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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 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 karyotype
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,
contained the full complement of 46
chromosomes
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
chromosomes present in a human cell, both
autosomes and sex chromosomes, biologists write
46,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
generation
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
passed 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 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
the same way through generations of a
family
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
are 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
genome 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
• Rh 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 Rhnegative
Blood Group Genes
•
•
•
•
The ABO blood group is more complicated
There are three alleles for this gene, IA, IB, and i
Alleles IA and IB 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 i 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 i allele (ii) produce no
antigen, 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
carried 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
whether they are at risk of having a child with the
disorder
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 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
mucus that clogs their lungs and breathing
passageways
Cystic Fibrosis
Cystic Fibrosis
•
•
•
Cystic fibrosis involves a very
small genetic change
The figure illustrates how
information carried in a
chromosome's DNA specifies
the 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
amino 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
unaffected, because they can produce
enough of the chloride channel protein to
allow 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 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
acid
– 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
central Africa, where malaria is a major threat
to health, the sickle cell allele is actually
beneficial 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
and 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
3,000 base pairs while the largest gene in the
human genome has more than 2 million base
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
chromosome
• More than 100 sex-linked genetic disorders have now
been mapped to the X chromosome
• The human Y chromosome is much smaller than the
X chromosome and appears to contain only a few
genes
Sex-Linked Genes
Colorblindness
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•
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•
•
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?
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 sexlinked genetic disorder tends to be much more
common 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
clotting proteins, which are now produced using recombinant
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
switched 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 spots
• Male cats, which have just one X chromosome, can have spots
of 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 nondisjunction, 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 sexdetermining 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
working copy of the human genome was
essentially 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