid; in meiosis II, two of four. n + 1 gamete → trisomy (47); n − 1 → monosomy (45).
- Down syndrome: about 95 % free trisomy 21 (nondisjunction, mostly maternal meiosis I), about 3 % Robertsonian translocation (check the parents' karyotypes), about 2 % mosaic.
- Maternal-age risk of a Down syndrome pregnancy: about 1 in 1500 at 20, 1 in 800 at 30, 1 in 270 at 35 and 1 in 100 at 40. Most affected babies are still born to younger mothers, who have most of the babies.
- Turner 45,X is the only viable monosomy (short stature, coarctation of the aorta, ovarian failure). Klinefelter 47,XXY: tall, small testes, infertility.
- Vinca alkaloids (vincristine) block spindle microtubules, so dividing cells arrest in metaphase. Cytogenetics labs use colcemid the same way to collect metaphase chromosomes.
- Chronic myeloid leukaemia: the Philadelphia chromosome, t(9;22), fuses BCR and ABL; imatinib blocks the fusion kinase.
Sources: American Family Physician review of Down syndrome prenatal risk (aetiology percentages); GPnotebook maternal-age table; standard medical genetics texts. Educational summary: follow current national and hospital protocols and your supervisors.
Chromosomes and ploidy
A chromosome is one continuous DNA molecule packaged with proteins (chromatin). Human somatic cells are diploid: 46 chromosomes in 23 homologous pairs (the two members carry the same genes in the same order, though possibly different alleles), one member of each pair from each parent. Gametes are haploid with 23. We write the number of chromosome sets as $n$ and the DNA content as $C$ (one haploid genome = 1C, about $3.1\times10^9$ bp in humans):
After replication each chromosome consists of two identical sister chromatids joined at the centromere, where the kinetochore (a protein patch that spindle microtubules grab) assembles. The sisters are held together along their length by rings of a protein called cohesin. Chromosomes are classified by centromere position: metacentric (arms equal, e.g. 1, 3), submetacentric (e.g. 4–12, X) and acrocentric (very short p arm, e.g. 13–15, 21, 22). The short arm is p, the long arm q, and the ends are protected by telomeres (TTAGGG repeats).
The cell cycle and mitosis
Interphase (G1, S, G2) occupies most of the cycle. Checkpoints at G1/S, G2/M and the spindle assembly checkpoint in metaphase ensure DNA is intact and every kinetochore is attached before anaphase. Mitosis separates sister chromatids so that each daughter cell receives an identical copy of the genome. It is used for growth, repair and asexual reproduction.
- Prophase: chromatin condenses (condensin), centrosomes separate, spindle forms.
- Prometaphase: nuclear envelope breaks down; microtubules capture kinetochores.
- Metaphase: chromosomes align at the equator; sister kinetochores bi-oriented.
- Anaphase: the enzyme separase cuts the cohesin rings; sisters move to opposite poles (anaphase A) and poles move apart (anaphase B).
- Telophase and cytokinesis: nuclei re-form; a contractile ring of actin and myosin divides the cytoplasm (a cell plate in plants).
Meiosis: making haploid, varied gametes
Meiosis I is the reductional division (it halves the chromosome number): homologues pair up as bivalents (also called tetrads: two homologues, four chromatids), recombine and separate. Meiosis II is equational, like mitosis, separating sister chromatids. Genetic variation arises from three sources:
- Crossing over in prophase I exchanges segments between non-sister chromatids at chiasmata. Genes far apart on a chromosome recombine more often; the recombination frequency between two loci gives the genetic map distance (1 % = 1 centimorgan).
- Independent assortment: each bivalent orients at random at metaphase I, giving $2^n$ combinations of whole chromosomes, $2^{23} = 8\,388\,608$ for a human gamete.
- Random fertilisation of any egg by any sperm squares this: $2^{23}\times2^{23} \approx 7\times10^{13}$ chromosome combinations before counting crossovers.
