THE HUMAN GENOME

• The children in this family have some traits that are similar to their mother’s and some that are similar to their father’s

Human Heredity

• Of all the living things that inhabit this remarkable world, there is one in particular that has always drawn our interest, one that has always made us wonder, one that will always fire our imagination

• That creature is, of course, ourselves, Homo sapiensHomo sapiens

Human Heredity • Scientists once knew much less about humans than

about other organisms• Until very recently, human genetics lagged far

behind the genetics of “model” organisms such as fruit flies and mice

• That, however, has changed• Scientists are now on the verge of understanding human

genetics at least as well as they understand that of some other organisms

• From that understanding will come a new responsibility to use that information wisely

Human Chromosomes• What makes us human? • Biologists can begin to answer that question by

taking a look under the microscope to see what is inside a human cell

• To analyze chromosomes, cell biologists photograph cells in mitosis, when the chromosomes are fully condensed and easy to see

• The biologists then cut out the chromosomes from the photographs and group them together in pairs

• A picture of chromosomes arranged in this way is known as a karyotypekaryotype

KAROTYPE

• Photograph of the chromosomes of a cell, arranged in order from the largest to the smallest

KAROTYPE OF NORMAL CELL

Human Chromosomes• The chromosomes shown are from a typical

human body cell• The number of chromosomes—46—helps

identify this karyotype as human• This karyotype is the result of a haploid sperm,

carrying just 23 chromosomes, fertilizing a haploid egg, also with 23 chromosomes

• The diploid zygote, or fertilized egg, The diploid zygote, or fertilized egg, contained the full complement of 46 contained the full complement of 46 chromosomeschromosomes

DOWN’S SYNDROME

• Nondisjunction of the 21st chromosome• Extra copy of the 21st chromosome• Results in abnormal eyelids, noses with

low bridges, large tongues, and hands that are short and broad

• Usually short in stature• Often mentally retarded• Many deformed heart

Karyotype  • These human

chromosomes have been cut out of a photograph and arranged to form a karyotype.

KAROTYPE OF DOWN’S SYNDROME

Human Chromosomes• Two of those 46 chromosomes are known as sex

chromosomes, because they determine an individual's sex

• Females have two copies of a large X chromosome(XX)

• Males have one X and one small Y chromosome(XY)• To distinguish them from the sex chromosomes, the

remaining 44 chromosomes are known as autosomal chromosomes, or autosomes

• To quickly summarize the total number of To quickly summarize the total number of chromosomes present in a human cell, both chromosomes present in a human cell, both autosomes and sex chromosomes, biologists write autosomes and sex chromosomes, biologists write 46,XX for females and 46,XY for males46,XX for females and 46,XY for males

Human Chromosomes• As you can see in the figure, males and females are

born in a roughly 50 : 50 ratio because of the way in which sex chromosomes segregate during meiosis

• All human egg cells carry a single X chromosome (23,X)

• However, half of all sperm cells carry an X chromosome (23,X) and half carry a Y chromosome (23,Y)

• This ensures that just about half of the zygotes will be 46,XX and half will be 46,XY

• The human male determines the sex of the next The human male determines the sex of the next generationgeneration

Human Chromosomes

Human Chromosomes• Segregation of Sex

Chromosomes:– In humans, egg cells

contain a single X chromosome

– Sperm cells contain either one X chromosome or one Y chromosome

– In a population, approximately half of the zygotes are XX (female) and half are XY (male)

Human Traits• Human genes are inherited according to the

same principles that Gregor Mendel discovered in his work with garden peas

• However, in order to apply Mendelian genetics to humans, biologists must identify an inherited trait controlled by a single gene

• First, they must establish that the trait is actually inherited and not the result of environmental influences

• Then, they have to study how the trait is they have to study how the trait is passed from one generation to the nextpassed from one generation to the next

GENETICS• Sex-Linked Traits:

– Examples:• Hemophilia: disease in which there is the inability to form a

blood clot– Recessive trait– Genes for the proteins necessary for blood clotting are located

on the X chromosome– A pedigree (diagram of relationships in the family genetic line)

can be used to show the history of a disease in a family» Circle represents a female» Square represents a male» Filled-in symbols represents a person who is homozygous

recessive for the alleles» Half-filled symbols represent carriers

Pedigree Charts  • A pedigree chartpedigree chart, which shows the

relationships within a family, can be used to help with this task

• The pedigree in the figure at right shows how an interesting human trait, a white lock of hair just above the forehead, is transmitted through three generations of a family

