How Genes Travel on Chromosomes

Chromosomal
Rearrangements
and Changes in
Chromosome Number

Rearrangements of DNA Sequences

Copyright The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 13

Figure 13.1 Comparing the mouse and human

genomes.
Mouse chromosome 1 contains large blocks of
sequences found on human chromosomes 1, 2, 5, 6,
8, 13, and 18 (portrayed in different colors).
Arrows indicate the relative orientations of sequence
blocks from the same human chromosome.

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

Chromosomal rearrangements

Table 13.1

Changes in chromosome number

Table
13.1
(cont)

REARRANGEMENTS OF DNA SEQUENCES

All chromosomal rearrangements alter DNA
sequence.
FOCUS ON!!
on heritable rearrangements that can be
transmitted through the germ line from one
generation to the next

the genomes of somatic cells can undergo

changes in nucleotide number or order.

1) Deletions: origin and detection

deletions remove one or more contiguous base pairs of DNA
from a chromosome
errors in replication, from faulty meiotic or mitotic recombination,
exposure to X-rays or other chromosome-damaging agents that
break the DNA backbone
Small only one gene, whereas large deletions can generate
chromosomes lacking tens or even hundreds of genes

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)

b) One way to detect deletions is by PCR. The two PCR primers shown
will amplify a larger PCR product from wild-type DNA than from DNA
Fig. 13.2
with a deletion.

Most point mutations would not cause such changes as in the PCR
detected mutations

Larger deletions are sometimes identifiable because they affect the

expression of two or more adjacent genes.

Very large deletions are visible at the relatively low resolution of a

karyotype

10

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

11

Del/ + individual is known as a deletion heterozygote

Even small deletions can be harmful in heterozygotes.
a relatively small deletion from the short arm of chromosome 5
have cri du chat syndrome

Why should heterozygosity for a deletion

have harmful consequences when the Del/+
individual has at least one wild-type copy of
all of its genes?
gene dosage the number of times a given gene is
present in the cell nucleuscan create a genetic
imbalance.
This imbalance in gene dosage
changes the phenotypic effects.

12

Some rare genes, the normal diploid level

of gene expression is essential to
individual survival; fewer than two
copies of such a gene results in lethality.

Decrease in gene dosage are noticeable

but not catastrophic for some genes

Drosophila containing only one copy

of the wild-type Notch gene have
visible wing abnormalities but
otherwise seem to function normally

13

ANOTHER REASON why heterozygosity for a deletion can be

harmful
If the gene encodes a protein that helps control cell division, a cell
without any wild-type protein may divide out of control and
generate a tumor.
Thus, individuals born heterozygous for certain deletions have a greatly
increased risk of losing both copies of certain genes and developing
cancer.

Retinoblastoma (RB), the most malignant form of eye cancer

Reveal heterozygosity for deletions on chromosome 13
Cells from the retinal tumors of these same patients have a
mutation in the remaining copy of the RB gene on the nondeleted
chromosome 13.

14

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

15

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
A fly of genotype st/Del
displays the recessive
scarlet eye color.

Fig. 13.5

The deletion has thus

uncovered the scarlet (st)
mutation.

16

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

17

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

18

2) Types of duplications (Dp)

Duplications
increase the number
of copies of a
particular
chromosomal
region.
In tandem duplications,
repeats
of a region lie adjacent to
each other, either in the
same order or in reverse
order
In nontandem (or dispersed ) duplications, the two or more copies of a
region are not adjacent to each other and may lie far apart on the same
chromosome or on different chromosomes.

19

Chromosome breakage can produce duplications

Duplications arise by chromosomal breakage and faulty repair, unequal

crossing-over, or errors in DNA replication

According to one scenario, nontandem duplications could be

produced by insertion of a fragment elsewhere on the homologous
chromosome

Fig. 13.11b

20

Most duplications have no obvious phenotypic consequences

can be detected only by cytological or molecular means

During the prophase of meiosis I in heterozygotes for such

duplications ( Dp/ +), the repeated bands form a duplication loop
a bulge in the Dp -bearing chromosome that has no similar
region with which to pair in the unduplicated normal homologous
chromosome.

21

Different kinds of duplication loops in duplication

heterozygotes (Dp/+)
Different configurations can occur in prophase I of meiosis

Fig. 13.11c

22

Duplication heterozygosity can cause visible

phenotypes
Increased gene dosage can result in a mutant phenotype

Most duplications have no obvious phenotypic consequences and

can be detected only by cytological or molecular means.

