Difficulty: Intermediate to Advanced | Prerequisites: Parts 1 and 2 of these notes, understanding of meiosis (anaphase I, anaphase II), basic chromosome structure
Sometimes chromosomes do not behave normally during cell division, and sometimes inheritance does not follow the nuclear, biparental rules Mendel described. This section covers two broad areas: what goes wrong when chromosome number or structure changes (and the human disorders that result), and what happens when inheritance follows non-Mendelian patterns, specifically genomic imprinting and organelle (cytoplasmic) inheritance. These topics round out the chapter by showing the limits of the classical model.
Errors in chromosome separation during meiosis (nondisjunction) produce cells with too many or too few chromosomes, leading to conditions such as Down syndrome and Turner syndrome. Chromosomes can also break and rearrange, causing deletions, duplications, inversions, and translocations. Beyond these errors, two forms of inheritance break Mendelian rules: genomic imprinting (where expression depends on which parent donated the allele) and organelle inheritance (where mitochondrial and chloroplast genes pass almost exclusively from the mother).
Nondisjunction
The failure of homologous chromosomes to separate properly during meiosis I, or of sister chromatids to separate during meiosis II. Results in gametes with abnormal chromosome numbers.
Think of it as chromosomes that "refuse to let go" when they should be moving to opposite poles.
Aneuploidy
A condition in which a cell has an abnormal number of a particular chromosome (not a complete extra set). Caused by nondisjunction.
Monosomic (2n - 1)
An aneuploid cell missing one chromosome of a pair. The organism has one fewer chromosome than normal.
Trisomic (2n + 1)
An aneuploid cell with one extra chromosome. Down syndrome (trisomy 21) is the best-known example in humans.
Polyploidy
The condition of having more than two complete sets of chromosomes in somatic cells. Includes triploidy (3n) and tetraploidy (4n). Common in plants, usually lethal in animals.
Deletion
A chromosomal alteration in which a fragment of a chromosome is lost, removing genes from that chromosome.
Duplication
A chromosomal alteration in which a fragment becomes attached as an extra copy to a sister or non-sister chromatid, so part of the chromosome is repeated.
Inversion
A chromosomal alteration in which a fragment reattaches to the original chromosome in the reverse orientation. All genes are present but their order is flipped in that segment.
Translocation
A chromosomal alteration in which a fragment joins a nonhomologous chromosome. In a reciprocal translocation, two nonhomologous chromosomes exchange fragments.
Genomic imprinting
Variation in phenotype depending on whether an allele was inherited from the male or female parent. Involves silencing one allele through DNA methylation during gamete formation.
In simple terms, this means the same allele can behave differently depending on whether Mum or Dad passed it on.
Extranuclear genes (cytoplasmic genes)
Genes located in organelles (mitochondria, chloroplasts) rather than on nuclear chromosomes. These are inherited maternally in most organisms and do not follow Mendelian patterns.
Nondisjunction can occur at meiosis I (homologs fail to separate) or meiosis II (sister chromatids fail to separate).
The result: one gamete gets two copies of a chromosome, another gets none.
If an aberrant gamete fuses with a normal one, the zygote is aneuploid.
Monosomic (2n - 1): missing one chromosome
Trisomic (2n + 1): one extra chromosome
Mitosis transmits the anomaly to every descendant cell.
Nondisjunction can also occur during mitosis, leading to patches of aneuploid cells in an otherwise normal organism.
Polyploidy
Organisms with more than two complete chromosome sets: triploidy (3n), tetraploidy (4n).
Triploidy can arise when a diploid egg (from nondisjunction of all chromosomes) is fertilised by normal sperm.
Tetraploidy can arise when a 2n zygote replicates its chromosomes but fails to divide.
Common and well-tolerated in plants. Usually lethal in animals.
Polyploids look more nearly normal than aneuploids. One extra or missing chromosome disrupts genetic balance more than an entire extra set.
Four types of structural change, all triggered by chromosome breakage during meiosis:
Deletion: a chromosomal fragment is lost. The chromosome is now missing genes.
Duplication: a fragment attaches as an extra copy to a chromatid, so part of the chromosome is repeated.
Inversion: a fragment reattaches to the same chromosome but in reverse orientation. Gene order is flipped, but no genes are lost.
Translocation: a fragment joins a nonhomologous chromosome. In a reciprocal translocation, two nonhomologous chromosomes swap fragments.
