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Mutations. What is a gene?. Prokaryotic Genes. PROMOTER. 3’. 5’. antisense. --- TTGACAT ------ TATAAT ------- AT -/-AGGAGGT-/- ATG CCC CTT TTG TGA --- AACTGTA ------ ATATTA ------- TA -/-TCCTCCA-/- TAC GGG GAA AAC ATT. sense. (-35). 3’. (-10). 5’. RIBOSOME BINDING SITE. 3’. 5’.

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what is a gene
What is a gene?

Prokaryotic Genes

PROMOTER

3’

5’

antisense

---TTGACAT------TATAAT-------AT-/-AGGAGGT-/-ATGCCC CTT TTG TGA

---AACTGTA------ATATTA-------TA-/-TCCTCCA-/-TAC GGG GAA AAC ATT

sense

(-35)

3’

(-10)

5’

RIBOSOME

BINDING

SITE

3’

5’

U-/-AGGAGGU-/-AUGCCC CUU UUG UGA

Met Pro leu leu stp

When ALL OF THESE RULES ARE SATISFIED THEN THEN A PIECE OF DNA WILL GENERATE A RNA WHICH WILL BE READ AND TRANSLATED INTO A PROTEIN.

reading the genetic code
Reading the genetic code

U U U

A A A

U A C

Lys

Phe

Met

5’

3’

A T G

T T T

A A A

T A G

C C C

C A T

A A A

T T T

C T A

G G G

3’

5’

5’

3’

A T G

T T T

A A A

T A G

C C C

5’

3’

5’

3’

A U G U U U A A A U A G C C C

C A T

A A A

T T T

C T A

G G G

3’

5’

A U G

U U U

A A A

U A G

C C C

S T P

no gaps
No Gaps

5’

5’

3’

3’

A U G

A U G

U U U

U U U

A A A

A A A

U A G

U A G

C C C

C C C

A A U

U U A

U U U

A A A

U A C

U A C

Asn

Met

Lys

Phe

Met

Leu

S T P

no overlaps
No overlaps

5’

5’

3’

3’

A U G

A U G

A A A

A A A

C C C

C C C

U A G

U A G

C C C

C C C

U U U

U G G

G G G

U U U

U A C

U A C

Lys

Met

Pro

Lys

Met

Trp

S T P

the genetic code
The GENETIC CODE

The code is a three letter code.

Second letter

U

C

A

G

UUU

UUC

UUA

UUG

CUU

CUC

CUA

CUG

AUU

AUC

AUA

AUG

GUU

GUC

GUA

GUG

UCU

UCC

UCA

UCG

CCU

CCC

CCA

CCG

ACU

ACC

ACA

ACG

GCU

GCC

GCA

GCG

UAU

UAC

UAA

UAG

CAU

CAC

CAA

CAG

AAU

AAC

AAA

AAG

GAU

GAC

GAA

GAG

UGU

UGC

UGA

UGG

CGU

CGC

CGA

CGG

AGU

AGC

AGA

AGG

GGU

GGC

GGA

GGG

U

C

A

G

U

C

A

G

U

C

A

G

U

C

A

G

Phe

Tyr

Cys

U

Ser

STOP

STOP

Leu

Trp

His

C

Arg

Pro

Leu

Gln

Third letter

First letter

Asn

Ser

Ile

A

Thr

Arg

Lys

Met

Asp

G

Val

Ala

Gly

Glu

the code
The code

Ser

Ser

Ser

Ser

Ser

AGG

AGU

UCG

AGG

AGG

3 amino acids are specified by 6 different codons

5 amino acids are specified by 4 different codons

1 amino acid is specified by 3 different codons

9 amino acids are specified by 2 different codons

2 amino acids are specified by 1 different codons

The degeneracy arises because

More than one tRNA specifies a given amino acid

A single tRNA can base-pair with more than one codon

tRNAs do not normally pair with STOP codons

----UCC------UCA------AGC

----UCC------UCA------

the genetic code1
The Genetic Code

Properties of the Genetic code:

