Chapter 16
Variations in Chromosome
Structure and Number

Most human malignant tumors have
chromosomal mutations.
◦ a. The most common are translocations.
◦ b.There is much variation in chromosome
abnormalities, however, and they include simple
rearrangements to complex changes in
chromosome structure and number.
◦ c. Many tumor types show a variety of mutations.
◦ d.Some, however, are associated with specific
chromosomal abnormalities.

Chronic myelogenous leukemia
(CML; OMIM 151410) involves a
reciprocal translocation of
chromosomes 9 and 22.
◦ i. Myeloblasts (stem cells of white
blood cells) replicate uncontrollably.
◦ ii. 90% of CML patients have the
Philadelphia chromosome (Ph1)
reciprocal translocation.
◦ iii. The reciprocal translocation causes
transition from a differentiated cell to
a tumor cell, by translocating a protooncogene from chromosome 9 to
chromosome 22 and probably
converting it to the ABL oncogene.
◦ iv. The hybrid gene arrangement
causes expression of a leukemiaproducing constitutively activated
tyrosine kinase. The drug Gleevec
blocks the tyrosine kinase, reducing
white blood cell proliferation.
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Sometimes inversions or translocations change
phenotypic expression of genes by the position
effect, for example, by moving a gene from
euchromatin to heterochromatin (transcription
generally occurs in euchromatin but not in
heterochromatin).
This is an example of an epigenetic effect since
the DNA sequence of the gene is not affected.
An example is the white-eye (w) locus in
Drosophila:
◦ a. An inversion moves the w1 gene from a euchromatin
region of the X chromosome to a position in
heterochromatin.
◦ b. In a w1 male, or a w1/w female, where w1 is involved in
the inversion, the eyes will have white spots resulting from
the cells where the w1 allele was moved and inactivated.


Chromosomes in cultured human cells develop
narrowings or unstained areas (gaps) called
fragile sites; over 40 human fragile sites are
known.
A well-known example is fragile X syndrome, in
which a region at position Xq27.3 is prone to
breakage and mental retardation may result.
◦ a. Fragile X syndrome has an incidence in the United
States of about 1/1,250 in males, and 1/2,500 in
females (heterozygotes).
◦ b. Inheritance follows Mendelian patterns, but only 80%
of males with a fragile X chromosome are mentally
retarded. The 20% with fragile X chromosome but a
normal phenotype are called normal transmitting males.
 i. A normal transmitting male can pass the chromosome
to his daughter(s).
 ii.Sons of those daughters frequently show mental
retardation

Molecular analysis shows a repeated 3-bp sequence, CGG, in
the FMR-1 (fragile X mental retardation-1) gene, at the fragile
X site.
◦ i. Normal individuals have 6 to 54 CGG repeats, with an average of 29.
◦ ii. Normal transmitting carrier males, their daughters, and some other
carrier females have 55 to 200 copies but do not show symptoms.
◦ iii.Individuals with fragile X syndrome have 200 to 1,300 copies,
indicating that tandem amplification of this sequence is tolerated until
a threshold number of copies is reached.
◦ iv.Amplification of CGG repeats occurs only in females, perhaps during
a slipped mispairing process during DNA replication.
◦ v. The FMR-1 product (FMRP) is an RNA-binding protein. The triplet
repeat expansion in FMR-1 affects expression of certain mRNAs,
blocking protein synthesis. FMRP is active at synapses in the brain.
◦ vi. In individuals with the full mutation, C nucleotides of the CGG
repeats are methylated, silencing the FMR-1 gene and resulting in
mental retardation.


An organism or cell is euploid when it has one
complete set of chromosomes, or exact
multiples of complete sets. Eukaryotes that are
normally haploid or diploid are euploid, as are
organisms with variable numbers of
chromosome sets.
Aneuploidy results from variations in the
number of individual chromosomes (not sets),
so that the chromosome number is not an
exact multiple of the haploid set of
chromosomes.