Deletions and duplications are especially likely during crossing over, when non-sister chromatids exchange unequal-sized segments.
A large homozygous deletion is usually lethal (essential genes missing). Duplications and translocations also tend to be harmful. Inversions and reciprocal translocations keep all genes intact, but can still alter phenotype because a gene's expression can be influenced by its chromosomal neighbours (position effect).
Down syndrome (trisomy 21)
Affects about 1 in 830 live births in the US.
Caused by an extra copy of chromosome 21 (47 chromosomes total).
Associated with increased risk of leukaemia and Alzheimer's disease, but lower rates of high blood pressure, atherosclerosis, stroke, and many solid tumours.
Almost all males and about half of females with Down syndrome are sexually underdeveloped and sterile.
Frequency increases with maternal age: about 4 per 10,000 births in women under 30, rising to 92 per 10,000 in women 40 and older.
Most cases result from nondisjunction during meiosis I.
Aneuploidy of sex chromosomes
Generally less severe than autosomal aneuploidy, because the Y carries few genes and extra X chromosomes are inactivated.
Klinefelter syndrome (XXY): 1 in 500 to 1,000 male births. Male sex organs present but testes are small, sterile. Some breast enlargement, possible subnormal intelligence.
XYY males: about 1 in 1,000 male births. Tend to be taller than average. No other consistent effects.
Trisomy X (XXX): 1 in 1,000 female births. Tend to be taller than average. At risk for learning disabilities.
Turner syndrome (monosomy X, 45,X): 1 in 2,500 female births. The only viable monosomy in humans. Phenotypically female, sterile because sex organs do not mature.
Disorders from structural alterations
Cri du chat: deletion on chromosome 5. Severe intellectual disability, small head, distinctive cry resembling a cat.
Chronic myelogenous leukaemia (CML): a reciprocal translocation between chromosomes 9 and 22 during mitosis of white blood cell precursors. Produces a shortened chromosome 22 (the Philadelphia chromosome) and a fused gene that drives uncontrolled cell division.
For most genes, an allele's effect is the same regardless of which parent passed it on. Genomic imprinting is the exception: certain genes are silenced depending on the parent of origin.
Imprinting occurs during gamete formation. Methyl groups (-CH3) are added to cytosines of one allele, which can silence it (or, in some cases, activate it).
The offspring expresses only one allele of an imprinted gene, the one from Mum or Dad depending on the specific gene.
Imprints are erased and re-established each generation in gamete-producing cells, according to the sex of the individual forming the gametes.
Example: IGF2 in mice
The gene for insulin-like growth factor 2 (IGF2) is required for normal prenatal growth.
Only the paternal allele is expressed. The maternal allele is silenced.
A heterozygous mouse inheriting the mutant allele from its father is a dwarf (the only active copy is mutant). The same heterozygous mouse inheriting the mutant allele from its mother is normal-sized (the active paternal copy is wild type).
Methylation of certain cytosines on the paternal chromosome activates the paternal IGF2 allele through effects on chromatin structure.
Not all genes are in the nucleus. Mitochondria and chloroplasts carry their own small, circular DNA molecules with their own genes.
These extranuclear (cytoplasmic) genes do not follow Mendelian inheritance, because organelles are not distributed by the meiotic spindle.
In most organisms, organelle genes are inherited maternally: the egg contributes virtually all the cytoplasm (and its organelles) to the zygote.
Carl Correns first observed this in plants: leaf coloration was determined entirely by the maternal plant.
Mitochondrial inheritance in humans
Defects in mitochondrial genes reduce ATP production and most commonly affect the nervous system and muscles.
Mitochondrial myopathy: weakness, exercise intolerance, muscle deterioration.
Leber's hereditary optic neuropathy: sudden blindness, often in the 20s or 30s.
All mitochondrial disorders are inherited from the mother.
Students often think Down syndrome is caused by nondisjunction during meiosis II. Most cases result from nondisjunction during meiosis I, when homologous chromosomes fail to separate.
Students sometimes confuse aneuploidy with polyploidy. Aneuploidy is one or a few extra or missing chromosomes; polyploidy is one or more complete extra sets. Polyploids tend to be more viable than aneuploids.
Students often assume that inversions and translocations are always harmful because the chromosome "broke." In fact, reciprocal translocations and inversions keep all genes present. They can still cause problems through position effects, but the mechanism is different from a deletion.
Students sometimes think genomic imprinting means one parent's allele is always dominant. Imprinting is about silencing, not dominance. The silenced allele is not expressed at all, regardless of whether it is dominant or recessive.