• The allele for the white forelock trait is dominant

• At the top of the chart is a grandfather who had the white forelock trait

• Two of his three children inherited the trait, although one child did not

• Three grandchildren have the trait, and two do not

Pedigree Charts 

Pedigree Charts  • Genetic counselors analyze pedigree charts

to infer the genotypes of family members• For example, since the white forelock trait is

dominant, all the family members that lack the trait must have homozygous recessive alleles

• Since one of the grandfather's children lacks the white forelock trait, the grandfather must be heterozygous for the trait

• Colorblindness and hemophilia can be traced Colorblindness and hemophilia can be traced the same way through generations of a the same way through generations of a familyfamily

PEDIGREE

PEDIGREE

Genes and the Environment  • Unfortunately for folks who would like to

settle burning issues, like which side of the family is responsible for your good looks, some of the most obvious human traits are almost impossible to associate with single genes

• There are two reasons for this:– First, things you might think of as single traits, such as

the shape of your eyes or ears, are actually polygenic, meaning they are controlled by many genes

– Second, many of your personal traits are only partly governed by genetics

Genes and the Environment• Remember that the phenotype of an

organism is only partly determined by its genotype

• Many traits are strongly influenced by environmental, or nongenetic, factors, including nutrition and exercise– For example, even though a person's maximum

possible height is largely determined by genetic factors, nutritional improvements in the United States and Europe have increased the average height of these populations about 10 centimeters over their average height in the 1800s

Genes and the Environment  • Although it is important to consider the influence

of the environment on the expression of some genes, it must be understood that environmental effects on gene expression environmental effects on gene expression are not inherited; genes areare not inherited; genes are– Genes may be denied a proper environment in

which to reach full expression in one generation– However, these same genes can, in a proper

environment, achieve full potential in a later generation

Human Genes• The human genome—our complete set of

genetic information—includes tens of thousands of genes

• The DNA sequences on these genes carry information for specifying many characteristics, from the color of your eyes to the detailed structures of proteins within your cells

• The exploration of the human genome has been a major scientific undertaking

• By 2000, the DNA sequence of the human By 2000, the DNA sequence of the human genome was almost completegenome was almost complete

Human Genes• Studying the genetics of our species has not been easy• Until recently, the identification of a human gene took

years of scientific work• Humans have long generation times and a complex

life cycle, and they produce, at least compared with peas and fruit flies, very few offspring

• Still, in a few cases, biologists were able to identify genes that directly control a single human trait

• Some of the very first human genes to be identified were those that control blood type

Blood Group Genes    • Human blood comes in a variety of genetically

determined blood groups• Knowing a person's blood group is critical

because using the wrong type of blood for a transfusion during a medical procedure can be fatal

• A number of genes are responsible for human blood groups, but the best known are the ABO blood groups and the Rh blood groups

Blood Group Genes    • The Rh blood group is determined by a single

gene with two alleles—positive and negative• RhRh stands for “rhesus monkey,” the animal in

which this factor was discovered• The positive (Rh+) allele is dominant, so

persons who are Rh+/Rh+ or Rh+/Rh− are said to be Rh-positive

• Individuals with two Rh− alleles are Rh-Individuals with two Rh− alleles are Rh-negativenegative

Blood Group Genes  • The ABO blood group is more complicated• There are three alleles for this gene, IA, IB, and i• Alleles Alleles IIA and A and IIB are codominantB are codominant• These alleles produce molecules known as antigens

on the surface of red blood cells• Individuals with alleles IA and IB produce both A and B

antigens, making them blood type AB• The The ii allele is recessive allele is recessive

– Individuals with alleles IAIA or IAi produce only the A antigen, making them blood type A

– Those with IBIB or IBi alleles are type B– Those who are homozygous for the Those who are homozygous for the ii allele ( allele (iiii) produce no ) produce no

antigen, and are said to have blood type Oantigen, and are said to have blood type O

MULTIPLE ALLELES

MULTIPLE ALLELES

Blood Group Genes 

Blood Group Genes  • Blood Groups:

– This table shows the relationship between genotype and phenotype for the ABO blood group

– It also shows which blood types can safely be transfused into people with other blood types

Blood Group Genes• When a medical worker refers to blood

groups, he or she usually mentions both groups at the same time

• For example, if a patient has AB-negative blood, it means the individual has IA and IB alleles from the ABO gene and two Rh− alleles from the Rh gene

