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					Genetics
                        Genetics
• A few facts about
  inheritance known since
  ancient times:
   – children resemble their
     parents.
   – Domestication followed by
     selective breeding to
     improve plants and
     animals. Mostly 10-12,000
     years ago.
   – Some lines are true-
     breeding, others have a
     variety of offspring types.
     Different breeds can be
     produced through selective
     breeding.
    Some Older, Incorrect Theories
•   Hippocrates, an ancient Greek, taught the
    idea of pangenesis, that inheritance comes
    from the presence in each organ of tiny
    replica organs. These replicas moved
    through the blood to the semen, where they
    formed a tiny human which grew in its
    mother‘s womb. Problem: if you cut off
    someone‘s arm, their children still have
    arms.
•   Preformation is the idea that each sperm
    contains a miniature person: development is
    merely a process of enlarging and maturing
    the person already present in the sperm cell.
    There is another version of this theory that
    puts the miniature person in the egg instead
    of the sperm.
•   Inheritance of acquired characteristics. The
    idea that events that occur in your life affect
    your offspring directly. For instance,
    constant stretching of the giraffe‘s neck
    made its offspring‘s neck longer. Often
    associated with Lamarck, but the idea is
    much older.
                   More Ancient Ideas
•   Relative contribution of male and
    female. Many cultures believed that
    the child grew from the semen, with
    the female‘s role merely to act as a
    source of nutrition, like planting a seed
    in the garden. Also, allegedly some
    New Guinea cultures didn‘t know that
    sex was necessary for reproduction,
    which implies the female was the sole
    source of the child.
•   Blending inheritance. Like mixing red
    paint with white paint: the results is
    pink paint, and there is no way to ever
    separate out the red and white.
•   Plants and sex. Although it was
    known to many ancient cultures, the
    idea that all plants have male and
    female parts wasn‘t widely accepted
    until the early 1700‘s.
                                     Mendel
•   Gregor Mendel lived in what is now the Czech
    Republic (then part of the Austria-Hungarian
    Empire) from 1822 to 1884
•   After high school he became a monk. The
    monastery sent him to the University of Vienna.
•   After college he did plant hybridization
    experiments in the monastery garden, growing
    more than 28,000 pea plants between 1856 and
    1863.
•   Wrote up the work as ―Experiments on Plant
    Hybridization‖ in a local scientific journal, where it
    was promptly forgotten. In those days, Darwin‘s
    work was stirring controversy. Darwin had an
    incorrect notion of genetics: evolution was
    reconciled with genetics in the 1930‘s, in the
    ―modern synthesis‖.
•   Mendel was elected abbot and gave up his
    studies, dying in 1884.
•   In 1900, 3 scientists working on plant breeding
    independently found his paper, read it, and
    understood how it explained their own work: the
    ―rediscovery‖ of Mendel. This is the start of
    modern genetics.
       Mendel‘s Basic Innovations
•   Inheritance is particulate: genes are
    not blended together, even if the
    effects of the genes get blended. For
    instance, in some plants if you cross a
    red flower with a white flower, the
    offspring have pink flowers. But, if you
    then cross 2 of the pink flowers
    together, the next generation has
    some red flowers and some white
    flowers, unchanged by having been in
    a pink parent.
•   Counting offspring, and seeing
    experimental numbers as imperfect
    reflections of underlying simple ratios.
    As an example, if you flipped a coin
    1000 times you might get 477 heads
    and 523 tails. This represents a 1:1
    ratio that contains a small amount of
    random error.
             Mendel‘s Experiments
•   He worked with pea plants. Peas
    have male and female parts all
    within one flower. You can take
    the pollen (male gamete,
    equivalent to sperm) and put it on
    the pistils (female structures) of
    another plant, where it fertilizes
    the ovule (female gamete) to form
    a zygote, the first cell of the next
    generation.