1- The code is written in a linear form using the nucleotides

that comprise the mRNA

2- The code is a triplet: THREE nucleotides specify

ONE amino acid

3- The code is degenerate: more than one triplet specifies

a given amino acid

4- The code is unambiguous: each triplet specifies only

ONE amino acid

5- The code contains stop signs- There are three different stops

6- The code is comma less

7- The code is non-overlapping

generation of mutations
Generation of mutations

Spontaneous mutations

Replication induced mutations of DNA

Usually base substitutions (Most errors are corrected)

Meiotic crossing over can induce mutations

Small additions and deletions AND Large changes as well

Environment induced changes

Exposure to physical mutagens - Radioactivity or chemicals

Depurination (removal of A or G)

Repair results in random substitution during replication

Deamination (removal of amino group of base) (nitrous acid)

Cytosine--uracil--bp adenine--replication--

Oxidation (oxoG)

guanine--oxoguanine--bp adenine--replication --

Base analog incorporation during replication BU-T

Intercalating agents

methods used to study mutations
Methods used to study mutations

Gross chromosomal changes-

deletions, insertions, inversions, translocations

Cytology- microscopy- karyotype

Small mutations

Small deletions, insertions and point mutations

Recombinant DNA technologies

mutation rate
Mutation rate

There are approximately 1013 cells in the human body

Each cell receives 10,000 DNA lesions per day (Lindahl and Barnes 2000).

Most pervasive agent is UV. 100,000 lesions per exposed cell per hour (Jackson and Bartek 2009).

Ionizing agents (X-rays/g-rays) are most toxic because they generate double strand breaks (Ward 1988).

Chromosome instability (gain or loss of entire segments) is frequent - 40% of imbalances are entire arm imbalance while 45% are terminal segment imbalance (double strand break, nondysjunction etc)

Sequencing 179 humans as part of the 1000 genome project:

On average, each person is found to carry approximately 250 to 300 loss-of-function variants in genes of which 50 are in genes previously implicated in inherited disorders.

1.3 million short indels (1-10,000 bp) were identified and 20,000 large (>10,000 bp) variants were identified.

Variation detected by the project is not evenly distributed across the genome: certain regions, containing repetitive sequences (sub-telomeres etc), show high rates of indels.

slide13

Sequencing the whole genomes of a family (2010 Science 328 636).

98 crossovers in maternal genome

57 crossovers in paternal genome

Mutation rate is 1x10-8 per position per haploid genome

(human genome is 3x109 bp)

It was calculated that there are ~70 new mutations in each diploid human genome

Some sites such as CpG sites mutate at a rate 11 times higher than other sites

Exome sequencing of 2440 individuals (Science 2012 337 40)

Each person has ~100 loss of function mutations (~35 nonsense).

20 loss of function mutations are homozygous

Some alterations in sequence concentrate in specific geographic populations

Rare changes are population specific and their frequencies vary for each geographic population

chromosomes and chromosome rearrangements
Chromosomes and chromosome rearrangements

Cytogenetics is the study of genetics by visualizing chromosomes. This area of research is germane to several areas of biological research.

Cytogenetics has been fundamental to understanding the evolutionary history of a species (for example, although the Chimp and the human are morphologically very different, at the level of the chromosome (and DNA sequence) they are extremely similar.

H = human

C= chimp

G = Gorilla

O = Orang utang

karyotype
Karyotype

Chromosomes are classified by size, centromere position and banding pattern:

Shown below is the human karyotype (description of the chromosome content of a given species)

Karyotype is the chromosome description of length, number, morphology.

Karyotype analysis is extremely important in medicine. Alternations in karyotypes are linked to birth defects and many human cancers.

Metacentric- centromere in the middle

Acrocentric- centromere off center

telocentric centromere at one end

slide16

Banding patterns

Specialized stains produce unique banding patterns along each chromosome. Banding patterns are extremely useful for detecting abnormalities in chromosome structure.

For many of the chromosome stains- the molecular basis of the banding patterns is unclear. Nonetheless these techniques remain fundamental in many areas of genetic research

mu to bp
MU to bp

Genetic maps are based on recombination frequencies and describe the relative order and relative distance between linked genes.

Remember genes reside on chromosomes.

So what we would like to know is where are the genes located on the chromosomes

22% Rf = 22MU

What does this mean in terms of chromosomes and DNA?

physical maps
Physical maps

Physical maps provide information concerning the location of genes on chromosomes

Where are the genes on chromosomes?