MULTIPLE ALLELES

Recessive Alleles  • Many human genes

have become known through the study of genetic disorders

• The table lists some common genetic disorders

• In most cases, the presence of a normal, functioning gene is revealed only when an abnormal or nonfunctioning allele affects the phenotype

Recessive Alleles 

Recessive Alleles  • One of the first genetic disorders to be understood

this way was phenylketonuria, or PKU• People with PKU lack the enzyme that is needed to

break down phenylalanine• Phenylalanine is an amino acid found in milk and many

other foods• If a newborn has PKU, phenylalanine may build up in

the tissues during the child's first years of life and cause severe mental retardation– Fortunately, newborns can be tested for PKU and then

placed on a low-phenylalanine diet that prevents most of the effects of PKU

• PKU is caused by an autosomal recessive allele PKU is caused by an autosomal recessive allele carried on chromosome 12carried on chromosome 12

Recessive Alleles  • Many other disorders are also caused by autosomal

recessive alleles• One is Tay-Sachs disease, which is caused by an allele

found mostly in Jewish families of central and eastern European ancestry

• Tay-Sachs disease results in nervous system breakdown and death in the first few years of life

• Although there is no treatment for Tay-Sachs disease, there is a test for the allele

• By taking this test, prospective parents can learn prospective parents can learn whether they are at risk of having a child with the whether they are at risk of having a child with the disorderdisorder

Dominant Alleles  • Not all genetic disorders are caused by recessive alleles• You may recall that the effects of a dominant allele are expressed

even when the recessive allele is present• Therefore, if you have a dominant allele for a genetic disorder, it will

be expressed• Two examples of genetic disorders caused by autosomal

dominant alleles are a form of dwarfism known as achondroplasia and a nervous system disorder known as Huntington's disease– Huntington's disease causes a progressive loss of muscle

control and mental function until death occurs– People who have this disease generally show no symptoms

until they are in their thirties or older, when the gradual damage to the nervous system begins

HUNTINGTON’S DISEASE

Codominant Alleles  • Sickle cell disease, a serious disorder

found in about 1 out of 500 African Americans, is caused by a codominant allele

From Gene to Molecule• How do the actual DNA sequences in genes affect

phenotype so profoundly?• What is the link between the DNA bases in the allele

for a genetic disorder and the disorder itself?• For many genetic disorders, scientists are still working to

find the answer• But for two disorders, the connection is understood

very well indeed• In both cystic fibrosis and sickle cell diseaseIn both cystic fibrosis and sickle cell disease, a

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

Cystic Fibrosis  • Cystic fibrosis, or CF, is a common genetic

disease• Cystic fibrosis is most common among people

whose ancestors came from Northern Europe• The disease is caused by a recessive allele

on chromosome 7• Children with cystic fibrosis have serious

digestive problems• In addition, they produce a thick, heavy In addition, they produce a thick, heavy

mucus that clogs their lungs and breathing mucus that clogs their lungs and breathing passageways passageways

Cystic Fibrosis 

Cystic Fibrosis  • Cystic fibrosis involves a very

small genetic change• The figure illustrates how The figure illustrates how

information carried in a information carried in a chromosome's DNA specifies chromosome's DNA specifies the trait of cystic fibrosisthe trait of cystic fibrosis

• Most cases of cystic fibrosis are caused by the deletion of 3 bases in the middle of a sequence for a protein– This protein normally allows

chloride ions (Cl−) to pass across biological membranes

– The deletion of these 3 bases removes just one one amino acidamino acid from this large protein, causing it to fold improperly

Cystic Fibrosis• Because of this, the cells do not transport the

protein to the cell membrane, and the misfolded protein is destroyed– Unable to transport chloride ions, tissues

throughout the body malfunction• People with one normal copy of the allele are People with one normal copy of the allele are

unaffected, because they can produce unaffected, because they can produce enough of the chloride channel protein to enough of the chloride channel protein to allow their tissues to function properlyallow their tissues to function properly

Sickle Cell Disease  • Sickle cell disease is a common genetic disorder found

in African Americans• Sickle cell disease is characterized by the bent and

twisted shape of the red blood cells• These sickle-shaped red blood cells are more rigid than

normal cells and tend to get stuck in the capillaries, the narrowest blood vessels in the body

• As a result, blood stops moving through these vessels, damaging cells, tissues, and organs

• Sickle cell disease produces physical weakness and damage to the brain, heart, and spleen

• In some cases, it may be fatalmay be fatal

Sickle Cell Disease 

Sickle Cell Disease  • Sickle Cell Disease:

– These red blood cells contain the abnormal hemoglobin characteristic of sickle cell disease.