•   Peas can self-pollinate (or ―self‖):
    the male pollen can fertilize the
    female ovule within a single plant.
    This is the closest possible
    genetic relationship.
•   He worked with true-breeding
    lines: all peas within the line
    looked similar.
•   He started with 7 different true-
    breeding lines, which differed for 7
    distinct characters.
                 Examining One Trait
•   Start with flower colors: one line has
    purple flowers, another line has white
    flowers. These two lines are called the
    ―P generation‖, for parental. When
    crossed, their offspring are the F1
    generation. All of the F1 offspring are
    purple. Purple is called the dominant
    trait, because it is expressed in the F1
    offspring. White is recessive, not
    expressed in the F1 offspring.
•   When the F1 plants are self-pollinated
    (or crossed with each other), their
    offspring are the F2 generation. The
    F2 are the grandchildren of the P
    generation. The F2 were found in a
    ratio of ¾ purple to ¼ white.
•   The same effects were seen for all 7
    traits: if two lines are crossed together,
    the F1 all look like one of the parents,
    and the F2 are ¾ like one parent (the
    dominant trait) and ¼ like the other
    parent (the recessive trait).
      Explanation and Vocabulary
•   Genes are the factors that control the inherited traits. Genes are made of DNA; they
    are part of the chromosomes.
•   Individual versions of a gene are called alleles. Here, the flower color gene has two
    alleles: a purple allele and a white allele.
•   Pea plants (and humans and most higher organisms) are diploid: they have 2 copies
    of each gene, one from each parent. The gametes (sperm and egg, or pollen and
    ovule) are haploid: only 1 copy of each gene.
•   When the sperm fertilizes the egg, the two haploid genomes mix, forming a new
    diploid, which is the zygote, the first cell of the offspring.
•   The true breeding purple line produces only pollen carrying the purple allele, and all
    the ovules from the true-breeding white line have the white allele. The true breeding
    lines are homozygotes: the two copies of the flower color gene in each plant are
    identical. True breeding is the same as homozygous.
•   So, when pollen from a purple flower fertilizes ovules from a white flower, the F1
    offspring gets one purple allele and one white allele. It is a heterozygote: the two
    copies of the gene are different. ―Hybrid‖ is the same as heterozygous.
•   In the heterozygote, the dominant allele is expressed and the recessive allele is not
    expressed. The heterozygote looks just like the dominant homozygote. The
    genotype of the plants-- their genetic constitutions-- are different (one is a
    homozygote and one is a heterozygote), but their phenotype--their physical
    appearance– is the same: purple flowers.
More Explanation
                    More Explanation
•   P is the symbol we will use for the
    purple allele.
•   p is the symbol for the white allele.
    Both alleles are different versions of
    the flower color gene.
•   Since peas have 2 copies of each
    gene (diploid), a pea plant can be PP,
    Pp, or pp.
•   The parental plants, from true
    breeding lines, are homozygous: PP
    (purple) and pp (white).
•   PP parents can only make P gametes,
    and pp parents can only make p
    gametes.
•   The P pollen fertilizes the p ovule,
    producing the diploid Pp F1 offspring.
•   The Pp plants are purple, because P is
    dominant and p is recessive.
•   The homozygous PP plants and the
    heterozygous Pp plants are both
    purple: they have different genotypes
    (genetic constitutions) but the same
    phenotype (physical appearance).
                Still More Explanation
•   The F1 heterozygotes are Pp. Half of the
    gametes they make are P and the other half
    are p.
•   When the F1 plants are self-pollinated, both
    the male and the female parts make P and p
    gametes.
•   Fertilization is random, so there are 4
    possibilities:
•      1. P pollen fertilizes a P ovum, giving PP
    zygote
•      2. P pollen fertilizes a p ovum, giving Pp
    zygote
•      3. p pollen fertilizes a P ovum, giving Pp
    zygote
•      4. p pollen fertilizes a p ovum, giving pp
    zygote.