Aneuploidy can occur due to nondisjunction during meiosis.
◦ a. Nondisjunction during meiosis I will produce four gametes, two with
a chromosome duplicated and two that are missing that chromosome.
 i. Fusion of a normal gamete with one containing a chromosomal
duplication will produce a zygote with three copies of that chromosome
and two of all others.
 Ii. Fusion of a normal gamete with one missing a chromosome will result
in a zygote with only one copy of that chromosome, and two of all
others.
◦ b. Nondisjunction during meiosis II produces two normal gametes and
two that are abnormal (one with two sibling chromosomes and one
with that chromosome missing).
 i. Fusion of abnormal gametes with normal ones will produce the
genotypes discussed above.
 Ii. Normal gametes are also produced, and when fertilized will produce
normal zygotes.
◦ c. More complex gametic chromosome composition can result when:
 i. One chromosome is involved.
 Ii. Nondisjunction occurs in both meiotic divisions.
 Iii. Nondisjunction occurs in mitosis (result is somatic cells with unusual
chromosome complements).

Autosomal aneuploidy is not well
tolerated in animals, and in mammals it
is detected mainly after spontaneous
abortion. Aneuploidy is much better
tolerated in plants. There are four main
types of aneuploidy:
◦ a. Nullisomy involves loss of one
homologous chromosome pair (the cell is
2N - 2).
◦ b. Monosomy involves loss of a single
chromosome (2N - 1).
◦ c. Trisomy involves one extra
chromosome, so the cell has three copies
of one chromosome and two of all the
others (2N + 1).
◦ d. Tetrasomy involves an extra
chromosome pair, so the cell has four
copies of one chromosome and two of all
the others (2N + 2).


A monosomic cell (2N - 1):
◦ i. May produce gametes that are N (normal) and
N - 1 (monosomic).
◦ Ii. Or, the unpaired chromosome may be lost
completely, producing gametes that are all N 1.
A trisomic cell (2N + 1) with the genotype
+/+/a is an example (assuming that this
organism can tolerate trisomy, and no
crossing-over occurs).
◦ i. Gametes produced belong to four genotypic
classes, in these proportions:
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


(1)
(2)
(3)
(4)
Two gametes with genotype +/a.
Two gametes with genotype +.
One gamete with genotype +/+.
One gamete with genotype a.
◦ Ii. The cross of a +/+/a trisomic to an a/a
individual will produce a phenotypic ratio of 5
wild type : 1 mutant (a).

Trisomy-21 occurs in an estimated 3,510/106
conceptions, and 1,430/106 births.
◦ a. Down syndrome (OMIM 190685) individuals are
characterized by:
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i. Low IQ
ii. Epicanthal folds over eyes
iii. Short and broad hands
iv. Below-average height
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A female fetus before birth produces primary oocytes in her
ovaries that stop their development at prophase I of meiosis.
After puberty, secondary oocytes develop from the primary ones,
entering the second meiotic division but again arresting, this
time at metaphase II.
If fertilization occurs, the second meiotic division is completed.
The probability of nondisjunction increases with the length of
time the primary oocyte is in the ovary.
Amniocentesis or chorionic villus sampling can determine
whether the fetus has a normal complement of chromosomes.
Additional risks for Down syndrome include:
◦ i. Increased paternal age
◦ ii. Smoking in mothers who have an error in meiosis II, especially if they
use oral contraceptives (oral contraceptives alone do not increase risk)

Robertsonian translocation (centric fusion) produces three
copies of the long arm of chromosome 21, resulting in familial
Down syndrome (Figure 16.18).
◦ i. In this nonreciprocal translocation, two nonhomologous acrocentric
(centromeres near end) chromosomes break at centromeres.
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(1) Both long arms become
attached to the same centromere,
creating a chromosome with the
long arm of chromosome 21 and
the long arm of chromosome 14
(or 15).
(2) The short arms also fuse,
forming a reciprocal product that
is usually lost within a few cell
divisions.
(3) The heterozygous carrier of
this chromosome is phenotypically
normal, since the two copies of
each major chromosome arm
supply two copies of all essential
genes.

Trisomy-13
◦ Trisomy-13 (Patau syndrome) occurs in 2/104 live births, and most die
within the first 3 months. Characteristics:
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a. Cleft lip and palate
b. Small eyes
c. Polydactyly (extra fingers and toes)
d. Mental and developmental retardation
e. Cardiac and other abnormalities
Trisomy-18
◦ Trisomy-18 (Edwards syndrome) occurs in 2.5/104 live births, and 90% die
within 6 months. About 80% of Edwards syndrome infants are female.
Characteristics include (Figure 16.21):
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a. Small size with multiple congenital malformations throughout the body.
b. Clenched fists.
c. Elongated skull.
d. Low-set ears.
e. Mental and developmental retardation.