Sickle Cell Disease  • Hemoglobin is the protein in red blood cells that

carries oxygen• The normal allele for the gene differs little from the

sickle cell allele—just one DNA base is changed– This change substitutes the amino acid valine for glutamic This change substitutes the amino acid valine for glutamic

acidacid– As a result, the abnormal hemoglobin is somewhat less

soluble than normal hemoglobin• Any decrease in blood oxygen levels causes many of

the hemoglobin molecules to come out of solution and stick together

• The stuck-together molecules form long chains and fibers that produce the characteristic shape of sickled cells

Sickle Cell Disease  • Why do so many African Americans carry the sickle cell

allele?• Most African Americans can trace their ancestry to west

central Africa• Malaria, a serious parasitic disease that infects red

blood cells, is common in this region of Africa• People who are heterozygous for the sickle cell

allele are generally healthy– In addition, they have the benefit of being resistant to

malaria• The relationship between the incidence of malaria and

the presence of the sickle cell allele is shown in the following maps

Sickle Cell Disease 

Sickle Cell Disease• The map on the left shows where malaria is

common• The map on the right shows regions where

people have the sickle cell allele

Sickle Cell Disease  • Low oxygen levels cause some red blood cells

to become sickle shaped• When the body destroys the sickled cells, it

also destroys the parasite that causes malaria

• Therefore, in parts of the world such as west Therefore, in parts of the world such as west central Africa, where malaria is a major threat central Africa, where malaria is a major threat to health, the sickle cell allele is actually to health, the sickle cell allele is actually beneficial in heterozygous personsbeneficial in heterozygous persons

Dominant or Recessive? • What makes an allele dominant, recessive, or

codominant?• CF and sickle cell disease show biologists that it all

depends on the nature of a gene's protein product depends on the nature of a gene's protein product and its role in the celland its role in the cell

• In the case of CF, just one copy of the normal allele can supply cells with enough chloride channel proteins to function– Therefore, the trait has only two phenotypes: the normal

phenotype or the cystic fibrosis phenotype– Because of this, the normal allele is considered dominant

over the recessive CF allele

Dominant or Recessive? • The allele for normal hemoglobin was once also

considered dominant over the sickle cell allele, but biologists now know that this situation is more complex

• In contrast to cystic fibrosis, there are three phenotypes associated with the sickle-cell gene

• An individual with both normal and sickle cell alleles has a different phenotype—resistance to malaria—from someone with only normal alleles

• Therefore, the sickle cell alleles are thought to be codominant because both alleles contribute to the phenotype

Human Chromosomes • A human diploid cell contains more than 6 billion base

pairs of DNA• All of this DNA is neatly packed into the 46

chromosomes present in every diploid human cell• In its own way, each of these chromosomes is like a

library containing hundreds or even thousands of books

• Although biologists are many decades away from mastering the contents of those books, biology is now in the early stages of learning just how many books there are and what they deal with

Human Chromosomes • You may be surprised to learn that genes make

up only a small part of chromosomes• In fact, only about 2 percent of the DNA in

your chromosomes functions as genes—that is, is transcribed into RNA

• Genes are scattered among long segments of DNA that do not code for RNA

• The average human gene consists of about The average human gene consists of about 3,000 base pairs while the largest gene in the 3,000 base pairs while the largest gene in the human genome has more than 2 million base human genome has more than 2 million base pairs!pairs!

Human Genes and Chromosomes

• Chromosomes 21 and 22 are the smallest human autosomes

• Chromosome 22 contains approximately 43 million DNA base pairs

• Chromosome 21 contains roughly 32 million base pairs

• These chromosomes were the first two human chromosomes whose sequences were determined

• Their structural features seem to be representative of other human chromosomes

Human Genes and Chromosomes

• Chromosome 22 contains as many as 545 different genes, some of which are very important for health

• Genetic disorders on chromosome 22 include an allele that causes a form of leukemia and another associated with neurofibromatosis, a tumor-causing disease of the nervous system

