CHAPTER 14

THE HUMAN GENOME

14-1 Human Heredity

Key Concepts

• How is sex determined?

• How do small changes in DNA cause genetic disorders?

How do biologists go about studying human DNA?

•They use something called a KARYOTYPE

•Biologists photograph cells in mitosis, when chromosomes are easier to see. They cut out the chromosomes from the photographs and group them together

in pairs

• Humans have a total of 46 chromosomes – half (23) from mom and half (23) from dad

• Out of those 46, two are called SEX CHROMOSOMES– Determine an individual’s sex

• Females have two copies of a larger X chromosome

• Males have one large X and a smaller Y chromosome

• AUTOSOMES–The other 44 chromosomes

• Females – 46XX

• Males - 46XY

• Look at the karyotype in your notes, is this individual male or female?–Male

•How is the X chromosome different from the Y chromosome?–The X chromosome is longer

• How is sex determined?

–All egg cells carry a single X chromosome.

–However, half of all sperm cells carry an X chromosome.

–This ensures that about half of the zygotes will be 46XX and half will be 46XY

X X

X

Y

Finish this Punnett Square to see how sex is determined

X XX XX XX

Y XY XY

• How do biologists identify an inherited trait that is controlled by a single gene?

–They must establish that the trait is actually inherited and not a result of environmental influences

-They have to study how the trait is passed from one generation to the next

• PEDIGREE–Shows the relationship within a family; helps to study genetic traits

–Can help parents understand the probability of having a child with a genetic disorder

A circle represents a female.

A square represents a male.

A horizontal line connecting a male and female represents a marriage.

A vertical line and a bracket connect the parents to their children.

A half-shaded circle or square indicates that a person is a carrier of the trait.

A completely shaded circle or square indicates that a person expresses the trait.

A circle or square that is not shaded indicates that a person neither expresses the trait nor is a carrier of the trait.

Figure 14-3 A Pedigree

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• What do circles represent? -Females

•What do squares represent?-Males

•What does a horizontal line represent?–Between a male and

female represents a marriage•What does a vertical line

represent?–Connects parent to their children

• What does a circle or square that is not shaded represent?

-That person does not express a trait nor are they a carrier

•What does a fully shaded circle or square represent?

-The person expresses a trait

• What does a half shaded circle or square represent?

–The person is a carrier of the trait

•What is the sex of the last person in the second row? Does that person have the trait?

–Female; no

Pedigree analysis

• Pedigree analysis reveals Mendelian patterns in human inheritance– data mapped on a family tree

= male = female = male w/ trait = female w/ trait

• POLYGENIC– A trait controlled by many genes

• How can you find out where you get your good looks from?– This is actually rather difficult– Many traits are polygenic like the shape of

your eyes or ears– Many of your traits are only partly

governed by genetics – environmental influences (nutrition, exercise) can affect how a trait is expressed

What is your blood type?

• Why is it important for a doctor to know your blood type before they give you a blood transfusion?

–Using the wrong blood type during a transfusion can be fatal

The best known blood groups are ABO and Rh

• Rh-Rh blood group is determined by a

single gene with two alleles – –positive and negative

-Rh stands for rhesus monkey – this was the first animal where they discovered this factor

• The positive allele is dominant –If you are Rh+/Rh+ or Rh+/Rh- you are considered Rh positive

• The negative allele is recessive– If you have two Rh- alleles you are Rh negative

ABO• a little more complicated

• There are three alleles IA, IB, and I

• Alleles IA and IB are codominant

• These alleles produce molecules known as antigens that your immune system can recognize on the surface of red blood cells

• If you have IAIA you only produce A antigens etc. – see fig 14-4 p. 344

Phenotype(Blood Type Genotype

Antigen on Red Blood Cell

Safe Transfusions

To From

Figure 14-4 Blood Groups

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• If you are homozygous ii you have no antigen on your red blood cells this is blood type O

• Typically nurses and doctors will use both blood types like AB negative or O positive

• What happens if you give type A blood to a type O patient?

