PowerPoint to accompany
Genetics: From Genes to
Genomes
Fourth Edition
Leland H. Hartwell, Leroy Hood,
Michael L. Goldberg, Ann E. Reynolds,
and Lee M. Silver
Prepared by Mary A. Bedell
University of Georgia
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Hartwell et al., 4th edition
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PART
IV
How Genes Travel on Chromosomes
CHAPTER
Chromosomal
Rearrangements
and Changes in
Chromosome Number
CHAPTER OUTLINE





13.1 Rearrangements of DNA Sequences
13.2 Transposable Genetic Elements
13.3 Rearrangements and Evolution: A Speculative Comprehensive Example
13.4 Changes in Chromosome Number
13.5 Emergent Technologies: Beyond the Karyotype
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Two main themes underlying the observations
on chromosomal changes
1. Karyotypes generally remain constant within a species
• Most genetic imbalances result in a selective disadvantage
2. Related species usually have different karyotypes
• Closely-related species differ by only a few rearrangements
• Distantly-related species differ by many rearrangements
• Correlation between karyotypic rearrangements and
speciation
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Chromosomal rearrangements
Table 13.1
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Changes in chromosome number
Table
13.1
(cont)
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Deletions: origin and detection
Symbols for a deletion are Del or
Df (i.e. Del/+ or Df/+ is a deletion
heterozygote and Del/Del or Df/Df
is a deletion homozygote)
Fig. 13.2
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Heterozygosity for deletions may have
phenotypic consequences
With some genes, an
abnormal phenotype can be
caused by an imbalance in
gene dosage (i.e. 2 copies
vs. 1 copy of an autosomal
gene)
In humans, deletion
heterozygotes with loss of
>3% of genome are not
viable
Fig. 13.3
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Deletion loops form in the chromosomes
of deletion heterozygotes
Recombination between homologs can occur only at
regions of similarity
No recombination can occur within a deletion loop
Consequently, genetic map distances in deletion
heterozygotes will not be accurate
Fig. 13.4
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In deletion heterozygotes, pseudodominance
can "uncover" a recessive mutation
Similar to a complementation test
Examine phenotype of a heterozygote for recessive allele
and deletion:
• If the phenotype is mutant, the mutant gene must lie
inside the deleted region
• If the phenotype is wild-type, the mutant gene must lie
outside the deleted region
Fig. 13.5
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Polytene chromosomes in the salivary
glands of Drosophila larvae
In Drosophila, interphase
chromosomes replicate 10
times without going through
mitosis
• Each chromosome has
210 double helices
Banding patterns are
reproducible and provide
detailed physical guide to
gene mapping
• Total ~5000 bands, size
of each band is 3-150 kb
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Fig. 13.6a
10
Deletion loops also form in polytene chromosomes
of Drosophila deletion heterozygotes
In Drosophila, homologous
chromosomes pair with each
other during interphase
Comparison of banding
patterns in polytene
chromosomes of a deletion
heterozygote can reveal the
position of deletion
Fig. 13.7
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Using deletions to assign genes to bands
on Drosophila polytene chromosomes
Complementation tests with several deletions used to determine
the locations of white (w), roughest (rst), and facet (fa) genes
Fig. 13.8
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In situ hybridization as a tool for locating
genes at the molecular level
A DNA probe containing the white gene hybridizes to the tip
of the Drosophila wild-type polytene X chromosome
Fig. 13.9a
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Characterizing deletions with in situ
hybridization to polytene chromosomes
Labeled DNA probe hybridizes to the wild-type chromosome
but not to the deletion chromosome
Fig. 13.9b
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Diagnosing DiGeorge syndrome by
fluorescence in situ hybridization (FISH)
DiGeorge syndrome in humans:
• Accounts for 5% of all congenital heart defects
• Affected people are heterozygous for a 22q11 deletion
FISH on human metaphase
chromosomes
Green dots; control probe
for chromosome 22
Red dot; probe from 22q11
region
Fig. 13.10
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Summary of phenotypic and genetic
effects of deletions
Homozygosity or heterozygosity for deletions can be lethal
or harmful
• Depends on size of deletions and affected genes
In deletion heterozygotes, deletions reveal the effects of
recessive mutations
• Deletions can be used to map and identify genes
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Types of duplications (Dp)