• However, chromosome 22 also contains long stretches of repetitive DNA that do not code for proteins– These long stretches of repetitive DNA are unstable sites where

rearrangements can occur

Human Genes and Chromosomes

• The structure of chromosome 21 is similar• It contains about 225 genes, including

one associated with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease

• Chromosome 21 also has many regions with no genes at all

Human Genes and Chromosomes

• As exploration of the larger human chromosomes continues, molecular biologists may gradually learn more about how the arrangements of genes on chromosomes affect gene expression and development

Human Genes and Chromosomes

• As you may recall, genes located close together on the same chromosome are linked, meaning that they tend to be inherited together

• This is true for human genes• You also read earlier that linked genes

may be separated by crossing-over during meiosis; this applies to human chromosomes as well

CROSSING OVER• Is a very precise process• Genes on homologous chromosomes are lined up in the same order• Homologous chromatids cross over, they break and fuse at exactly

the same points– Crossing over is an equal trade– Each chromatid ends up with a complete set of genes but each new

chromosome has a combination of alleles not found in either parent• Occurs during meiosis• Can happens numerous times in the same homologous chromatids

– Genes that are far apart on a chromosome will cross over more frequently than genes that are close together

• Genes that are close together are unlikely to end up on separate chromosomes

– This knowledge helps in chromosome mapping

CROSSING OVER

GENETICS

• Chromosome Theory:– Sex-linked genes are located (linked) on the X

chromosome• Traits determined by sex-linked genes are called

sex-linked traits– Example:

» In the Drosophila fruit fly: eye color, wing shape, body color, etc.

SEX-LINKED TRAITS

SEX-LINKED TRAITS

Sex-Linked Genes• Is there a special pattern of inheritance for genes located

on the X chromosome or the Y chromosome? • The answer is yes• Because these chromosomes determine sex, genes

located on them are said to be sex-linked genes• Many sex-linked genes are found on the X Many sex-linked genes are found on the X

chromosomechromosome• More than 100 sex-linked genetic disorders have now

been mapped to the X chromosome• The human Y chromosome is much smaller than the The human Y chromosome is much smaller than the

X chromosome and appears to contain only a few X chromosome and appears to contain only a few genes genes

Sex-Linked Genes

Colorblindness • Three human genes associated

with color vision are located on the X chromosome

• In males, a defective version of any one of these genes produces colorblindness, an inability to distinguish certain colors

• The most common form of this disorder, red-green colorblindness, is found in about 1 in 10 males in the United States

• Among females, however, colorblindness is rare—only about 1 female in 100 has colorblindness

• Why the difference? Why the difference?

Colorblindness • Males have just one X chromosome• Thus, all X-linked alleles are expressed in males,

even if they are recessive• 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, one on each of the two X chromosomes

• This means that the recessive phenotype of a sex-This means that the recessive phenotype of a sex-linked genetic disorder tends to be much more linked genetic disorder tends to be much more common among males than among femalescommon among males than among females

• In addition, because men pass their X chromosomes along to their daughters, sex-linked genes move from fathers to their daughters and may then show up in the sons of those daughters

Colorblindness

Hemophilia • Hemophilia is another example of a sex-linked disorder• Two important genes carried on the X chromosome help

control blood clotting• A recessive allele in either of these two genes may produce a

disorder called hemophilia• In hemophilia, a protein necessary for normal blood clotting is

missing• About 1 in 10,000 males is born with a form of hemophilia• People with hemophilia can bleed to death from minor cuts and

may suffer internal bleeding from bumps or bruises• Fortunately, hemophilia can be treated by injections of normal Fortunately, hemophilia can be treated by injections of normal

clotting proteins, which are now produced using recombinant clotting proteins, which are now produced using recombinant DNA DNA

Duchenne Muscular Dystrophy  • Duchenne muscular dystrophy is a sex-linked

disorder that results in the progressive weakening and loss of skeletal muscle

• In the United States, one out of every 3000 males is born with this condition

• Duchenne muscular dystrophy is caused by a defective version of the gene that codes for a muscle protein

• Researchers in many laboratories are trying to find a way to treat or cure this disorder, possibly by inserting a normal allele into the muscle cells of Duchenne muscular dystrophy patients

X-Chromosome Inactivation• Females have two X chromosomes, but males have only

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?