–The immune system will recognize the blood cells as foreign (they don’t belong) because of the A antigens on the cell’s surfaces. The immune system will produce antibodies against these blood cells and destroy them

• Why are type AB people called universal acceptors?

– They can accept any blood type

• Why are type O called universal donors?

– They can donate to any blood type

• What blood type do you think most blood banks want to have on hand?

– Type O because is has no antigens and can be given to any blood type without causing an antibody reaction

• If a woman with type O blood and a man with type AB blood have children, what are the children’s possible phenotypes?

• Use a Punnett Square to answer

IA IB

i

i

IA IB

i IAi IBi

i IAi IBi

Genotypes: IAi and IBiPhenotypes: Type A and Type B

caused by

includeincludeinclude

AutosomolDisorders

Recessive alleles

Dominant allelesCodominant

alleles

Albinism Galactosemia Tay-Sachs disease

Huntington’s disease

Sickle cell disease

Cystic fibrosis

Phenylketonuria AchondroplasiaHypercholes-

terolemia

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Genetic Disorders-they are disorders that are inherited in our genes

If there is a known genetic condition a doctor may suggest a couple go through genetic counseling to determine their risk of having a child with an inherited genetic condition.• A pedigree can help us understand the

past & predict the future• Thousands of genetic disorders are

inherited as simple recessive traits– benign conditions to deadly diseases– albinism– cystic fibrosis– Tay sachs– sickle cell anemia– PKU

Genetic testing - may be done to determine if an unborn child has a genetic disorder.

Example: Amniocentesis

Recessive diseases

• The diseases are recessive because the allele codes for either a malfunctioning protein or no protein at all

– Heterozygotes (Aa) • carriers

• have a normal phenotype because one “normal” allele produces enough of the required protein

Heterozygote crosses

Aa x Aa

A amale / sperm

A

a

fem

ale

/ eg

gs

AA

Aa aa

Aa

Aa

A

a

Aa

A

a

AA

Aa aa

Aa

• Heterozygotes as carriers of recessive alleles

Albinism – homozygous recessive (aa)

Phenylketonuria – PKU

• People lack an enzyme to break down phenylalanine

• Phenylalanine is an amino acid found in milk and many other foods

• If a child with PKU eats phenylalanine and it builds up in their tissues – mental retardation occurs

• There is a test• Treatment – the person must be on a low-

phenylalanine diet their entire life• Caused by a recessive allele on chromosome 12

Tay-Sachs

• Primarily Jews of eastern European (Ashkenazi) descent & Cajuns– strikes 1 in 3600 births

• 100 times greater than incidence among non-Jews or Mediterranean (Sephardic) Jews

– non-functional enzyme fails to breakdown lipids in brain cells• symptoms begin few months

after birth • seizures, blindness &

degeneration of motor & mental performance

• child dies before 5yo

Tay-Sachs disease(continued)• Caused by an allele found in Jewish

families with central and eastern European ancestry

• Results in nervous system breakdown and death in the first few years of life

• There is no treatment• Parents can be tested ahead of time

to see if they are carriers

Dominant allele disorders

• Achondroplasia– One type of dwarfism– The person never reaches a height

greater than 4 feet 4 inches tall– Arms and legs form disproportionately

short– 1 in about 10,000 people are affected

Huntington’s disease

• Causes progressive loss of muscle control and mental function until death occurs

• Symptoms don’t show until people are in their thirties and forties

Codominant allele disordersSickle cell anemia • Primarily Africans

– strikes 1 out of 400 African Americans– caused by substitution of a single amino acid in

hemoglobin– when oxygen levels are low, sickle-cell

hemoglobin crystallizes into long rods– Due to this shape the cells are more rigid and

they tend to get stuck in capillaries causing blockages

– Causes physical weakness, brain damage, damage to the heart and spleen• deforms red blood cells into

sickle shape• sickling creates pleiotropic

effects = cascade of other symptoms

Sickle cell phenotype

• 2 alleles are codominant – both normal & abnormal hemoglobins are

synthesized in heterozygote (Aa)– carriers usually healthy, although some

suffer some symptoms of sickle-cell disease under blood oxygen stress• exercise

• Heterozygous people still have sickle shaped red blood cells but not as many

• When the body destroys sickled cells, it gets rid of the Malaria parasite at the same time

