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THE HUMAN GENOME

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Title: THE HUMAN GENOME


1
THE HUMAN GENOME
  • The children in this family have some traits that
    are similar to their mothers and some that are
    similar to their fathers

2
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

3
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

4
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

5
KAROTYPE
  • Photograph of the chromosomes of a cell, arranged
    in order from the largest to the smallest

6
KAROTYPE OF NORMAL CELL
7
Human Chromosomes
  • The chromosomes shown are from a typical human
    body cell
  • The number of chromosomes46helps 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

8
DOWNS 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

9
Karyotype 
  • These human chromosomes have been cut out of a
    photograph and arranged to form a karyotype.

10
KAROTYPE OF DOWNS SYNDROME
11
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

12
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

13
Human Chromosomes
14
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)

15
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

16
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

17
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

18
Pedigree Charts 
19
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

20
PEDIGREE
21
PEDIGREE
22
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

23
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

24
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

25
Human Genes
  • The human genomeour complete set of genetic
    informationincludes 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

26
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

27
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

28
Blood Group Genes   
  • The Rh blood group is determined by a single gene
    with two allelespositive 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 Rh-negative

29
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

30
MULTIPLE ALLELES
31
MULTIPLE ALLELES
32
Blood Group Genes 
33
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

34
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

35
MULTIPLE ALLELES
36
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

37
Recessive Alleles 
38
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

39
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

40
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

41
HUNTINGTONS DISEASE
42
Codominant Alleles 
  • Sickle cell disease, a serious disorder found in
    about 1 out of 500 African Americans, is caused
    by a codominant allele

43
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

44
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

45
Cystic Fibrosis 
46
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

47
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

48
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

49
Sickle Cell Disease 
50
Sickle Cell Disease 
  • Sickle Cell Disease
  • These red blood cells contain the abnormal
    hemoglobin characteristic of sickle cell disease.

51
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 allelejust 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

52
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

53
Sickle Cell Disease 
54
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

55
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

56
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

57
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 phenotyperesistance to
    malariafrom someone with only normal alleles
  • Therefore, the sickle cell alleles are thought to
    be codominant because both alleles contribute to
    the phenotype

58
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

59
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 genesthat 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!

60
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

61
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

62
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

63
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

64
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

65
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

66
CROSSING OVER
67
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.

68
SEX-LINKED TRAITS
69
SEX-LINKED TRAITS
70
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

71
Sex-Linked Genes
72
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
    rareonly about 1 female in 100 has
    colorblindness
  • Why the difference?

73
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-linked 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

74
Colorblindness
75
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

76
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

77
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

78
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 colorswhite with
    orange and black spots, for exampleyou can
    almost be certain that it is female

79
X-Chromosome Inactivation
80
X-Chromosome Inactivation
  • Calico Cat This cat's fur color is controlled by
    a gene on the X chromosome.

81
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

82
Chromosomal Disorders
83
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

84
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

85
Sex Chromosome Disorders 
  • Disorders also occur among the sex chromosomes
  • Two of these abnormalities are Turner's syndrome
    and Klinefelter's syndrome

86
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

87
TURNERS 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

88
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

89
KLINEFELTERS 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

90
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

91
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

92
GENETICS
  • Sex-Influenced Traits
  • Certain genes are dominant in one sex and
    recessive in the other
  • Example baldness

93
SEX-INFLUENCED TRAIT
94
 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

95
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 informationyou 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

96
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

97
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

98
DNA Fingerprinting 
  • The great complexity of the human genome ensures
    that no individual is exactly like any other
    geneticallyexcept, 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

99
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

100
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

101
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

102
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
    yeasta single-celled eukaryoteand Drosophila
    melanogaster, the fruit fly
  • In June 2000, scientists announced that a working
    copy of the human genome was essentially complete

103
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

104
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

105
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 containpossibly 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

106
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

107
Searching for Genes
108
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

109
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

110
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

111
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

112
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

113
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

114
Gene Therapy
115
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

116
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

117
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 citizensnot just
    scientistsare 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
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