Fig. 13.11a
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Chromosome breakage can
produce duplications
According to one scenario, nontandem duplications could
be produced by insertion of a fragment elsewhere on the
homologous chromosome
Fig. 13.11b
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Different kinds of duplication loops in
duplication heterozygotes (Dp/+)
Different configurations can occur in prophase I of meiosis
Fig. 13.11c
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Duplication heterozygosity can
cause visible phenotypes
Increased gene dosage can result in a mutant phenotype
Fig. 13.12a
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For rare genes, survival requires
exactly two copies
Fig. 13.12b
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Unequal crossing-over can increase or
decrease copy number
Genotype of X chromosome
Phenotype
Out-of-register pairing during meiosis can
occur in a Bar-eyed female
Fig. 13.13
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Summary of phenotypic and genetic
effects of duplications
Novel phenotypes may occur because of increased gene
copy number or because of altered expression in new
chromosomal environment
Homozygosity or heterozygosity for a duplication can be
lethal or harmful
• Depends on size of duplication and affected genes
Unequal crossing-over between duplicated regions on
homologous chromosomes can result in increased and
decreased copy number
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Chromosome breakage can
produce inversions (In)
Pericentric inversion – centromere is within the inverted
segment
Paracentric inversion – centromere is not within the
inverted segment
Fig. 13.14a
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Intrachromosomal recombination can also
produce inversions
Recombination occurs between related sequences that are
in opposite orientations on the same chromosome
Fig. 13.14b
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Phenotypic effects of inversions
Most inversions do not result in an abnormal phenotype
Abnormal phenotypes can occur if:
• Inversion disrupts a gene (Fig. 13.14c)
• Inversion places a gene in chromosomal environment
that alters its expression
 i.e. Gene is placed near regulatory sequences for other
genes or near heterochromatin (PEV, chapter 12)
Inversions can act as crossover suppressors
•
In inversion heterozygotes, no viable offspring are
produced that carry chromosomes resulting from
recombination in inverted region
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Inversions can disrupt a gene
Fig. 13.14c
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Inversion loops form in inversion
heterozygotes
Formation of inversion loop allows
tightest possible alignment of
homologous regions
Crossing over within the inversion
loop produces aberrant recombinant
chromatids
Fig. 13.15
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Why pericentric inversion heterozygotes
produce few if any recombinant progeny
Each recombinant chromatid has a centromere, but each
will be genetically unbalanced
Zygotes formed from union of normal gametes with
gametes carrying these recombinant chromatids will be
nonviable
Fig. 13.16a
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Why paracentric inversion heterozygotes
produce few if any recombinant progeny
One recombinant chromatid lacks a
centromere and the other recombinant
chromatid has two centromeres
Zygotes formed from union of normal
gametes with gametes carrying the
broken dicentric recombinant chromatids
will be nonviable
Fig. 13.16b
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Balancer chromosomes are useful tools
for genetic analysis
Balancer chromosomes have a dominant visible marker and
multiple, overlapping inversions
In progeny of crosses of heterozygotes with a marked
balancer and a non-inversion chromosome
• No viable progeny with recombinants on this chromosome
will be produced because of crossover suppression
• Progeny that don't carry the marked chromosome must carry
the nonrecombined, unmarked chromosome
Balancer chromosome
Normal chromosome with
mutations of interest
Fig. 13.17
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Summary of phenotypic and genetic
effects of inversions
Inversions don't add or remove DNA, but can disrupt a gene
or alter expression of a gene
In inversion heterozygotes, recombination within inverted
segment results in genetically unbalanced gametes
Balancer chromosomes with inversions are useful genetic
tools
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Translocations attach part of one chromosome
to another chromosome
Reciprocal translocation (Fig. 13.18)
• Two different chromosomes each have a chromosome
break
• Reciprocal exchange of fragments – each fragment
replaces the fragment on the other chromosome
Robertsonian translocation (Fig. 13.19)