• In regions where Malaria is a problem, it is beneficial for people to be heterozygous for sickle cell disease

Heterozygote advantage

Malaria– single-celled eukaryote parasite spends

part of its life cycle in red blood cells• Heterozygous people still have sickle

shaped red blood cells but not as many

• When the body destroys sickled cells, it gets rid of the Malaria parasite at the same time

• In regions where Malaria is a problem, it is beneficial for people to be heterozygous for sickle cell disease

• In tropical Africa, where malaria is common:– homozygous normal individuals die of

malaria– homozygous recessive individuals die of

sickle cell anemia– heterozygote carriers are relatively free of

both

Malaria, a serious parasitic disease that infects red blood cells, is common in certain regions of Africa. People who are heterozygous for sickle cell disease are generally healthy and they are resistant to Malaria

Prevalence of Malaria

• High frequency of sickle cell allele in African Americans is vestige of African roots

Prevalence of SickleCell Anemia

Cystic Fibrosis• Common in people whose ancestors come from

Northern Europe– strikes 1 in 2500 births

• 1 in 25 whites is a carrier (Aa)• Recessive allele on chromosome number 7 the

normal allele codes for a membrane protein that transports Cl- across cell membrane

• defective or absent protein channels cause high

extracellular levels of Cl- • thicker & stickier mucus coats around cells • mucus build-up in the pancreas, lungs, digestive

tract & causes bacterial infections• Children with CF have serious digestive

problems• They produce thick, heavy mucous that clogs

their lungs and breathing passages• Without treatment children die before 5;

with treatment can live past their late 20s

Normal Lungs Chloride channelTransports chloride through protein channel out of cell.Osmotic effects:

H2O follows Cl-

airway

cells lining lungs

Cl-

Na+

mucus secreting glands

Cystic fibrosis

airway

cells lining lungs

Cl-

Na+

bacteria & mucus build up

thickened mucus hard to secrete

damaged lung tissue

• Heterozygous people are unaffected because they produce enough of this protein to allow their tissues to function properly

Heterozygous Advantage

14-2 Human Chromosomes

Key Concepts

Why are sex linked disorders more common in males, than in females?

What is nondisjunction, and what problems does it cause?

• Look at page 341.

Which chromosomes are the largest?

1 and 2

Which chromosomes are the smallest?

18-22

Considering the chromosome sizes, how many bases might chromosome 1 have if chromosome 22 has about 43 million bases?

About three times as many – 129 million

• Chromosome 21 and 22 are the smallest human autosomes

• These were the first two chromosomes whose sequences were discovered–Chromosome 22 has 545 genes

• Problems with this chromosome – genetic disorders are: an allele

associated with a form of leukemia and another associated with neurofibromatosis (a tumor-causing disease of the nervous system)

• Chromosome 21 has 225 genes

• Genetic disorders are: amyotrophic lateral sclerosis (ALS) also known as Lou Gehrigs disease – this disease causes a

progressive loss of muscle control due to the destruction of nerves in the brain and spinal cord

Recall:• Genes located on the same

chromosome are linked, meaning they tend to be inherited together

• Genes may be separated by recombination (during crossing-over) in meiosis

• Look at p. 350 fig 14-12• Which chromosome carries more

genes?The X chromosome

SEX-LINKED GENESA gene located on the X or Y chromosome

• More than 100 sex-linked genetic disorders have been mapped to the X chromosome

• The Y chromosome is much smaller and appears to only carry a few genes

• Why are sex-linked disorders more common in males than in females?–Males have just one X chromosome.

Thus, all X-linked alleles are expressed in males, even if they are recessive.

Colorblindness

• the person cannot see certain colors• the human genes associated with

colorblindness are located on the X chromosome

• in males, a defective version of any one of these genes produces colorblindness

• red-green colorblindness (cannot see green) found in 1 out of 10 males in US but only 1 in 100 females

Can you see the numbers in each circle?