• The answer was discovered by the British geneticist Mary Lyon

• In female cells, one X chromosome is randomly In female cells, one X chromosome is randomly switched offswitched off– That turned-off chromosome forms a dense region in the

nucleus known as a Barr body– Barr bodies are generally not found in males because their

single X chromosome is still active

X-Chromosome Inactivation• The same process happens in other mammals• In cats, for example, a gene that controls the color of coat

spots 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 cells in some parts of the body, one X chromosome is switched

off– In other parts of the body, the other X chromosome is switched off

• As a result, the cat's fur will have a mixture of orange and black spotsAs a result, the cat's fur will have a mixture of orange and black spots• Male cats, which have just one X chromosome, can have spots Male cats, which have just one X chromosome, can have spots

of only one colorof only one color• By the way, this is one way to tell the sex of a cat

– If the cat's fur has three colors—white with orange and black spots, for example—you can almost be certain that it is female

X-Chromosome Inactivation

X-Chromosome Inactivation• Calico Cat: This cat's

fur color is controlled by a gene on the X chromosome.

Chromosomal Disorders• Most of the time, the mechanisms that separate

human chromosomes in meiosis work very well, but every now and then something goes wrong

• The most common error in meiosis occurs when homologous chromosomes fail to separate– This is known as nondisjunctionnondisjunction, which means “not coming

apart”• If nondisjunction occurs, abnormal numbers of

chromosomes may find their way into gametes, and a disorder of chromosome numbers may result

Chromosomal Disorders

Down Syndrome  • If two copies of an autosomal chromosome fail to

separate during meiosis, an individual may be born with three copies of a chromosome

• This is known as a trisomy, meaning “three bodies”• The most common form of trisomy involves three

copies of chromosome 21 and is called Down syndrome

• In the United States, approximately 1 baby in 800 is born with Down syndrome

• Down syndrome produces mild to severe mental retardation

• It is also characterized by an increased susceptibility to many diseases and a higher frequency of some birth defects

Down Syndrome  • Why should an extra copy of one

chromosome cause so much trouble?• That is still not clear, and it is one of the

reasons scientists have worked so hard to learn the DNA sequence for chromosome 21

• Now that researchers know all of the genes on the chromosome, they can begin experiments to find the exact genes that cause problems when present in three copies

Sex Chromosome Disorders  • Disorders also occur among the sex

chromosomes• Two of these abnormalities are Turner's

syndrome and Klinefelter's syndrome

Sex Chromosome Disorders  • In females, nondisjunction can lead to Turner's

syndrome• A female with Turner's syndrome usually

inherits only one X chromosome (karyotype 45,X)

• Women with Turner's syndrome are sterile, which means that they are unable to reproduce

• Their sex organs do not develop at puberty

TURNER’S SYNDROME• Nondisjunction of the sex chromosomes• Resulting in a female who is missing one sex

chromosome • Genotype XO instead of XX• Appear normal at birth but throughout life tend to

be shorter and stockier than other girls• Large necks• Sex organs and breasts do not develop to the

adult stage• sterile

Sex Chromosome Disorders  • In males, nondisjunction causes Klinefelter's syndrome

(karyotype 47,XXY)• The extra X chromosome interferes with meiosis and

usually prevents these individuals from reproducing• Cases of Klinefelter's syndrome have been found in

which individuals were XXXY or XXXXY• There have been no reported instances of babies

being born without an X chromosome, indicating that the X chromosome contains genes that are vital for the survival and development of an embryo

KLINEFELTER’S SYNDROME

• Nondisjunction of the sex chromosomes• Resulting in a male with an extra X chromosome

(XXY)• Do not develop the physical traits typical of adult

man• Enlarged breast• High-pitched voice• Sterile• May have below normal intelligence

Sex Chromosome Disorders  • These sex chromosome abnormalities point out

the essential role of the Y chromosome in male sex determination in humans

• The human Y chromosome contains a sex-determining region that is necessary to produce male sexual development, and it can do this even if several X chromosomes are present

• However, if this region of the Y chromosome is absent, the embryo develops as a female

GENETICS

• Sex-Limited Traits:– Some genes are expressed (phenotype) only

if they are carried by an individual of a particular sex

• Expressed (phenotype) only in individuals of one sex

– Genes for most sex-limited traits are located on autosomes, although a few are located on the sex chromosomes

– Example: heavy beard

GENETICS

• Sex-Influenced Traits:– Certain genes are dominant in one sex and

recessive in the other– Example: baldness

SEX-INFLUENCED TRAIT

 Human Molecular Genetics • Watson and Crick took the first step in making

genetics a molecular science when they discovered the double-helical structure of DNA in 1953