• Chromosomal breaks occur at or near centromeres of
two acrocentric chromosomes
• Generates one large metacentric chromosome and one
small chromosome, which is usually lost
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Two chromosome breaks can produce a
reciprocal translocation
Fig. 13.18a
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Chromosome painting reveals
a reciprocal translocation
Translocated chromosomes
are stained red and green
Non-translocated
chromosomes are stained
entirely red or entirely green
Fig. 13.18b
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Robertsonian translocations can
reshape genomes
Fig. 13.19
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Phenotypic effects of reciprocal translocations
Most reciprocal translocations don't affect the phenotype
because they don't add or remove DNA
Abnormal phenotypes can be caused if translocation
breakpoint disrupts a gene or results in altered expression
of a gene
Translocations in somatic cells can result in oncogene
activation (Fig. 13.20)
Defects that are observed in translocation heterozygotes
• Unbalanced gametes are produced, which results in
reduced fertility (Fig. 13.21)
• Genetic map distance are altered because of
pseudolinkage
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A reciprocal translocation is the basis for
chronic myelogenous leukemia
Fig. 13.20b
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In a translocation homozygote, chromosomes
segregate normally during meiosis I
If the breakpoints of a reciprocal translocation do not affect
gene function, there are no genetic consequences in
homozygotes
Fig. 13.21a
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Chromosome pairing in a
translocation heterozygote
In a translocation heterozygote, the two haploid sets of
chromosomes carry different arrangements of DNA
• Chromosome pairing during prophase I of meiosis is
maximized by formation of a cruciform structure
Three segregation patterns
are possible (Fig. 13.21c)
Fig. 13.21b
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Three chromosome segregation patterns
are possible in a translocation heterozygote
Balanced gametes are produced only by alternate segregation,
and not by adjacent-1 or adjacent-2 segregation
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Fig.
13.21
c
41
Semisterility in a corn plant that is
heterozygous for a reciprocal translocation
Slightly less than 50% of gametes arise
from alternate segregation and are viable
Unbalanced ovules resulting from
adjacent-1 or adjacent-2 segregation are
aborted
Fig. 13.21d
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Pseudolinkage is observed in heterozygotes
with reciprocal translocations
In non-translocation heterozygotes, there are only two
possible segregation patterns
• With all offspring viable, Mendel's law of independent
assortment would be observed with unlinked genes
In a reciprocal translocation heterozygote, only the alternate
segregation pattern results in viable progeny
• In outcrosses, genes located on the nonhomologous
chromosomes would behave as if they are linked
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Down syndrome arising from a Robertsonian
translocation between chromosomes 21 and 14
14q21q
translocation
heterozygote
Three chromosome segregation patterns
Fig. 13.22
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Transposable elements (TEs) are movable
genetic elements
TEs are any segment of DNA that evolves the ability to
move from place to place within a genome
Marcus Rhoades (1930s) and Barbara McClintock (1950s)
inferred existence of TEs from genetic studies of corn
TEs have now been found in all organisms
• Previously considered to be selfish DNA – carried no genetic
information useful to host
• Now known that some TEs have evolved functions that are
beneficial to host
• TE length ranges from 50 bp to 10 kb
• TEs can be present in hundreds of thousands of copies per
genome
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Barbara McClintock: Discoverer of
transposable elements
Received Nobel
Prize in 1983
Fig. 13.23
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TEs can move to many locations in a genome
In situ hybridization for the copia TE in Drosophila
Fig. 13.24
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Mammals have two major classes of TEs
Long interspersed elements (LINEs)
• Main LINE in humans is L1
 Up to 6.4 kb in length
 20,000 copies in human genome
Short, interspersed elements (SINEs)
• Main SINE in humans is Alu
 0.28 kb in length
 300,000 copies in human genome, dispersed at ~ 10 kb
intervals
L1 and Alu sequences make up 7% of the human genome
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TEs in the corn genome
Mottling of kernels caused by movements of a TE into and
out of a pigment gene
Fig. 13.25b
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Two groups of TEs
Retroposons