• Why do fewer females have colorblindness?–In order for a recessive allele, such as the one for colorblindness, to be expressed in females, there must be two copies of the allele

• Pedigrees and pedigree Punnett squares are used to trace genetic disorders through families and to determine the chances that future generations will have the disorder

Father(normal vision)

ColorblindNormal vision

Mother (carrier)

Daughter(normal vision)

Son(normal vision)

Daughter(carrier)

Son(colorblind)

Male

Female

Figure 14-13 Colorblindness

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• Why is the circle for the mother shaded only halfway?–She is heterozygous and is a carrier

• Would you expect the colorblind son to have sons who are colorblind?–No, the son can only pass the Y

chromosome to his sons• What is the probability that the

daughter who is a carrier will have a colorblind child if she marries a man with normal vision?–25%

Hemophilia• A protein necessary for normal blood clotting is missing• Two important genes carried on the X chromosome help

control blood clotting – a recessive allele in either of these two genes may produce the disorder

• 1 in 10,000 males are born with it• People with hemophilia can bleed to death from a minor

cut or could suffer internal bleeding from bumps or bruises

• These people are treated with injections of clotting proteins

Duchenne Muscular Dystrophy

• Results in the progressive weakening and loss of skeletal muscle

• People rarely live past adulthood

• 1 in 3000 males is born with it

• Females have two X chromosomes, but males only have one

• If just one X chromosome is enough for cells in males, how does the cell adjust to the extra X chromosome in female cells?– Scientists have

found that in female cells, one X chromosome is randomly switched off

Calico cats

• A gene that controls coat color is located on the X chromosome

• One X chromosome may have an allele for orange spots and the other may have an allele for black spots.

• In some cells on the cat’s body one X chromosome (orange spots) is switched on while the other X chromosome in those cells is switched off

• Then in other areas the opposite occurs – the black spots X chromosome switches on and the other switches off

• Male cats have only one X chromosome so they can only have spots of one color

• The turned off chromosome forms a dense region in the nucleus known as a Barr Body

• Barr bodies are not found in males because their X is always turned on

• What is the sex of the cat in fig. 14-14?–Female

Chromosomal abnormalities

• Incorrect number of chromosomes– nondisjunction

• chromosomes don’t separate properly during meiosis

– breakage of chromosomes• deletion• duplication• inversion• translocation

Nondisjunction • Problems with meiotic spindle cause errors in

daughter cells– tetrad chromosomes do not separate properly

during Meiosis 1– sister chromatids fail to separate during Meiosis

2– too many or too few chromosomes

2n n

n

n-1

n+1

Alteration of chromosome number

Nondisjunction

• Baby has wrong chromosome number– trisomy

• cells have 3 copies of a chromosome – monosomy

• cells have only 1 copy of a chromosome

trisomy2n+1

monosomy2n-1

Human chromosome disorders

• High frequency in humans– most embryos are spontaneously

aborted– alterations are too disastrous– developmental problems result from

biochemical imbalance• Certain conditions are tolerated

– upset the balance less = survive– characteristic set of symptoms =

syndrome

Down syndrome

• Trisomy 21– 3 copies of chromosome 21– 1 in 700 children born in U.S.

• Chromosome 21 is the smallest human chromosome– but still severe effects

• Frequency of Down syndrome correlates with the age of the mother

Trisomy 21

Down syndrome & age of mother

Mother’s ageIncidence of Down

Syndrome

Under 30 <1 in 1000

30 1 in 900

35 1 in 400

36 1 in 300

37 1 in 230

38 1 in 180

39 1 in 135

40 1 in 105

42 1 in 60

44 1 in 35

46 1 in 20

48 1 in 16

49 1 in 12

Genetic testing

• Amniocentesis in 2nd trimester– sample of embryo cells– stain & photograph chromosomes