Monoploidy and polyploidy involve complete
sets of chromosomes, and so both are cases of
euploidy. Euploidy is lethal in most animal
species but often tolerated in plants, where it
has played a role in speciation and
diversification.
Monoploidy and polyploidy can result when
either round of meiotic division lacks
cytokinesis, or when meiotic nondisjunction
occurs for all chromosomes.
◦ a. Complete nondisjunction at meiosis I will produce
1⁄ gametes with normal chromosomes, 1⁄ with two sets
2
4
of chromosomes, and 1⁄4 with no chromosomes.
◦ b. A gamete with two sets of chromosomes fused with
a normal gamete produces a triploid (3N) zygote.
◦ c. Fusion of two gametes that each have two sets of
chromosomes produces a tetraploid (4N) zygote.
◦ d. Polyploidy of somatic cells can result from mitotic
nondisjunction of complete chromosome sets.

Monoploidy is rare in adults of diploid species
due to recessive lethal mutations.
◦ a. Males of some species (e.g., wasps, ants, and
bees) develop from unfertilized eggs and are
monoploid.
◦ b.Mutants are easily produced from monoploid
individuals since mutants can be isolated directly.

Polyploidy involves three or more sets of
chromosomes and may occur naturally (e.g., by
breakdown of the mitotic spindle) or by induction
(e.g., with chemicals such as colchicine).
◦ a. Nearly all plants and animals probably have some
polyploid tissues. Examples:
 i. Plant endosperm is triploid.
 ii. Liver of mammals (and perhaps other vertebrates) is
polyploid.
 iii. Giant abdominal neuron of Aplysia has about 75,000
copies of the genome.
 iv. Wheat is hexaploid (6N); the strawberry is octaploid (8N).
 v. North American sucker fish,
salmon, and some salamanders
are polyploid.

There are two classes of polyploids based on the number of
chromosome sets:
◦ i. Even-number polyploids are more likely to be at least partially fertile,
because the potential exists for equal segregation of homologs during
meiosis.
◦ ii. Odd-number polyploids will always have unpaired chromosomes.
Balanced gametes are rare, and these organisms are usually sterile or
have increased zygote death.

Triploids are unstable in meiosis because random segregation
means that balanced gametes (either exactly N or exactly 2N)
are rare.
◦ i. The probability of a triploid organism producing a haploid gamete is
(1/2)n, where n is the number of chromosomes.
◦ ii. Triploidy is always lethal in humans, accounting for 15–20% of
spontaneous abortions and 1/104 live births, with most dying in the first
month.
◦ iii. Tetraploidy in humans is also lethal, usually before birth, accounting
for 5% of spontaneous abortions.

Polyploidy is more common in plants, probably
due to self-fertilization, allowing even-number
polyploids to produce fertile gametes and
reproduce. Plant polyploidy occurs in two types:
◦ i. Autopolyploidy results when all sets of chromosomes
are from the same species, usually due to meiotic
error. Fusion of a diploid gamete with a haploid one
produces a triploid organism. Examples include:
 (1) “Seedless” fruits such as bananas, grapes, and
watermelons
 (2) Grasses, garden flowers, crop plants, and forest trees

ii. Allopolyploidy results when the chromosomes are from
two different organisms, typically from the fusion of haploid
gametes followed by chromosome doubling. For example:
◦ (1) Fusion of haploid gametes from plant 1 and plant 2 produces
an N1 1 N2 hybrid plant. No chromosomal pairing occurs at
meiosis, viable gametes are not produced, and the plants are
sterile.
◦ (2) Rarely, division error doubles the chromosome sets (2N1 1 2N2).
The diploid sets function normally in meiosis, and fertile
allotetraploid plants result.
◦ (3) An example of allopolyploidy is that of crosses between
cabbages (Brassica oleracea) and radishes (Raphanus sativus),
which both have a chromosome number of 18.
 (a) The F1 hybrids have 9 chromosomes from each parent, and have a
morphology intermediate between cabbages and radishes. They are
mostly sterile.
 (b) A few seeds, some fertile, can be produced by the F1 through meiotic
errors.
 (i) Somatic cells in the resulting plants have 36 chromosomes, a full diploid set
from both cabbages and radishes.
 (ii) -These fully fertile plants look much like the F1 hybrids and are named
Raphanobrassica.

Polyploidy is the rule in agriculture, where
polyploids include all commercial grains (e.g.,
bread wheat, Triticum aestivum, an
allohexaploid of three plant species), most
crops, and common flowers.