•   Adding these up, ¼ of the offspring are PP,
    ½ are Pp, and ¼ are pp.
•   Phenotypes: PP and Pp are purple, so ¾
    purple. Pp is white, so ¼ white.
•   The Punnett square is a simple way of
    combining gametes and seeing the
    genotypes of the next generation.
              Cross Summary




• Mendel‘s Law of Segregation: Diploids produce equal
  numbers of gametes from each allele. The gametes
  combine at random to produce the next generation.
                                 Back Cross
•   So far we have seen what happens when two
    homozygotes are crossed (all the offspring are
    heterozygotes), and what happens when two
    heterozygotes are crossed (genotype ratio of ¼
    PP, ½ Pp, ¼ pp; phenotype ratio of ¾ purple to ¼
    white).
•   One other possibility: crossing a heterozygote to a
    homozygote. This is called a backcross: an F1
    heterozygote is crossed to one of the parental
    homozygotes.
•   A backcross can be made to the dominant
    parental type or to the recessive parental type. A
    testcross is the latter type: crossing a
    heterozygote to a homozygous recessive parental
    type.
•   In a backcross, the heterozygote (Pp) produces ½
    P gametes and ½ p gametes. The homozygote
    produces only one kind of gamete, P or p.
•   When the gametes combine, ½ are homozygotes
    and ½ are heterozygotes.
•   If the backcross is to the dominant parent, all
    offspring show the dominant phenotype.
•   If the backcross is to the recessive parent (a
    testcross), ½ the offspring have the dominant
    phenotype and ½ have the recessive phenotype.
          Complications: Variations in
                 Dominance
•   All of Mendel‘s traits had two alleles, a
    dominant allele (expressed in the
    heterozygote) and a recessive allele
    (not expressed in the heterozygote).
•   This all-or-nothing expression is now
    called ―complete‖ dominance
•   Another form is ―incomplete‖
    dominance, where the phenotype of
    the heterozygote is intermediate
    between the two parental
    homozygotes. The classic case is red
    flowers x white flowers giving pink
    heterozygotes.
•   How incomplete dominance works:
    each red flower color allele makes red
    pigment. The white alleles don‘t make
    pigment. So, the red homozygotes
    make twice as much pigment as the
    heterozygotes. We perceive the
    difference in the amount of pigment as
    red vs. pink.
                           Co-dominance
•   In co-dominance, the heterozygote expresses both
    parental types. A good example is the ABO blood
    group.
•   There are 4 blood types: A, B, AB, and O. Red
    blood cells of type A have a glycolipid (a
    carbohydrate attached to a lipid in the membrane)
    on their cell membranes. B cells have a different
    glycolipid. AB cells have both glycolipids, and O
    cells have neither.
•   The glycolipids are made by genes with the symbol
    I. The IA allele makes A glycolipids, and the IB
    allele makes the B glycolipids. People with AB
    blood have a heterozygous genotype: IA IB. They
    express both types of glycolipids on their red blood
    cells. This is what ―co-dominant‖ means.
•   O blood comes from the third allele, called i
    because it is recessive. Homozygotes (ii) don‘t
    make either A or B glycolipids. An IA i
    heterozygote had A blood, and a IB i heterozygote
    makes B blood.
•   This is an example of multiple alleles (3 alleles in
    this case: IA, IB, and i). Most genes have more than
    2 alleles.
  Single Genes Can Have Multiple
             Effects
• Sickle cell anemia—
  caused by a change
  in hemoglobin gene.
  Gives rise to many
  symptoms: skull
  deformation, heart
  failure, joint and
  muscle pain, spleen
  enlargement. Also—
  resistance to
  malaria.
                           Lethal Genes
•   In another variation on dominance,
    some alleles are lethal when
    homozygous—they kill the organism
    before birth.
•   Two examples: achondroplastic
    dwarves and Manx cats.