• Move via reverse transcription of an RNA intermediate
 e.g. copia elements in Drosophila, L1 and Alu in humans
Transposons
• Move directly without being transcribed into RNA
 e.g. TEs studied by McClintock in corn, P elements in
Drosophila
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Two kinds of retroposons
Both types carry a gene for reverse transcriptase
Has polyA tail at
3'end of an RNA-like
DNA strand
Has long terminal
repeats (LTRs)
oriented in the same
direction on either
side of element
Fig. 13.26a
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Evidence that retroposons move
via RNA intermediates
Experiment done with
Ty1 retroposon of yeast
Ty1 with an intron
cloned into a plasmid
All new insertions of
this Ty1 into the yeast
genome lacked the
intron
The intron must have
been removed by
splicing from an RNA
Fig. 13.26b
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How retroposons move
Reverse transcriptase
makes a double-stranded
retroposon cDNA
Staggered cut is made in
genomic target site
Retroposon cDNA inserts
into target site
Sticky ends of target site are
filled in, creating two copies
of the 5 bp target site
Original copy remains while
new copy inserts into
another genomic location
Fig. 13.26c
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Transposon structure
Most transposons contain:
• Inverted repeats (IRs) of 10-200 bp long at each end
• Gene encoding transposase, which recognizes the IRs
and cuts at border between the IR and genomic DNA
Fig. 13.27a
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P elements in Drosophila melanogaster
Most laboratory strains of D. melanogaster are M strains
• Isolated in early 1900s
• Have no P elements
Natural populations of D. melanogaster are P strains
• Isolated since 1950
• Have many copies of P elements
Hybrid dysgenesis - cross P male with M female
• Offspring are sterile, have high levels of mutation, and
chromosome breaks
• Elevated levels of P element transposition
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How P element transposons move
Fig. 13.27b
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Genomes often contain defective copies of TEs
Many TEs sustain deletions during the process of
transposition or after transposition
• Deletion of promoter for retroposon transcription
• Deletion of reverse transcriptase gene or transposase gene
• Deletion of IRs
• Most SINEs and LINEs in human genome are defective
Autonomous TEs – nondeleted TEs that can transpose on
their own
Nonautonomous TEs – defective TEs that can transpose
only if transposase activity expressed from intact TE
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TEs can disrupt genes and alter genomes
TE insertion can result in altered phenotype
• TE can insert within coding region of a gene
• TE can insert near a gene and affect its expression
• Examples: Drosophila white gene (Fig. 13.28), wrinkled peas
studied by Mendel, hemophilia in humans caused by Alu
insertion into clotting factor IX
TEs can trigger spontaneous chromosomal rearrangements
• Unequal crossing over between TEs (Fig. 13.29a)
Gene relocation due to transposition
• Formation of composite TE (Fig. 13.29b)
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Spontaneous mutations in the white gene of
Drosophila arising from TE insertions
Eye color phenotype depends on the TE involved (pogo,
copia, roo, and Doc) and where it inserts
Fig. 13.28
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Unequal crossing-over between TEs
Can occur between TEs found in slightly different locations
on homologous chromosomes
Fig. 13.29a
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Two transposons can form a large,
composite transposon
Composite transposons
• Can occur when two copies of a TE integrate in nearby
locations on the same chromosome
• Transposase can recognize outermost IR sequences and
move intervening sequences to a different location
• Can move up to 400 kb of DNA
• Mediates transfer of drug resistance genes between different
strains and species of bacteria (discussed in Chapter 14)
Fig. 13.29b
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Rearrangements and evolution:
A speculative comprehensive example
Deletions
• May move the coding region of one gene closer to regulatory
sequences of another gene
• Timing or tissue-specificity of expression may be altered
Duplications
• One copy of the gene retains original function and the new
copy evolves new functions
• Generation of multi-gene families
Inversions
• Crossover suppression can ensure that beneficial alleles of
closely-linked genes do not separate by recombination
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Rearrangements and evolution:
A speculative comprehensive example (cont)
Translocations
• Robertsonian translocations can lead to reproductive
isolation and speciation
 e.g. Two populations of mice on the island of Madeira (Fig.