Cytological studies have been successfully used to map genes to specific regions of a chromosome.

For example in Drosophila in some cells the chromosomes become highly replicated and exhibit very characteristic banding patterns:

in situ hybridization
In situ hybridization

Salivary glands

Squash on slide

Denature/Stain polytene chromosomes

label gene probe (you can only use this method if you have the gene cloned)

Hybridize probe to polytene chromosomes

Autoradiography

chromosome loss
Chromosome loss

Chromosome instability-

Elevated gain or loss of complete chromosomes

Frequent in tumors

Frequent in in vitro fertilized embryos

Gross chromosomal rearrangements during in vitro fertilization. 40% of embryos carried entire chromosome imbalance

Gain or loss of segments of chromosomes

CNV- copy number variation of chromosome segments

5% of individuals genome displays CNV

Synuclein gene CNV is involved in Parkinsons

Many cancers- malignant cells most often gain additional copies of chromosome segments- genes in these segments are mis-expressed or mis-express other genes)

Microarray hybridization of DNA from tissues of identical twins- differences at several loci seen (Bruder et al 2008)

Microarray hybridization of DNA from different tissues of single individual (Piotrowski et al., 2008)

Gross chromosomal rearrangements during in vitro fertilization

55% of embryos carried terminal imbalance (sub-telomere loss)

(Vanneste et al., 2009) -microarray based screen of IVF 35 embryo

gross chromosomal changes
Gross chromosomal changes

The Cri du chat syndrome in humans is a result of a deletion in the short arm of chromosome 5. This was determined by comparing banding patterns with normal and Cri du Chat individuals

Types of chromosome rearrangements that can be studied by karyotype analysis:

GROSS CHROMOSOMAL CHANGES

Deletions, Duplications, Inversions, Translocations

slide22
DDIT

A____B____C________D____E____F

A____B____C________D____F

A____B____C________D____E____E____F

A____B____C________E____D____F

A____B____C________D____E____F

A____B____C________D____L

H____I____J________K____L

H____I____J________K____E____F

Normal Chromosome

Deletions (deficiency)

Duplications

Inversions

Translocation

slide23

Insertion and deletions are frequent: Sequencing 179 humans as part of the 1000 genome project:

On average, each person is found to carry approximately 250 to 300 loss-of-function variants in genes of which 50 are in genes previously implicated in inherited disorders.

20,000 large structural variants were identified and 1.3 million short indels were identified.

Variation detected by the project is not evenly distributed across the genome: certain regions, such as subtelomeric regions, show high rates of variation.

1 in 500 children have reciprocal translocation but Such translocations are usually harmless. (However gametes produced by the children will have defects).

1 in 50 children have inversions (small and large). The heterozygous inversion carrier generally show no adverse phenotype (but produce abnormal meiotic products from crossing-over in the inversion loop).

deletions
Deletions

Deletions are often detected cytologically by comparing banding patterns between the normal and the partially deleted chromosomes

Deleted

segment

Chromosome no

female

deletion

chromosome1

Band

46,XX, del(1)(q24q31)

Female with a deletion of chromosome 1 on the long arm (q) between bands q24 to q31.

slide25

In many instances deletions are too small to be detected cytologically. In these instances genetic/molecular techniques are used.

Since cytological deletions remove a contiguous set of genes, there is a high probability that an essential gene will be deleted. Therefore deletions will survive as heterozygotes and not homozygotes.

A____B________C____D

Normal

A____B________C____D

A____________C____D

Homologous deletion

(Lethal?)

A____________C____D

A____________C____D

Heterologous deletion

(NOT Lethal)

A____B________C____D

consequences of deletions
Consequences of deletions

A+_____B+_____C+___________D+

Normal

A+_____B+_____C+___________D+

In individuals heterozygous for the deletion, pairing is disrupted in the regions surrounding the deletion. Therefore recombination is also significantly reduced in these regions.

B+

A+____/ \_____C+___________D+

A+___________C+___________D+

Genotype

A+_____b______c____________D+

Normal

A+_____B+_____C+___________D+

A deletion on one homologue unmasks recessive alleles on the other homologue. The effect is called pseudo-dominance.