•   The heterozygote shows the unusual
    phenotype.
•   When two heterozygotes mate, their
    sperm and eggs combine randomly,
    producing ¼ DD, ½ Dd, and ¼ dd
    zygotes. BUT: the DD zygotes all die.
    This leaves only the Dd (dwarf) and dd
    (normal) types, in a ratio of 2:1, or 2/3
    dwarf and 1/3 normal.
•   Thus, dwarves and Manx cats don‘t
    breed true: they always produce 1/3 of
    the ―wrong‖ type of offspring.
More on Lethal Genes
               Environmental Effects
•   Most inherited traits are affected by
    environmental conditions.
•   For instance, the hydrangea has white,
    pink, and purple versions. There are
    only 2 alleles: white and pigmented.
    The pink and purple come from
    growing the plants in different acidity
    conditions.
•   Some effects are more direct. Manx
    cats have no tails due to a mutant
    allele. But, cats can also have no tail
    because it has been cut off—an
    environmental condition.
•   Genetic traits are also affected by
    ‗background‖ genetics—other genes
    present. Former Chicago Cubs relief
    pitcher Antonio Alfonseca has a
    condition called polydactyly, having
    extra fingers and toes. He has 6 on
    each hand and foot. More commonly
    people with this condition have just a
    single extra digit with no bone in it, but
    the range is quite large
 Two Genes Affecting One Trait
• Most traits are due to the
  interaction of several
  genes.
• New phenotypes can
  arise from the interactions
  between genes. Also,
  unusual ratios of
  offspring.
               Continuous Variation
•   Many traits don‘t seem to fall into
    discrete categories: height, for
    example. Tall parents usually
    have tall children. Short parents
    have short children, and tall x
    short often gives intermediate
    height. In all cases, wide
    variations occur.
•   Simple interactions between
    several genes can give rise to
    continuous variation. Also:
    variations caused by environment,
    and our inability to distinguish fine
    distinctions lead us to see
    continuous variation where there
    actually are discrete classes.
           Independent Assortment
•   Much of Mendel‘s work involved pairs of
    genes: how do they affect each other when
    forming the gametes and combining the
    gametes to form the next generation?
•   Simple answer: in most cases pairs of genes
    act completely independently of each other.
    Each gamete gets 1 copy of each gene,
    chosen randomly.
•   Two genes:
•       1. seed shape. Dominant allele S is
    smooth; recessive allele s is wrinkled.
•       2. seed color. Dominant allele Y is
    yellow; recessive allele y is green.
•   Heterozygous for both has genotype Ss Yy,
    which is smooth and yellow. Gametes are
    formed by taking 1 copy of each gene
    randomly, giving ¼ SY, ¼ Sy, ¼ sY, and ¼
    sy.
•   These gametes can be put into a Punnett
    square to show the types of offspring that
    arise. Comes out to 9/16 smooth yellow,
    3/16 smooth green, 3/16 wrinkled yellow,
    and 1/16 wrinkled green.
                          Linkage
• Most pairs of genes assort
  independently.
• However, if two genes are
  close together on the same
  chromosome, they are said to
  be linked, which means the
  genes don‘t do into the
  gametes independently of
  each other.
• The closer two genes are, the
  more the parental combination
  of alleles stays together. This
  relationship can be used to
  make maps of genes on
  chromosomes.
    Some Common Genetics Diseases
•   Tay-Sachs disease is a neural degenerative disease
    caused by the lack of the enzyme hexose aminidase
    A, which normally breaks down certain membrane
    lipids in the lysosomes, especially in the nerve cells
    of the brain. Without the enzyme, these lipids
    accumulate in the cells, poisoning them. The child is
    apparently normal at birth, but starting between 6
    months and two years, the child has seizures and a
    loss of all skills such as crawling, sitting and feeding.
    100% lethal in early childhood. No cure or treatment
    known.
