Essentials of Biology Sylvia S. Mader Chapter 13 Lecture Outline Copyright © The McGraw-Hill...

Essentials of BiologySylvia S. Mader

Chapter 13Lecture Outline

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

13.1 Counseling for chromosomal disorders

• Genetic counseling – potential parents are advised on their risk of inherited disorders.

• Counselor helps couple understand the mode of inheritance, medical consequences of disorder and decisions they might wish to make.

• Karyotyping – visual display of chromosomes arranged by size, shape and banding pattern

• Can be from white blood cells or fetal cells by amniocentesis or chorionic villus sampling

Figure 13.2 Testing for chromosomal mutationsCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

© CNRI/SPL/Photo Researchers, Inc.

c. Karyotype of a person with Down syndrome. Note the three number 21 chromosomes.

• Amniocentesis Sample of amniotic fluid taken 0.3% risk of spontaneous abortion Not until 14-17th week of pregnancy

Figure 13.2 continuedCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

amnioticcavity

a. During amniocentesis, a long needle is used to withdraw amniotic fluid containing fetal cells.

•Chorionic villus samplingChorionic cells from where placenta will developAs early as 5th week of pregnancyGreater risk (0.8%) but earlier results

Figure 13.2 continuedCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

chorionicvilli

b. During chorionic villi sampling, a suction tube is used to remove cells from the chorion, where the placenta will develop.

• Chromosomal mutations Karyotype reveals changes in chromosome

number and differences in structure. In humans only a few variations in number are

typically seen.• Down syndrome, Turner syndrome, Klinefelter

syndrome

Changes in chromosome structure more common

• Due to breakage and failure to reunite properly• Results in deletion, duplication, translocation or

inversion

• Deletion When a single break causes a chromosome to lose

an end or 2 breaks result in the loss of an internal segment

Williams syndrome – chromosome 17 loses a tiny end piece.

Cri du chat – chromosome 5 loses an end piece.

Figure 13.3 Deletion

a.

ha b c d e f g

a b c d e f g h

lost

deletion

+


Figure 13.3 continued

b.


Courtesy The Williams Syndrome Association

• Duplication Chromosome segment repeated Individual has more than 2 alleles for certain

traits. Inv dup 15 syndrome – inverted duplication of

chromosome 15• Inversion – segment joins in direction opposite

from normal.

Figure 13.4 Duplication

a.

b.

duplication inversion

a b c d de ef f g h

a b c d e f g h


Courtesy Kathy Wise

• Translocation Exchange of chromosome segments between

nonhomologous chromosomes A person with both the involved chromosomes

has a normal amount of genetic material and is healthy unless the exchange disrupts a gene.

5% of Down syndrome cases caused by a translocation in previous generation between chromosome 21 and 14

• Not related to parental age but is inherited

• Alagille syndrome Translocation between chromosome 2 and 20 Normal amount of genetic material but distinctive

face, some abnormalities and severe itching Translocation disrupted allele on chromosome

20 Father did not realize he had the syndrome until

he had this child.

Figure 13.5 Translocation

a

bc

defgh

st

uvwxyz

a

bc

defyz

st

uvwxgh

translocation

a.


• Inversion Segment of a chromosome is turned 180° Reverse sequence of alleles can lead to

altered gene activity if it disrupts control of gene expression.

Usually do not cause problems During meiosis, crossing-over can lead to

recombinant chromosomes.• Alignment only possible when inverted

chromosome forms a loop

Figure 13.6 Inversion

d

a a

b b

c c

d

e e

E

F

G

f f

g g

a b

c d

eA B

C D

E

F

G

fg

a

b

d

e E

F

G

crossing-overABCD

E

F

G

A

B

C c

D

f

ga

b

d

e

c

f

g

E

F

G

A

B

C

D

A

B

C

D

invertedsegments

duplicationand deletionin both

nonsisterchromatids

homologouschromosomes


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13.2 Counseling for Genetic Disorders

• Even if no chromosomal abnormality is likely, amniocentesis might still be done to perform biochemical tests for over 400 different disorders caused by specific genes.

• Counselor needs to know medical history of family to construct a pedigree

• Determines what tests are warranted

• Pedigree Chart of a family’s history with regard to a

particular genetic trait• Males are squares• Females are circles• Shading represents individuals expressing disorder.• Horizontal line between circle and square is a union.• Vertical line down represents children of that union.

Counselor may already know pattern of inheritance and then can predict chance that child born to a couple would have the abnormal phenotype.

• Pedigrees for autosomal disorders Autosomal recessive disorder

• Child can be affected when neither parent is affected

• Heterozygous parents are carriers• Parents can be tested before having children

Figure 13.7 Autosomal recessive pedigree

aa aa

Aa Aa

Aa

A?