Fig. 13.12a

23

For rare genes, survival requires exactly two

copies

In a very large

duplication have
additive deleterious
effects that risk
survival.

In humans,
heterozygosity for
duplications

covering more than 5%

of the haploid genome
is most often lethal.

Fig. 13.12b

24

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

25

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

26

3) Chromosome breakage can produce inversions

(In)
The half-circle rotation of a chromosomal region known as an
inversion ( In )
Pericentric inversion centromere is within the inverted segment
Paracentric inversion centromere is not within the inverted segment

radiation produces
two double-strand
breaks in a
chromosomes DNA
Fig. 13.14a

27

Intrachromosomal recombination can also produce

inversions
Recombination occurs between related sequences that are
in opposite orientations on the same chromosome

Fig. 13.14b

28

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

29

Inversions can disrupt a gene

Fig. 13.14c

30

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

31

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

32

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

33
Fig. 1.Consequences of a single or
double crossover between a
WT X chromosome and
an X chromosome carrying a single
inversion, In(1)dl-49. Euchromatin is
shown in blue, heterochromatin is
shown in gray, and centromeres are
depicted as circles. Thin white lines
mark locations of inversion
breakpoints, and yellow crosses/thin
lines mark locations of crossover
events. (A) A single crossover event
within the inverted segment results in
the formation of chromosomes with
deletions and zero (acentric)
centromeres or duplications and two
(dicentric) centromeres, neither of
which will segregate properly during
meiosis. (B) A double crossover within
an inverted segment results in intact
chromosomes with one centromere
that will segregate properly during
meiosis.

34

whether an inversion is pericentric or paracentric,

crossing-over within the inversion loop of an inversion
heterozygote has the same effect:
formation of recombinant gametes that after fertilization prevent the
zygote from developing.

only gametes containing chromosomes that did not

recombine within the inversion loop can yield viable
progeny, inversions act as crossover suppressors.

35

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

36

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 (nonviable zygotes)
Geneticists can take advantage of this:
Balancer chromosomes with inversions are useful genetic tools
The production of genetic lines of known composition.

37

4) 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

Two chromosome breaks can produce a reciprocal

translocation

38

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

39

Robertsonian translocations can reshape genomes

Robertsonian translocation (Fig. 13.19)
Chromosomal breaks occur at or near centromeres of two
acrocentric chromosomes (13,14,15,21,22 and theY chromosome)
Generates one large metacentric chromosome and one small
chromosome, which is usually lost

Fig. 13.19

40

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

41

How a reciprocal translocation helps cause one kind of leukemia

a) Uncontrolled divisions of large, dark-staining white blood cells in a

leukemia patient (right) produce a higher ratio of white to red blood
cells than that in a normal individual (left).

Translocations in somatic cells can result in oncogene

activation

42

A reciprocal translocation is the basis for chronic myelogenous leukemia

Fig. 13.20b

43

DIAGNOSIS AND TREATMENT OF CML

To confirm a diagnosis of myelogenous leukemia
a blood sample from the patient
a pair of PCR primers derived from opposite sides of the
breakpoint
The PCR will amplify the region between the primers only if the
DNA sample contains the translocation

To monitor the effects of chemotherapy

44

To treat CML
The protein encoded by c-abl is a protein tyrosine kinase, an
enzyme that adds phosphate groups to tyrosine amino acids on other
proteins.
cell growth and division (active with a growth signal)

the fused protein encoded by bcr/c-abl in cells carrying the

translocation is not amenable to regulation.
It is always active, even in the absence of growth factor, and this leads
to runaway cell division
Gleevec
inhibits the enzymatic activity of the protein tyrosine kinase encoded by

bcr/c-abl.
98% of participants experienced a complete disappearance of leukemic
blood cells

45

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

46

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 (crosslike) structure

Three segregation patterns

are possible (Fig. 13.21c)

Fig. 13.21b

47

during prophase of the first meiotic division, the translocated

chromosomes and their normal homologs assume a crosslike
configuration in which four chromosomes, rather than the normal
two, pair to achieve a maximum of synapsis between similar
regions

48

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

Fig.
13.21
c

49

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

50

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

Down syndrome arising from a Robertsonian

translocation between chromosomes 21 and 14
Three chromosome segregation patterns
14q21q
translocation
heterozygote

Fig. 13.22
Copyright The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 13

51

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END OF THE LECTURE!