Chiasmata also hold homologues together until anaphase I; a bivalent without a crossover is prone to mis-segregation. Cohesin along the arms is removed in anaphase I, while centromeric cohesin is protected by shugoshin until anaphase II.
Nondisjunction and aneuploidy
Nondisjunction is the failure of chromosomes to separate. In meiosis I, both homologues go to the same pole; all four gametes are abnormal (two $n+1$, two $n-1$). In meiosis II, sisters fail to separate in one cell, giving one $n+1$, one $n-1$ and two normal gametes. Fertilisation of an $n+1$ gamete gives a trisomy (2n + 1); an $n-1$ gamete gives a monosomy (2n − 1).
| Karyotype | Condition | Frequency at birth | Main features |
|---|---|---|---|
| 47,XX,+21 or 47,XY,+21 | Down syndrome | ≈1 in 700 | Intellectual disability, heart defects, characteristic facial features; risk rises with maternal age |
| 47,XX,+18 or 47,XY,+18 | Edwards syndrome | ≈1 in 5000 | Severe; most affected infants die within the first year |
| 47,XX,+13 or 47,XY,+13 | Patau syndrome | ≈1 in 10 000 | Severe brain, heart and facial malformations |
| 45,X | Turner syndrome | ≈1 in 2500 girls | Short stature, ovarian insufficiency; the only viable human monosomy |
| 47,XXY | Klinefelter syndrome | ≈1 in 600 boys | Tall stature, small testes, reduced fertility |
| 47,XYY | Jacobs syndrome | ≈1 in 1000 boys | Often unnoticed; tall stature |
| 47,XXX | Triple X | ≈1 in 1000 girls | Often unnoticed; tall stature |
Most aneuploidies arise in maternal meiosis I. Human oocytes enter meiosis I before birth and pause in prophase I for decades; cohesin deteriorates with age, which is one reason the risk of trisomy rises with maternal age. Sex chromosome aneuploidies are tolerated better because of X inactivation and the small number of genes on the Y.
| Feature | Mitosis | Meiosis |
|---|---|---|
| Purpose | Growth, repair, asexual reproduction | Production of gametes (animals) or spores (plants, fungi) |
| Divisions | One | Two (meiosis I and II), with no DNA replication between them |
| Daughter cells | 2, diploid (2n), 2C | 4, haploid (n), 1C |
| Genetic identity | Identical to parent and each other | All different from parent and each other |
| Pairing of homologues | No | Yes, synapsis in prophase I (bivalents/tetrads) |
| Crossing over | No (rare) | Yes, at least one chiasma per bivalent normally |
| Metaphase alignment | Individual chromosomes; sister kinetochores face opposite poles | MI: bivalents, homologues face opposite poles; MII: like mitosis |
| Anaphase separates | Sister chromatids | MI: homologues; MII: sister chromatids |
| Cohesin removal | All at anaphase | Arms at anaphase I, centromeres at anaphase II (shugoshin protects) |
| Where in humans | Somatic cells throughout the body | Ovaries and testes only |
| Error consequence | Somatic mosaicism, cancer (chromosomal instability) | Aneuploid gametes and conceptions (trisomy, monosomy) |
1. Chromosome number and DNA content
A human cell in G1 has 46 chromosomes and 2C ≈ 6.2 × 10⁹ bp. After S phase: 46 chromosomes, 92 chromatids, 4C.
After meiosis I: each cell has 23 chromosomes (each still two chromatids), 2C. After meiosis II: 23 chromosomes, 23 chromatids, 1C.
In the 2n = 4 model above: interphase after S = 4 chromosomes, 8 chromatids; telophase I = 2 chromosomes, 4 chromatids per cell; each gamete = 2 chromatids.
2. Combinations from independent assortment
Each of $n$ bivalents has 2 orientations, so a gamete can receive $2^n$ combinations of parental chromosomes.
$n = 3$: $2^3 = 8$. Probability that a gamete carries only maternal chromosomes: $(1/2)^3 = 0.125$.
Humans, $n = 23$: $2^{23} = 8\,388\,608$; $P(\text{all maternal}) = 2^{-23} \approx 1.2\times10^{-7}$.