A+____b______c____________D+

A+___ _____C+___________D+

deletions in x
Deletions in X

Females in Drosophila XX

Males in Drosophila XY or XO

Deletion series phenotype

sick

dead

sick

changes in chromosome structure
Changes in chromosome structure

Deletions:

Hemizygosity from large deletions results in lethality- even the smallest cytologically defined deletions take out tens of 1,000's of bps and are likely to remove essential genes.

2. Organisms can tolerate hemizygosity from small but not large deletions. The reason for this is not entirely clear and is placed under the rubric of disrupting the overall ratio of gene products produced by the organism

deletion mapping
Deletion mapping

Deficiency mapping or deletion mapping:

This provides a means of rapidly mapping a new mutation

A deficiency or deletion is the loss of a contiguous series

of nucleotides

ATGATCGGGCCCATCAAAAAAAAAAAATCATCCCCCGGGG

DELETION

ATGATCGGGCCCATC CATCCCCCGGGG

ATGATCGGGCCCATC|CATCCCCCGGGG

Defined deficiencies are very useful for mapping genes

deficiency mapping
Deficiency mapping

Say we have 6 sites defined by point mutations within

the rosy gene

---1-----2-----3-----4-----5-----6

----------------------------------

---------2------------------------

---------------------4------------

--------------DDDDDDDDDD----------

Can we get intragenic recombinants that will restore

normal rosy gene?

ry2 and ry4? Y

ry2 and the deletion? Y

ry4 and the deletion N

Say we isolate a new ry mutation you call it ry(zany)

You cross it to the deletion and do not find any

Recombinants

Where does ry(z) map

deficiency mapping1
Deficiency mapping

Say we have 6 sites defined by point mutations within

the rosy gene

---1-----2-----3-----4-----5-----6

----------------------------------

---------2------------------------

---------------------4------------

--------------DDDDDDDDDD----------

Can we get intragenic recombinants that will restore

normal rosy gene?

ry2 and ry4? YES

ry2 and the deletion? YES

ry4 and the deletion? No

Say we isolate a new ry mutation you call it ry(z)

You cross it to the deletion and do not find any

recombinants

Where does ry(z) map?

deficiency mapping2
Deficiency mapping

Generate a heterozygote

Gene point mutant/deletion mutant

Ask if you get intragenic recombinants

Heterozygote will be pseudodominant

The single point mutation will be observed over the deletion

multiple deficiencies
Multiple deficiencies

Specific deletions can define a series of regions within

a gene

Gene

---1-----2-----3-----4-----5-----6----7----8--

----------------------------------------------

DDDDDDDDDDDDDDDDDDDDDDDDDDDDD-----------------

------------------DDDDDDDDDDDDDDDDDDDDDD------

These two deletions define 4 regions within the gene

I II III IV

Now say a newly isolated mutation does not produce

normal recombinants with both deletions

To which region does it map?

multiple deficiencies1
Multiple deficiencies

Multiple deletions can define a series of regions within

a gene

Gene

---1-----2-----3-----4-----5-----6----7----8--

----------------------------------------------

DDDDDDDDDDDDDDDDDDDDDDDDDDDDD-----------------

------------------DDDDDDDDDDDDDDDDDDDDDD------

These two deletions define 4 regions within the gene

I II III IV

 4-7 + - - +

 1-5 - - + +

+ = If a mutation maps to this region, normal

recombinant flies are produced

- = If a mutation maps to this region, normal

recombinant flies are NOT produced

Now say a newly isolated white mutation does not produce

normal recombinants with both deletions

To which region does it map?

duplications
Duplications

A____B____C________D____E____F

A____B____C________D____E____E____F

normal

Duplication

Individuals bearing a duplication possess three copies of the genes present in the duplicated region.

In general, for a given chromosomal region, organisms tolerate duplications much better than deletions.

46,XY, dup(7)(q11.2q22)

Male with a duplication of chromosome 7 on the long arm (q) between bands 11.2 to 22

slide36

Tandem duplications- Important class of duplications!!!

This is a case in which the duplicated segment lies adjacent to the original chromosomal segment

A B C D ------ A B CB CB CB C D

Once a tandem duplication arises in a population, even more copies may arise because of asymmetrical pairing at meiosis.