• Today, the transformation they started is complete

• The exploration of human genes is now a major scientific undertaking

• Biologists can now read, analyze, and even change the molecular code of genes

Human DNA Analysis• The roughly 6 billion base pairs you carry in your DNA

are a bit like an encyclopedia with thousands of volumes• In principle, biologists would like to know everything the

volumes contain, but as a practical matter there isn't enough time to read all of them

• Nonetheless, if you've used an encyclopedia you've already learned one of the ways to handle huge amounts of information—you find a way to look up only what you need. In an encyclopedia, you can use an index or an alphabetical list of articles

• As you might suspect, biologists search the volumes of the human genome using sequences of DNA bases

Testing for Alleles  • If two prospective parents suspect they might be carrying

recessive alleles for a genetic disorder such as cystic fibrosis (CF) or Tay-Sachs disease, how could they find out for sure?

• Because the Tay-Sachs and CF alleles have slightly different DNA sequences from their normal counterparts, a variety of genetic tests have been developed that can spot those differences

• Sometimes these genetic tests use labeled DNA probes• These are specific DNA base sequences that detect the

complementary base sequences found in disease-causing alleles• Other tests search for changes in restriction enzyme cutting

sites• Tests also detect differences between the lengths of normal and

abnormal alleles

Testing for Alleles  • Genetic tests are now available for hundreds

of disorders, making it possible to determine whether prospective parents risk passing such alleles to their children

• In an increasing number of such cases, DNA testing can pinpoint the exact genetic basis of a disorder, making it possible to develop more effective treatment for individuals affected by genetic disease

DNA Fingerprinting  • The great complexity of the human genome ensures that

no individual is exactly like any other genetically—except, of course, for identical twins

• Molecular biology has used this biological fact to add a powerful new tool called DNA fingerprinting to the identification of individuals

• Unlike other forms of testing, DNA fingerprinting does not analyze the cell's most important genes, which are largely identical among most people

• Rather, DNA fingerprinting analyzes sections of DNA that have little or no known function but vary widely from one individual to another

DNA Fingerprinting  • The activity at right shows how DNA fingerprinting works• A small sample of human DNA is cut with a

restriction enzyme• The resulting fragments are separated by size using

gel electrophoresis• Fragments containing these highly variable regions

are then detected with a DNA probe, revealing a series of DNA bands of various sizes

• If enough combinations of restriction enzymes and probes are used, a pattern of bands is produced that can be distinguished statistically from the pattern of any other individual in the world

• DNA samples can be obtained from blood, sperm, and even hair strands with tissue at the base

DNA Fingerprinting  • DNA fingerprinting has been used in the United

States since the late 1980s• The reliability of DNA evidence has helped

convict criminals as well as overturn many convictions

• The precision that molecular biology brings to the justice system is good news not only for those who are victims of crime but also for those who have been wrongly convicted

The Human Genome Project• Advances in DNA sequencing technologies at the close

of the twentieth century made it possible, for the first time, to sequence entire genomes

• At first, biologists worked on relatively small genomes, such as those of viruses and bacteria

• The DNA sequence of the common bacterium Escherichia coli, which was determined in 1996, contains “only” 4,639,221 base pairs, making it just about as long as a printout of this iText if the sequence were printed on paper in a readable typeface

• The genomes of even the simplest eukaryotic organisms are much larger, and the human genome, which contains over 6 billion base pairs, is nearly 1400 times as large

The Human Genome Project• Despite the problem of size, in 1990, scientists

in the United States and other countries began the Human Genome Project

• The Human Genome Project is an ongoing effort to analyze the human DNA sequence

• Along the way, investigators completed the genomes of several other organisms, including yeast—a single-celled eukaryote—and Drosophila melanogaster, the fruit fly

• In June 2000, scientists announced that a In June 2000, scientists announced that a working copy of the human genome was working copy of the human genome was essentially completeessentially complete

Rapid Sequencing  • How did they do it?• Scientists first determined the sequence of

bases in widely separated regions of DNA• These regions were then used as markers,

not unlike the mile markers along a road thousands of miles long

• The markers made it possible to locate and return to specific locations in the genome

Rapid Sequencing  • Scientists then used a technique known as “shotgun

sequencing”• This method involved cutting DNA into random

fragments and then determining the sequence of bases in each fragment

• Computers found areas of overlap between the fragments and put the fragments together by linking the overlapping areas