A zygote: $2^{23}\times2^{23} = 2^{46} \approx 7.0\times10^{13}$ combinations, not counting crossing over.
3. Recombination and map distance
In the simulator, a single crossover between the centromere and locus A in a bivalent makes 2 of the 4 chromatids recombinant for that interval, so a crossover in every meiosis gives a recombination frequency of 50 %.
If crossovers in that interval occur in only 20 % of meioses, recombinant gametes are $0.20 \times 0.5 = 10\,\%$: a map distance of 10 cM. This is why recombination frequency never exceeds 50 %.
4. How much DNA, and how tightly packed?
A diploid human nucleus holds about $6.2\times10^9$ bp. At 0.34 nm per bp: $6.2\times10^9 \times 0.34\times10^{-9}\ \text{m} \approx 2.1$ m of DNA.
One nucleosome per ≈200 bp (147 bp core + ≈50 bp linker): $6.2\times10^9/200 \approx 3\times10^7$ nucleosomes per cell.
Chromosome 1 (248 Mb) is $248\times10^6\times0.34$ nm ≈ 8.4 cm long as naked DNA, but about 10 µm as a metaphase chromosome: a packing ratio near $8.4\times10^{-2}/10^{-5} \approx 8000$.
5. Products of nondisjunction
Meiosis I error for chromosome 21 in the mother: eggs with 24 (two copies of 21) or 22 (no 21) chromosomes. Fertilised by a normal sperm (23): 47,XX,+21 or 47,XY,+21 (Down syndrome), or 45,XX,−21 or 45,XY,−21 (not viable).
Meiosis II error: 1 egg 24, 1 egg 22, 2 eggs normal (23). Only half the products are abnormal.
Paternal meiosis I error for XY: sperm XY or O. XY + X egg → 47,XXY (Klinefelter); O + X egg → 45,X (Turner).
Guided challenges
Each challenge is checked automatically in the labs above.
Investigations
- Set the crossover on pair A to 30 % (p arm) and then to 65 % (between centromere and gene A). Which setting changes the alleles in the gametes? Explain using the positions of the centromere and locus.
- Run meiosis with no crossovers and count gamete genotypes for all four orientations of the two pairs. Which genotypes are possible, and how does crossing over add to them?
- With nondisjunction in meiosis I versus meiosis II, what fraction of gametes is aneuploid? Use the human explorer to connect each case to a karyotype.
- In the assortment lab with n = 23, how many shuffles would you expect before seeing the same gamete twice? (Hint: the birthday problem, about $\sqrt{\pi 2^{23}/2} \approx 3600$.)
Chromosomes in the clinic and the laboratory
| Karyotype | Condition | Findings you may meet | Practice points |
|---|---|---|---|
| 47,XX,+21 or 47,XY,+21 | Down syndrome | Hypotonia, upslanting palpebral fissures, single palmar crease, sandal gap | Echocardiogram (atrioventricular septal defect), check thyroid function, watch for duodenal atresia and leukaemia; translocation type: karyotype the parents |
| 47,XX,+18 or 47,XY,+18 | Edwards syndrome | Clenched hands with overlapping fingers, rocker-bottom feet, growth restriction | Most die in the first year; palliative care planning with the family |
| 47,XX,+13 or 47,XY,+13 | Patau syndrome | Cleft lip and palate, polydactyly, holoprosencephaly | Very poor survival; supportive care |
| 45,X | Turner syndrome | Lymphoedema at birth, short stature, webbed neck, primary amenorrhoea | Check for coarctation of the aorta and kidney anomalies; growth hormone and oestrogen replacement |
| 47,XXY | Klinefelter syndrome | Tall stature, small firm testes, gynaecomastia, infertility | Testosterone replacement; fertility referral |
| t(9;22) | Chronic myeloid leukaemia (acquired, in blood cells) | Very high white cell count, big spleen | BCR-ABL tyrosine kinase inhibitors such as imatinib |