Remember when the homologs pair during prophase of meiosis I, they line up base-pair for base pair. Duplications lead to mistakes in this pairing mechanism

slide37

Proper pairing:

A____B____C____B____C____D____E

A____B____C____B____C____D____E

A____B____C____B____C____D____E

A____B____C____B____C____D____E

Inappropriate pairing:

A____B____C____B____C____D____E

A____B____C____B____C____D____E

A____B____C____B____C__-----------__D____E

A____B____C____B____C__-----------__D____E

slide39

Tandem duplications expand by mistakes in meiosis during pairing

Paired non-sister chromatids

B

C

E

A

B

C

D

c

b

a

d

e

c

b

39

slide40

What happens if you get a crossover after mis-pairing in meiosisI?

A

B

C

B

C

D

A

B

C

B

C

D

c

b

b

c

c

b

a

b

d

a

c

d

B

C

E

A

B

C

D

A

B

C

B

C

D

A

B

C

B

C

B

C

D

c

b

a

d

e

A

B

C

D

c

b

A

B

C

B

C

D

slide41

The four meiotic products of a crossover between regions B and C:

A-B-C-B-C-D-E

A-B-C-D-E

A-B-C-B-C-B-C-D-E

A-B-C-B-C-D-E

This process may repeat itself many times, such that a small fragment of the genome is repeated 10,000 times.

slide42

An example of this is near the centromeres of the Drosophila genome:

If you look at the DNA sequence in this region it consists of small 5-10 bp sequences (AATAC)n repeated 1,000s of times. It is believed to have arisen from unequal crossing over.

Repetitive DNA- cell does not like it- They try to reduce recombination of repetitive DNA by packaging the DNA with proteins to form heterochromatin- cold spots of recombination along the chromosome

slide43

Duplications provide additional genetic material capable of evolving new function. For example in the above situation if the duplication for the B and C genes becomes fixed in the population- the additional copies of B and C are free to evolve new or modified functions.

This is one explanation for the origin of the tandemly repeated globin genes in humans. Each of these has a unique developmental expression pattern and provides a specialized function.

The hemoglobin in fetus has a higher affinity for oxygen since it acquires its oxygen from maternal hemoglobin via competition

slide44

Two distinct globin chains (each with its individual heme molecule) combine to form hemoglobin.

One of the chains is designated alpha. The second chain is called "non-alpha".

The fetus has a distinct non-alpha chain called gamma. After birth, a different non-alpha globin chain, called beta, pairs with the alpha chain. The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule.

The genes that encode the alpha globin chains are on chromosome 16. Those that encode the non-alpha globin chains are on chromosome 11.

The alpha gene complex is called the "alpha globin locus",

The non-alpha complex is called the "beta globin locus".

The expression of the alpha and non-alpha genes is closely balanced by an unknown mechanism. Balanced gene expression is required for normal red cell function. Disruption of the balance produces a disorder called thalassemia.

The closely linked globin genes may have originally arisen from tandem duplication.

slide45

Alternatively some duplicated genes accumulate mutations and are no longer expressed (these are akin to junked cars along the highway).

These are known as pseudogenes. One of the genes in the hemoglobin cluster is a pseudogene.

-G-A-*--

pseudogene

Unequal crossing over among the tandemly repeated hemoglobin gene cluster is the explanation for some inherited blood diseases.

Hemoglobin lepore

slide46

Alternatively some duplicated genes accumulate mutations and are no longer expressed (these are akin to junked cars along the highway).

The beta-globin gene cluster in humans contains 6 genes, called epsilon (an embryonic form), gamma-G, gamma-A (the gammas are fetal forms), pseudo-beta-one (an inactive pseudogene), delta (1% of adult beta-type globin), and beta (99% of adult beta-type globin. Gamma-G and gamma-A are very similar, differing by only 1 amino acid.

These are known as pseudogenes. One of the genes in the hemoglobin cluster is a pseudogene.

-G-A-*--

pseudogene

Unequal crossing over among the tandemly repeated hemoglobin gene cluster is the explanation for some inherited blood diseases.