⚠️ Know the four types of chromosomal structural change (deletion, duplication, inversion, translocation) and be able to identify each from a diagram.
⚠️ Be able to explain nondisjunction at meiosis I vs meiosis II and predict the resulting gamete chromosome numbers.
⚠️ Down syndrome, Klinefelter syndrome, and Turner syndrome are frequently tested. Know the karyotype, key features, and incidence for each.
⚠️ Understand why sex-chromosome aneuploidies are generally less severe than autosomal aneuploidies (Y carries few genes, extra X chromosomes are inactivated).
⚠️ Be able to explain genomic imprinting using the IGF2 example and predict offspring phenotypes depending on which parent contributes the mutant allele.
⚠️ Maternal inheritance of mitochondrial genes is a common short-answer or multiple-choice topic.
True or False: A trisomic organism has three complete sets of chromosomes. (False. It has one extra chromosome, not a full extra set. That would be triploidy.)
Fill in the blank: The only viable monosomy in humans involves the ______ chromosome. (X; Turner syndrome)
True or False: In genomic imprinting, the imprint is permanent and passes unchanged through all future generations. (False. Imprints are erased and re-established each generation in gamete-producing cells.)
Fill in the blank: Mitochondrial genes are inherited from the ______. (mother)
True or False: A reciprocal translocation results in a loss of genetic material. (False. Both chromosomes exchange fragments, so all genes are still present.)
Q: Nondisjunction occurs during meiosis I in a cell that is heterozygous (Aa) for a gene on the affected chromosome. What are the possible genotypes of the four resulting gametes?
A: Two gametes will carry both homologs (Aa), and two gametes will have no copy of that chromosome (nullisomic for that chromosome). Compare this with nondisjunction at meiosis II, which would produce one gamete with AA or aa (depending on which cell is affected), one normal gamete, and two nullisomic gametes.
Q: A couple has a child with Down syndrome. Explain the most likely chromosomal basis and why maternal age is a risk factor.
A: The child most likely has trisomy 21, caused by nondisjunction of chromosome 21 during meiosis I in the mother's egg cell. Maternal age is a risk factor because oocytes are arrested in meiosis I for decades; the longer the arrest, the higher the chance of errors in chromosome segregation.
Q: The IGF2 gene in mice is paternally imprinted for expression. A normal female is crossed with a male homozygous for a loss-of-function mutation in IGF2. What is the expected phenotype of the offspring?
A: All offspring are heterozygous (one normal allele from Mum, one mutant from Dad). Because only the paternal allele is expressed, and the paternal allele here is mutant, all offspring will be dwarfs, despite carrying a normal maternal allele.
Q: Why do mitochondrial disorders not follow Mendelian inheritance patterns?
A: Mitochondria are inherited almost exclusively from the mother (via the egg's cytoplasm). They are not distributed by the meiotic spindle and do not undergo segregation or independent assortment. An affected mother passes the disorder to all her children; an affected father passes it to none.
Q: A patient has chronic myelogenous leukaemia (CML). What chromosomal alteration is responsible, and how does it cause cancer?
A: A reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia chromosome (a shortened chromosome 22). The translocation fuses parts of two genes, producing a new hybrid gene whose protein product drives uncontrolled cell cycle progression.
Nondisjunction connects back to meiosis (Ch. 13), specifically the separation of homologs at anaphase I and sister chromatids at anaphase II. Genomic imprinting connects forward to gene regulation and epigenetics (DNA methylation, chromatin modification). Mitochondrial inheritance connects to cellular respiration (Ch. 9), since defects in mitochondrial genes reduce ATP output. The structural alterations (especially translocations) connect to cancer biology, where chromosomal rearrangements can activate oncogenes.
nondisjunction, aneuploidy, monosomic, trisomic, trisomy 21, Down syndrome, polyploidy, triploidy, tetraploidy, deletion, duplication, inversion, translocation, reciprocal translocation, Philadelphia chromosome, CML, Klinefelter syndrome XXY, Turner syndrome monosomy X, trisomy X, XYY, cri du chat, genomic imprinting, IGF2, paternal imprinting, maternal imprinting, DNA methylation, extranuclear genes, cytoplasmic genes, mitochondrial inheritance, maternal inheritance, organelle DNA, Leber's hereditary optic neuropathy, mitochondrial myopathy, position effect, chromosome breakage, linkage group