• Analysis of karyotype

Sex chromosomes

• Human development more tolerant of wrong numbers in sex chromosome

• But produces a variety of distinct conditions in humans– XXY = Klinefelter’s syndrome male – XXX = Trisomy X female– XYY = Jacob’s syndrome male– XO = Turner syndrome female

Klinefelter’s syndrome

• XXY male– one in every 2000

live births– have male sex

organs, but are sterile

– feminine characteristics

– tall– normal intelligence

Klinefelter’s syndrome

Klinefelter’s syndrome

Jacob’s syndrome male

• XYY Males – 1 in 1000 live male births– extra Y chromosome– somewhat taller than average– more active– slight learning disabilities– delayed emotional immaturity– normal intelligence, normal sexual

development

XYY Males

Trisomy X

• XXX– 1 in every 2000 live births– produces healthy females

• Why?

Turner syndrome

• Monosomy X or X0– 1 in every 5000

births– varied degree of

effects – webbed neck– short stature– immature sterile

females

Turner syndrome

14-3 Human Molecular Genetics

Key Concepts

What is the goal of the human genome project?

What is gene therapy?

Bioethics and You

• As you become more aware of scientific advances in genetics, you might realize that with the ability to manipulate genes, there comes responsibility.

• This ability provides an opportunity to improve the lives of many people.

• But there is also a potential for errors or intentional misuse of the technology.

Go to Section:

• If two prospective parents suspect they might be carrying recessive alleles for a genetic disorder such as cystic fibrosis or Tay-Sachs disease, how could they find out for sure?–Genetic tests have been developed

that can spot abnormalities in DNA. Scientists can compare normal sequences with these parents’ DNA to see if they are carriers

• DNA FINGERPRINTING–Analyzes sections of DNA that have little or no known function but vary widely from one person to the next – this tool can identify individuals

How to do DNA Fingerprinting

• A sample of DNA with genes and repeats (“junk DNA”) is taken

• Restriction enzymes cut the DNA into fragments containing genes and repeats

• The DNA fragments are separated according to size using gel electrophoresis

• Radioactive “probes” showing where the repeats are – this produces a series of bands

• This has been used since the 1980’s• It not only helps to convict criminals but

has also freed those who were wrongly accused

• HUMAN GENOME–Our complete set of genetic information

• What is the Human Genome Project?– 1990 the US and other countries began

trying to sequence all human DNA– This project was completed in 2003– They have mapped 20,000 – 50,000

human genes– They know the sequence of 3 billion

base pairs – Now that scientist know the entire

human genome they are trying to figure out how to prevent certain genetic disorders

Normal hemoglobin gene

Bone marrow cell

Chromosomes

Genetically engineered virus

Nucleus

Bone marrow

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GENE THERAPYThe process of changing the gene that causes a genetic disorder – it is replaced by a normal working gene

Food for thought

• Do you think it should be legal for people to affect their children’s characteristics?

• What will happen to the human population if we gain the opportunity to design our bodies?

Key Concepts Answered:

How is sex determined?• All egg cells carry a single X chromosome

(23X). However, half of all sperm cells carry an X chromosome (23X) and half carry a Y chromosome (23Y). This ensures that just about half of the zygotes will be 46XX and half will be 46XY. Egg cells contain a single X chromosome. Sperm cells contain either one X chromosome or one Y chromosome.

How do small changes in DNA cause genetic disorders?

• a small change in the DNA of a single gene affects the structure of a protein, causing a serious genetic disorder

Key Concepts Answered:

Why are sex linked disorders more common in males, than in females?

• Males have just one X chromosome. Thus, all X-linked alleles are expressed in males, even if they are recessive.

What is nondisjunction, and what problems does it cause?

• Nondisjunction causes gametes to have abnormal numbers of chromosomes. If nondisjunction occurs, abnormal numbers of chromosomes may find their way into gametes, and a disorder of chromosome numbers may result.

Key Concepts Answered:

What is the goal of the human genome project?

•  The Human Genome Project is an attempt to sequence all human DNA.

What is gene therapy?• In gene therapy, an absent or faulty

gene is replaced by a normal, working gene.