• The computers then aligned the fragments relative to the known markers on each chromosome

• The entire process is something like putting a jigsaw puzzle together, but instead of matching shapes, the scientists match identical base sequences

Searching for Genes  • Only a small part of a human DNA molecule is

made up of genes• In fact, one of the genome's scientific surprises

was how few genes it seems to contain—possibly as few as 35,000

• Since the genome of the fruit fly Drosophila contains approximately 14,000 genes and that of a tiny worm roughly 20,000, many researchers had expected to find far more in our own DNA

• The final number, however, is far from certain

Searching for Genes  • Molecular biologists continue to search for genes, which they can

locate in several ways• In one method, they find genes by finding DNA sequences that are

known to be promoters, which are binding sites for RNA polymerase• Promoters indicate the start of a gene• Shortly behind the promoter, there should be an open reading frame• An open reading frame is a sequence of DNA bases that will

produce an mRNA sequence, which then specifies a series of amino acids

• Recall that for most genes, the mRNA coding regions, or exons, are interrupted by introns, which are noncoding regions

• Therefore, investigators have to find the introns as well as the exons in order to follow the gene through its complete length

Searching for Genes

Searching for Genes• Locating Genes:• Researchers exploring the human genome can

use DNA sequences to locate many genes• Promoters are sequences in which RNA

polymerase can bind to DNA• A typical gene, such as the gene for insulin

shown above, has other DNA sequences that may serve as signals for RNA polymerase to start and stop transcription

Searching for Genes• Research groups around the world are analyzing

the huge amount of information in the DNA sequence, looking for genes that may provide useful clues to some of the basic properties of life

• In addition to its scientific significance, understanding the structure and control of key genes may have commercial value

• Biotechnology companies are rushing to find genetic information that may be useful in developing new drugs and treatments for diseases

A Breakthrough for Everyone  • One of the remarkable things about

genome research is the open availability of nearly all its data

• From its very beginning, data from publicly supported research on the human genome have been posted on the Internet on a daily basis

• You can read the latest genome data there and, if you wish, analyze it

Gene Therapy• The Human Genome Project will have an impact on

society as well as on scientific thought• For example, information about the human genome

might be used to cure genetic disorders by gene therapy• Gene therapy is the process of changing the gene that

causes a genetic disorder• In gene therapy, an absent or faulty gene is replaced

by a normal, working gene• This way, the body can make the correct protein or

enzyme it needs, which eliminates the cause of the disorder

Gene Therapy• The first authorized attempt to cure a human

genetic disorder by gene transfer occurred in 1990

• Then, in 1999, a young French girl was apparently cured of an inherited immune disorder when cells from her bone marrow were removed, modified in the laboratory, and then placed back in her body

• However, scientists do not yet know how long the beneficial effects of this treatment will last

Gene Therapy• The figure at right shows one of the ways in which

researchers have attempted to practice gene therapy• Viruses are often used because of their ability to enter a

cell's DNA• The virus particles are modified so that they cannot

cause disease• Then, a DNA fragment containing a replacement gene is

spliced to viral DNA• The patient is then infected with the modified virus

particles, which should carry the gene into cells to correct genetic defects

Gene Therapy

Gene Therapy• Unfortunately, gene therapy experiments

have not always been successful• Attempts to treat cystic fibrosis by spraying

genetically engineered viruses into the breathing passages have not produced a lasting cure

• For all the promise it holds, in most cases gene therapy remains a high-risk, experimental procedure

Ethical Issues in Human Genetics

• It would be marvelous to be able to cure hemophilia or other genetic diseases

• But if human cells can be manipulated to cure disease, should biologists try to engineer taller people or change their eye color, hair texture, sex, blood group, or appearance?

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

• What will be the consequences if biologists develop the ability to clone human beings by making identical copies of their cells?

• These are questions with which society must come to grips

Ethical Issues in Human Genetics

• The goal of biology is to gain a better understanding of the nature of life

• As our knowledge increases, however, so does our ability to manipulate the genetics of living things, including ourselves

• In a democratic nation, all citizens—not just scientists—are responsible for ensuring that the tools science has given us are used wisely

• This means that you should be prepared to help develop a thoughtful and ethical consensus of what should and should not be done with the human genome

• To do anything less would be to lose control of two of our most precious gifts: our intellect and our humanity