13.30)
Transpositions
• Create novel mutations, duplications, inversions that affect
gene functions in beneficial ways
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Rapid chromosomal evolution in house
mice on the island of Madeira
One population of mice introduced to island in 1400s
Two populations evolved different sets of Robertsonian
translocations, hybrid offspring are sterile
Fig. 13.30
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Aneuploidy is the loss or gain of one or more
chromosomes
Aneuploids – individuals whose chromosome number is not
an exact multiple of the haploid number (n) for that species
• Monosomic – individuals that lack one chromosome
from the normal diploid number (2n – 1)
• Trisomic – individuals that have one chromosome in
addition to the normal diploid number (2n + 1)
• Tetrasomic – organisms with four copies of a particular
chromosome (2n + 2)
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Deleterious effects of autosomal aneuploidy
in humans
Most autosomal aneuploidies and trisomies are lethal and
result in spontaneous abortion
Trisomy 21 (Down syndrome) is the most frequently
observed autosomal trisomy
• Majority of Down syndrome results from nondisjunction
during maternal meiosis I (Fig. 13.32a)
Individuals with monosomy 21 survive for only a short time
after birth
Two autosomal trisomies allow birth, but cause severe
developmental abnormalities and early death
• Trisomy 18 causes Edwards syndrome
• Trisomy 13 cause Patau syndrome
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X chromosome aneuploidies
X-inactivation results in dosage compensation for most
genes on the X chromosome
• Some genes on X chromosome escape inactivation
• X reactivation occurs in oogonia so that every mature ovum
receives an active X
XXY individuals – Klinefelter syndrome (see Fig. 13.31)
• Some X-linked genes expressed at twice the normal level and
result in skeletal abnormalities, long limbs, and sterility
XO individuals – Turner syndrome
• Sterility may be caused by decreased dosage of X-linked
genes in oogonia
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Humans tolerate X chromosome aneuploidy
because of X inactivation
Fig. 13.31
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Aneuploidy is caused by nondisjunction
Nondisjunction is the failure of chromosomes to segregate
normally and can occur during either meiosis I or meiosis II
Fig. 13.32a
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Aneuploids beget aneuploid progeny
Offspring of fertile aneuploids have an extremely high
chance of aneuploidy because of production of unbalanced
gametes
Fig. 13.32b
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Mistakes in chromosome segregation
can occur in somatic cells
Mitotic nondisjunction – failure of sister chromatids to
separate during anaphase of mitosis
Chromosome loss – lagging chromatid that is not pulled to
either spindle pole at mitotic anaphase
Mosaic organism
• Aneuploid cells can survive and undergo further rounds of
mitosis, producing clones of aneuploid cells
• Side-by-side existence of aneuploid and normal tissues
• e.g. Mitotic nondisjunction of X chromosome
 Gynandromorphs in XX Drosophila (Fig. 13.33c)
 Some cases of Turner and Down syndrome in humans
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Nondisjunction during mitosis can generate
clones of aneuploid cells
Fig. 13.33
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Some euploid species are not diploid
Euploids carry complete sets of chromosomes
• Polyploids – carry ≥ 3 complete sets of chromosomes
• Monoploids – 1x, carry only one set of chromosomes
• Triploids – 3x, three complete sets of chromosomes
• Tetraploids – 4x, four complete sets of chromosomes
• Monoploidy and polyploidy rarely observed in animals
 Exceptions – in some species of ants and bees, males are
monoploid and females are diploid; hermaphroditic worms
are polyploid; some fish are tetraploid
 Polyploidy in humans is lethal
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Chromosome numbers
x = the number of different chromosomes that make up a
single, complete set
n = number of chromosomes in gametes
In diploids, x = n
For polyploids, x ≠ n (e.g. bread wheat is hexaploid, x = 7, 6x
= 42, n = 21)
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Creation and use of monoploid plants
Creation of monoploid plants (see Fig. 13.34a):
• Special treatment of germ cells from diploid species
• Rare spontaneous events in large, natural populations
• Usually sterile, but can easily be converted to diploid (Fig.