A? A?

Aa

*

aa A?

A?A?

Key:• Affected children can have unaffected parents.

• Heterozygotes (Aa) have a normal phenotype.

• Both males and females are affected with equal frequency.

aa = affected

AA = normalA? = normal (one allele unknown)

Aa = carrier (normal)


Autosomal dominant disorder•Child can be unaffected even when parents are heterozygous and therefore affected.•When both parents are unaffected, none of their children will have the condition.

No dominant gene to pass on

Figure 13.8 Autosomal dominant pedigree

Aa

aa aa aa

aaaaaaaaAa

aa

Aa

Aa A?

Aa

Key:AA = affected

A? = affectedAa = affected

aa = normal

*

• Heterozygotes (Aa) are affected.

• Affected children will have at least one affected parent.

• Both males and females are affected with equal frequency.


• Pedigree for sex-linked disorder X-linked recessive disorder

• Sons inherit trait from mother – son’s X comes from mother.

• More males than females have disorder – allele on X is always expressed in males.

• Females who have the condition inherited the mutant allele from both their mother and their father.

• Conditions appear to pass from grandfather to grandson.

Figure 13.9 X-linked recessive pedigree

• More males than females are affected.

•

grandson

daughter

grandfather

Key:

XBXB = Normal femaleXBXB

XBXB

XBY XBY

XBY

XbY

XbY

XbY

XBXb

XBXb

XbXb

• An affected son can have parents who have the normal phenotype.

For a female to have the characteristic, her father mustalso have it. Her mother must have it or be a carrier.

XBXb = Carrier femaleXbXb = Color-blind female

XBY = Normal maleXbY = Color-blind male


X-linked dominant• Only a few traits• Daughters of affected males have the condition.• Affected females can pass condition to daughters

and sons. Depends on which X inherited from a carrier mother if

father is normal

Y chromosome• Only a few disorders• Present only in males and are passed to all sons

but not daughters

• Genetic disorders of interest Autosomal disorders

• Methemoglobinemia – lack enzyme to convert methemoglobin back to hemoglobin

Relatively harmless, bluish-purplish skin

Figure 13.10 Methemoglobinemia


Courtesy of Division of Medical Toxicology, University of Virginia

•Cystic fibrosis – autosomal recessive disorder

Most common lethal genetic disorder among Caucasians in USChloride ion channel defect causes abnormally thick mucus.

Figure 13.11 Cystic fibrosis


© Pat Pendarvis

nebulizer

percussion vest

•Alkaptonuria – autosomal recessive disorder

Lack function homogentisate oxygenase geneAccumulation of homogentisic acid turns urine black.

Figure 13.12 Alkaptonuria


© O.J. Staats, M.D./Custom Medical Stock Photo

• Sickle cell disease – autosomal recessive disorder

Single base change in globin gene changes 1 amino acid in hemoglobin.

Makes red blood cells sickle – leads to poor circulation, anemia, low resistance to infection

• Marfan syndrome – autosomal dominant disorder

Defect in connective tissue protein

Problems in tissues expressing this protein

Figure 13.13 Sickle cell disease


© Dr. Gopal Murti/SPL/Photo Researchers, Inc.

2500

•Huntington disease – autosomal dominant disorder

Progressive degeneration of neurons in brainMutation for huntingtin proteinPatients appear normal until middle-aged – usually after having children.Test for presence of gene

Figure 13.14 Huntington disease


(both): Courtesy Dr. Hemachandra Reddy

Loss of neurons in Huntington brain

Many neurons in normal brain

X-linked recessive disorders• Color blindness

About 8% of Caucasian men have red-green color blindness.

• Duchenne muscular dystrophy Absence of protein dystrophin causes wasting away of

muscles. Therapy – immature muscle cells injected into muscles

Figure 13.15 Muscular dystrophy

fibroustissue

normaltissue


(left, right): Courtesy Dr. Rabi Tawil; (center): Courtesy Muscular Dystrophy

• Testing for genetic disorders Testing for a protein

• Some disorders caused by a missing enzyme Test for quantity of enzyme produced

Testing the DNA• Genetic marker – relies on an abnormality in the

DNA sequence due to presence of abnormal allele. Fragments from restriction digest will differ from a normal

person’s results.