•   Tay-Sachs is a recessive genetic disease: the victim
    must inherit a defective copy of the gene from both
    parents. The parents are heterozygotes (carriers)
    who have no symptoms. There is a 1 in 4 risk of
    another Tay-Sachs child in a family where one was
    born.
•   There is a reliable blood test that can detect
    heterozygotes. High risk parents can take the test to
    determine their risk level. Tay-Sachs is especially
    prevalent among Ashkenazi (Eastern European )
    Jews. In American Jewish population, about 1
    person in 27 is a carrier. The French-Canadians
    from the St. Lawrence River area, and their cousins,
    the Louisiana Cajuns, also have a high risk of Tay-
    Sachs.
                        Sickle-cell Disease
•   Sickle-cell disease is caused by a defective
    hemoglobin molecule in the blood. The defect puts
    a hydrophobic amino acids on the outer surface of
    the protein instead of a hydrophilic amino acid. This
    causes the hemoglobin molecules to crystallize into
    long rods when the oxygen level in the blood gets
    low. These hemoglobin rods distort the red blood
    cells so they clog up the blood-carrying capillaries.
    The result is muscle pain, anemia, heart
    enlargement, kidney and spleen damage, and
    various other problems. Various medical
    treatments are used to ease the symptoms.
•   Sickle cell disease is recessive: homozygotes are
    quite sick. Heterozygotes are normal (sometimes
    called sickle cell trait), although they do have a
    higher rate of sudden death while exercising, due to
    sickling of the red blood cells under extreme
    conditions.
•   Sickle cell disease is common in West Africa, areas
    around the Mediterranean Sea, and in India, where
    malaria is found. Being a heterozygote confers a
    strong resistance to malaria, which has helped
    maintain this mutation in the human population.
    Other hemoglobin defects, such as hemoglobin C
    and thalassemia, confer malaria resistance and are
    found in the same populations. The malaria
    parasites live inside the red blood cells. The rods of
    hemoglobin that form when the cells sickle puncture
    and kill the parasites.
•   About 6% US African-Americans carry the HbS
    allele.
Malaria vs. Sickle Cell Disease
                             Cystic Fibrosis
•   Cystic fibrosis is primarily a disease of the
    lungs. The thin mucus that normally lines
    the lungs is replaced by heavy, thick mucus
    that traps bacteria and leads to lung
    infections. Other symptoms include salty
    skin and pancreas problems. In the US
    today, people with cystic fibrosis have an
    average life span of 33 years.
•   Cystic fibrosis is caused by a defective
    chloride ion channel, a protein that lets Cl-
    ions in and out of the cell. When chloride
    leaves the cell, sodium ions follow it, and
    water molecules follow the sodium. In cystic
    fibrosis, the chloride ions don‘t get out of the
    mucus-secreting cells, so not enough water
    is secreted to properly tin the mucus.
•   Treatment: attempts to remove the mucus
    through percussion on the back, mucus-
    thinning sprays, and antibiotics to treat
    infections.
•   Found primarily in Northern European
    populations: about 4% of US European-
    American populations are heterozygotes (no
    symptoms). There are DNA-based tests for
    this, but not 100% reliable.
                       Phenylketonuria
•   Phenylketonuria (PKU) is a disorder of
    the metabolism: the cells are unable to
    break down phenylalanine, which is an
    amino acid found in all proteins. The
    result is that phenylalanine levels in
    the blood build up to 30 times the
    normal level. This poisons the
    developing brain, leading to severe
    mental retardation.
•   PKU is a recessive condition: the
    parents are usually heterozygotes who
    have no symptoms. About 5% of the
    US population (all ethnic groups) is
    heterozygous for PKU.
•   There is a very simple blood test for
    PKU, which is given to all infants born
    in the US. The disease is easily
    treated by giving the children a low-
    phenylalanine diet until their brains
    mature. Infants in most states are also
    tested for several other easily detected
    and treated metabolic diseases.