Hemoglobin lepore anemia

-G-A--

-G-A-

-G-A--

slide47

***

  • If mispairing in meiosis occurs, followed by a crossover between delta and beta, the hemoglobin variant Hb-Lepore is formed.
  • This is a gene that starts out delta and ends as beta. Since the gene is controlled by DNA sequences upstream from the gene, Hb-Lepore is expressed as if it were a delta. That is, it is expressed at about 1% of the level that beta is expressed.
  • Since normal beta globin is absent in Hb-Lepore, the person has severe anemia.
inversion
Inversion

Chromosomes in which two breaks occur and the resulting fragment is rotated 180 degrees and reinserted into the chromosome.

Inversions involve no change in the amount of genetic material and therefore they are often genetically viable and show no abnormalities at the phenotypic level.

Gene fusions may occur

Inversions are defined as to whether they span the centromere

Paracentric inversions do not span the centromere:

A B C D E

A B DC E

Pericentric inversions span the centromere:

A CB D E

In a pericentric inversion one break is in the short arm and one in the long arm. Therefore an example might read 46,XY,inv(3)(p23q27).

A paracenteric inversion does not include the centromere and an example might be 46,XY,inv(1)(p12p31).

slide49

Homologs which are heterozygous for an inversion have difficulties pairing in meiosis.

During pairing homologous regions associate with one another. Consequently individuals heterozygous for an inversion will form a structure known as an inversion loop.

Crossover within inverted region?

A---B---C---D---E---F---G

A’--B’---C’---D’--E’---F’---G’

A---B---C---D---E---F---G

A’--B’---C’---E’---D’--F’---G’

D E

D’ E’

A B C

F G

‘F G’

A’ B’ C’

the consequence of crossover within a paracentric inversion
The consequence of crossover within a paracentric inversion

a-b-c

d-e

f-g

a-b-c

d-e

f-g

a-b-c

e-d

f-g

During meiosis, pairing leads to formation of an inversion loop

This is a problem if crossing over occurs within the inversion

D E

D’ E’

A B C

F G

‘F G’

A’ B’ C’

A-B-0-C-D-E’-C’--0--B’-A’ dicentric-fragmentation

G-F-E-D’-F’-G’ acentric- no segregation

the consequence of crossover within a pericentric inversion one that spans the centromere
The consequence of crossover within a pericentric inversion (one that spans the centromere).

a-b-c

d-e

f-g

a-b-c

d-e

f-g

a-b-c

e-d

f-g

During meiosis, pairing leads to formation of an inversion loop

This is a problem if crossing over occurs within the inversion

D E

D’ E’

A B C

F G

‘F G’

A’ B’ C’

A-B-C-D-0-E’-C’-B’-A’ fragment

G-F-E-0-D’-F’-G’ fragment

slide52

Paracentric inversion crosses over with a normal chromosome, the resulting chromosomes are an acentric, with no centromeres, and a dicentric, with 2 centromeres.

  • The acentric chromosome isn't attached to the spindle, so it gets lost during cell division, and the dicentric is usually pulled apart (broken) by the spindle pulling the two centromeres in opposite directions. These conditions are lethal.
  • Pericentric inversion crosses over with a normal chromosome, the resulting chromosomes are duplicated for some genes and deleted for other genes. (They do have 1 centromere apiece though).
  • The gametes resulting from these do not produce viable progeny.
  • Thus, either kind of inversion has lethal results when it crosses over with a normal chromosome.
  • The only offspring that survive are those that didn't have a crossover or crossed over in regions outside the inversion.
  • Thus when you count the offspring you only see the non-crossovers, so it appears that crossing over has been suppressed.
slide53

What are the consequences of crossing-over in an individual homozygous for an inversion?

Genotype for normal individual

A B 0 C D E F G

A B 0 C D E F G

Genotype of an individual heterozygous for an inversion:

A B 0 C D E F G

A B 0 C F E D G

Genotype of an individual homozygous for an inversion:

A B 0 C F E D G

A B 0 C F E D G

translocations
Translocations

A segment from one chromosome is exchanged with a segment from another chromosome.