Figure 13.16 Use of a genetic marker to test for a genetic mutation

affectedallele

normalallele

enzyme cleavage sites enzyme cleavage sites

fragments of DNA fragments of DNA

a. Normal fragmentation pattern b. Genetic disorder fragmentationpattern


• Genetic profiling Individual’s complete genotype DNA sample applied to DNA chip DNA chip contains probes – single-stranded

DNA that binds to complementary DNA from patient

Binding shows patient has particular mutated genes

Figure 13.17 Use of a DNA chip to test for mutated genes

mutant allele

fluorescent DN A did notbind to mutant allele

fluorescentgenomic DN A

DN Amicroarray

Testing subject’s DN A

fluorescent DN A didbind to mutant allele


(chip): Courtesy of Mergen, Ltd

Testing the fetus• Ultrasound – helps

evaluate fetal anatomy for serious abnormalities.

Uses high-frequency sound waves

• Testing fetal cells Cells from amniocentesis or

chorionic villus sampling Fetal cells can also be

collected from mother’s blood.

• PCR used to amplify DNA, no risk to fetus

Figure 13.18 UltrasoundCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

© Bernard Bennot/SPL/Photo Researchers, Inc.

Testing the embryo and egg

• Testing embryo – following IVF, 1 cell can be removed from embryo without harm.

Figure 13.19 Testing the embryo

Embryo developsnormally in uterus.

Cell isgeneticallyhealthy.

Embryonic cellis removed.

8-celled embryo


Testing the embryo and egg• Testing egg – meiosis results in single egg and 2

polar bodies.• Polar bodies can be used in genetic testing.• If a woman is a heterozygote, when the polar body

has the defective allele, the egg must be normal.

Figure 13.20 Testing the egg

Woman isheterozygous

Genetically healthyegg used for IVF.

Embryo developsnormally in uterus.

Polar body containsmutant allele.

Polar bodyis removed.

Egg

IVF


13.3 Gene Therapy

• Insertion of genetic material into human cells for treatment of a disorder

• 2 methods Ex vivo – outside the body In vivo – inside the body

• Ex vivo Treatment of SCIDS

• Severe combined immunodeficiency• Lack enzyme involved in maturation of cells

producing antibodies• Bone marrow are stem cells removed and infected

with RNA retrovirus carrying gene for normal enzyme.

• Cells are then retuned to patient. Treatment of familial hypercholesterolemia

• High levels of cholesterol lead to early fatal heart attacks.

• Small portion of liver is removed and infected with retrovirus containing normal cholesterol receptor.

• Tissue is returned to patient.


defectivegene

bonemarrow

Remove bonemarrow stem cells.

1

Figure 13.21 Ex vivo gene therapy in humans


defectivegene

retrovirus

normalgene

recombinantDNA

bonemarrow

Use a virus tocarry the normalgene into bonemarrow stem cells.

2


1



defectivegene

virus

normalgene

recombinantDNA

bonemarrow

Recombinant DNAmolecules carry the normal gene intothe genome of stem cells.

3

2


1

normalgene


recombinant DNA


Figure 13.21 Ex vivo gene therapy in humansCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Return geneticallyengineered stemcells to the patient.

4

defectivegene

2


1


virus

normalgene

recombinantDNA

recombinant DNA

Recombinant DNAmolecules carry the normal gene intothe genome of stem cells.

3

normalgene

bonemarrow

• In vivo Cystic fibrosis treatment

• Gene needed is sprayed into the nose or delivered to lower respiratory tract.

• Use adenoviruses or liposomes to carry gene Poor coronary circulation treatment

• Vascular endothelial growth factor can cause growth of new blood vessels.

• Genes coding for growth factor can be injected alone, or within a virus, into the heart to stimulate branching of coronary arteries.

Rheumatoid arthritis• Immune system destroys person’s own body.• Inject adenoviruses that contain anti-inflammatory

genes into the affected joint

Figure 13.23 Ex vivo gene therapy in humansCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Brain(gene transfer by injection)*• Huntington disease• Alzheimer disease• Parkinson disease• brain tumors

Skin(gene transfer by modified blood cells)*• skin cancer

Lungs(gene transfer by aerosol spray)*• cystic fibrosis• hereditary emphysema

Liver(gene transfer by retroviral implants)**• familial hypercholesterolemia

Blood(gene transfer by bone marrow transplant)**• sickle cell disease

Muscle(gene transfer by injection)*• Duchenne muscular dystrophyJoint(gene transfer by injection)• rheumatoid arthritis

Bone marrow(gene transfer by implantation ofgenetically altered stem cells)**• ADA deficient SCID• sickle cell disease

Endothelium (blood vessel lining)(gene transfer by implantation ofgenetically altered endothelium)**• hemophilia• diabetes mellitus

* in vivoex vivo**

Essentials of Biology Sylvia S. Mader Chapter 13 Lecture Outline Copyright © The McGraw-Hill...

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