               Some Dominant Traits
•   Huntington‘s Disease is a neural
    degenerative disease that doesn‘t
    appear until the victim is 40 years old
    or more. It starts with clumsiness and
    involuntary twitching, progresses
    through paranoia and psychosis, and
    ends in paralysis and death. The folk
    singer Woody Guthrie had this
    disease.
•   Dominant genetic diseases appear in
    heterozygotes. Homozygotes are rare
    because heterozygotes only rarely find
    and mate with each other.
    Huntington‘s shows complete
    dominance: the rare homozygotes
    have the same disease as the
    heterozygotes.
•   There is a genetic test: if it is positive,
    you will get the disease. Most people
    don‘t take the test.
                    Marfan Syndrome
•   Marfan syndrome is a disease of the
    connective tissue: the skeleton and
    cardiovascular system in particular.
    Symptoms include curvature of the
    spine, long fingers, tall stature,
    dislocated eye lens, and weakness of
    the aorta. People with Marfan‘s
    sometimes die suddenly due to the
    rupture of their aorta. Abraham
    Lincoln might have had this disease.
    Also Osama bin-Laden.
•   The disease is caused by an abnormal
    fibrillin gene. Fibrillin is one of the
    proteins that makes tissues elastic.
•   Marfan‘s is a dominant trait, meaning
    that the heterozygotes have the
    disease. People homozygous for
    Marfan‘s show a more extreme version
    and don‘t live past infancy. Just as in
    Huntington Disease, people with
    Marfan‘s have a 50% chance of
    passing the disease to their offspring.
                        Retinoblastoma
•   Retinoblastoma is a hereditary form of
    cancer. Like most hereditary cancers,
    it strikes young children, almost all
    before age 5. Tumors grow in the
    eyes, from the retinal precursor cells,
    the retinoblasts. It is quite treatable if
    caught early, using cryotherapy to
    freeze the tumors, or radiation and
    chemotherapy if necessary.
•   About 40% of the cases are
    hereditary, inherited from a parent who
    had the disease. The other 60% are
    spontaneous: due to newly arising
    mutations. The hereditary cases
    usually affect both eyes, while the
    spontaneous cases are confined to
    one eye. It is inherited as a dominant
    trait, so 50% of an affected person‘s
    children will get the disease.
    Homozygotes die as early embryos
    and are never born alive.
    Schizophrenia: a Complex Genetic
                  Trait
•   A mental disease: thought
    disorders (inability to think
    logically), delusions (person is
    being spied on or persecuted,
    thoughts are being overheard by
    others), hallucinations (voices
    inside the head). Also lack of
    emotional engagement, odd
    walking gait, social withdrawal.
•   NOT multiple personalities of
    ―split‖ personality.
•   Onset at any time, but generally
    age 16-25. Males and females
    equally affected.
•   Treatable with anti-psychotic
    drugs. But: the person must keep
    taking the drugs even after feeling
    better.
                 More Schizophrenia
•   Degree of risk for schizophrenia is strongly affected by relatives who have the
    disease:
•      1% risk for the general population
•      13% risk if you have 1 schizophrenic parent
•      35% risk if you have 2 schizophrenic parents
•      Monozygotic (identical) twins: 50% risk
•      13% of adopted children with a schizophrenic biological parent and normal
    adoptive parents develop the disease.
•   This ―runs in the family‖ phenomenon strongly implies genetic factors are involved.
•   Other factors are also involved: brain damage, viruses, family environment, life
    experiences, diet, plus others. Any or all of these.
•   Mapping: large family studies examine markers on the chromosomes to find locations
    associated with schizophrenia. That is, chromosomal locations where the alleles in a
    schizophrenic parent are also found in the schizophrenic child. Potential genes on
    chromosomes 22, 13, and 8.
•   But: the genes have been difficult to confirm. They seem to affect some families but
    not others. Maybe multiple causes of the disease?

				
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