Chromosome 1

A B C D E F

----------------------0-----------------------

----------------------0-----------------------

A B C D E F

Chromosome 2

O P Q R S T

----------------------0-----------------------

----------------------0-----------------------

O P Q R S T

Reciprocal translocation

A B C D S T

----------------------0-----------------------

O P Q R E F

----------------------0-----------------------

This is more specifically called a reciprocal translocation and like inversions (and unlike duplications and deficiencies) no genetic material is gained or lost in a reciprocal translocation.

Non-reciprocal translocations may also occur

slide55

long arms of chromosome 7 and 21 have broken off and switched places. So you can see a normal 7 and 21, and a translocated 7 and 21.

This individual has all the material needed, just switched around (translocated), so they should have no health problems. However there can be a problem when this person has children.

Remember that when the gametes are made, each parent gives one of each chromosome pair. What would happen if this person gave the normal seven and the 21p with 7q attached?

There are three copies of 7q instead of two. And there is only one copy of 21q

t(11;18)(q21;q21) translocation between chromosomes 11 and 18 at bands q21 and q21

Philadelphia chromosome: t(9;22)(q34;q11).

slide56

As with inversions, individuals heterozygous for a reciprocal translocation will exhibit abnormalities in chromosome pairing

A B C D E F

----------------------0-----------------------

----------------------0-----------------------

A B C D S T

O P Q R S T

----------------------0-----------------------

----------------------0-----------------------

O P Q R E F

Notice this individual has the normal amount of genetic material

(two copies of each gene).

However it is rearranged.

If the translocated fragment contains a centromere, you could get dicentri and acentric chromosomes

How will translocated chromosomes pair in meiosis?

slide57

F

F

N1

T1

E

E

A

B

C

D

R

Q

P

O

A

B

C

D

R

Q

P

O

S

S

T2

N2

T

T

Homologous regions associate with one another.

These chromosomes will follow Mendel's rule of independent of assortment. In this instance one must focus on the centromere

There are three possible patterns of segregation.

Normal Pairing of 10 chromosomes in maize

Chr8-9 translocation

slide58

F

F

N1

T1

  • Alternate segregation:
      • キN1 and N2 segregate to one pole
      • キT1 and T2 segregate the other pole
  • These gametes have the normal haploid gene content: one copy of each gene and are normal
  • Adjacent segregation:
      • キN1 and T1 segregate to one pole
      • キT2 and N2 segregate to the other pole
  • These gametes are anueploid: they are missing some genes and duplicated for other genes.
  • Adjacent segregation
      • キN1 and T2 segregate to one pole
      • キN2 and T1 segregate to one pole
  • Therefore, in a translocation heterozygote, some of the gametes are viable and some are inviable.

E

E

A

B

C

D

R

Q

P

O

A

B

C

D

R

Q

P

O

S

S

T2

N2

T

T

slide59

F

F

N1

T1

E

E

A

B

C

D

R

Q

P

O

A

B

C

D

R

Q

P

O

Reciprocal translocations result in genes that are known to map to different chromosomes but behave as linked genes.

Under normal circumstances genes E and R assort independently because they are on different chromosomes. However in a translocation they will behave as closely linked genes and segregate together.

S

S

T2

N2

T

T

slide60

Translocations (and inversion) breakpoints sometimes disrupt an essential gene. That is the break occurs in the middle of a gene.

In fact because of this, a number of specific translocations are causally associated with specific human cancers.

The inherited disease Duchenne muscular dystrophy was mapped through a translocation that specifically disrupted this gene.

glevec and the philadelphia chromosome
Glevec and the Philadelphia chromosome

Abl is a tyrosine kinase.

Function of the normal BCR gene product is not clear.

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl.

This is now a continuously active tyrosine kinase.

Glevec inhibits the abl protein of cancer and non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function. Tumourogenesis however is entirely dependent on Bcr-Abl and so these cells get inactivated.

slide63

abl/bcr Fusion protein Chronic myelogenous and acute lymphotic leukemia

ALK/NPM Fusion Large cell lymphomas

HER2/neu Fusion Breast and cervical carcinomas

MYH11/CBFB Fusion Acute myeloid leukemia

ML/RAR Fusion Acute premyelocytic leukemia

ERG/TMPRSS2 Fusion prostate cancer

Gene fusion -prostate cancer -ERG merges with a prostate-specific gene called TMPRSS2. ERG is a transcription factors