13.34c)
Uses of monoploid plants (see Fig. 13.34b):
• Can visualize recessive traits directly, without crosses to
homozygosity
• Introduce mutations into individual monoploid cells
• Select for desirable phenotypes (herbicide resistance)
• Hormone treatment to grow cells into monoploid plants
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The creation and use of monoploid plants
Fig. 13.34
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Colchicine treatment prevents spindle formation
and results in doubling of chromosome numbers
Fig. 13.34c
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Formation of a triploid organism
Diploid gametes may
arise from 4x parent or
from a diploid with
defects in meiosis
(defect in spindle or
defect at cytokinesis)
Fig. 13.35a
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Meiosis in a triploid organism
Regardless of how
chromosomes pair, there is
no way to ensure that
gametes contain a complete
balanced set of chromosomes
All polyploids with odd
numbers of chromosome sets
are sterile because they
cannot produce balanced
gametes
Fig. 13.35b
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Generation of tetraploid (4x) cells
Tetraploid cells occur during mitosis in a diploid when
chromosomes fail to separate into two daughter cells
• If tetraploidy occurs in gamete precursors, diploid gametes
are produced
• Union of two diploid gametes produces a tetraploid organism
• Autopolyploid – all chromosome sets are derived from the
same species
Fig. 13.36a
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In a tetraploid, pairing of chromosomes as
bivalents generates balanced gametes
Four copies of each
group of homologs pair
two-by-two to form two
bivalents
Successful tetraploids
produce balanced 2X
gametes and are fertile
Fig. 13.36b
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Gametes formed by A A a a tetraploids
Tetraploids generate unusual Mendelian ratios
Fig. 13.36c
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Polyploids in agriculture
One-third of all known flowering plant species are polyploid
Polyploidy often results in increased size and vigor
Many polyploid plants have been selected for agricultural
cultivation
• Tetraploids – alfalfa, coffee, peanuts, Macintosh apples,
Bartlett pear
• Octaploids – strawberries (Fig. 13.37)
Allopolyploid – hybrids in which chromosome sets come
from distinct, but related, species
Amphidiploid – has two diploid parental species
• e.g. Raphanobrassica – sterile F1 from crossing cabbages
and radishes, has 18 chromosomes (9 from each parent)
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Creation of the allopolyploid Triticale
F1 hybrid of wheat and
rye is sterile because
there are no pairing
partners for the rye
chromosomes
Fig. 13.38a
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Fertile Triticale can be created from
infertile F1 hybrid Triticale
Different Triticale hybrids have
been generated
• Some combine high yield of
wheat with ability of rye to grow
in unfavorable enviroments
• Some combine high level of
protein from wheat with high
level of lysine from rye
Fig. 13.38a
(cont)
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Emergent technologies: Beyond the karyotype
Two main problems with traditional karyotyping
• Procedure is tedious and microscopic analysis is subjective
• Very low resolution – cannot detect deletions or duplications
of < 5 Mb
Development of microarray-based technologies
• Can scan entire genome for chromosomal rearrangements
and aneuploidy
• Has much higher accuracy, resolution, and throughput
• Comparative genomic hybridization (Fig. 13.39)
 Also called "virtual karyotyping"
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Preparation of microarray and samples for
comparative genomic hybridization (CGH)
Fig. 13.39
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Detection of duplications and deletions by
CGH
After hybridization of DNA samples, analyze microarray for
ratio of yellow (control DNA) and orange (test DNA)
(c) Incubate microarray with combined samples
Fig. 13.39
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Aneuploidy in the human population
Incidence of abnormal
phenotypes caused by
aberrant chromosome
organization or number is
0.004%
Half of spontaneously
aborted fetuses have
chromosome abnormalities
Incidence of abnormal
phenotypes caused by
single-gene mutations is
0.010%
Table 13.2
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