Human Genetics

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Human Genetics
Chapter 15 The Chromosomal Basis of Inheritance
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Genes Chromosomes

• Mendels hereditary factors were genes, though
  this wasnt known at the time
• Today we can show that genes are located on
  chromosomes
• The location of a particular gene can be seen by
  tagging isolated chromosomes with a fluorescent
  dye that highlights the gene

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Chromosomal Theory of Inheritance

• Mitosis and meiosis were first described in the
  late 1800s
• The chromosome theory of inheritance states
• Mendelian genes have specific loci (locations) on
  chromosomes
• Chromosomes undergo segregation and independent
  assortment
• The behavior of chromosomes during meiosis was
  said to account for Mendels laws of segregation
  and independent assortment

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Experimental Evidence

• The first solid evidence associating a specific
  gene with a specific chromosome came from Thomas
  Hunt Morgan, an embryologist
• Morgans experiments with fruit flies provided
  convincing evidence that chromosomes are the
  location of Mendels heritable factors

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Experimental Evidence

• In one experiment, Morgan mated male flies with
  white eyes (mutant) with female flies with red
  eyes (wild type or normal)
• The F1 generation all had red eyes
• The F2 generation showed the 31 redwhite eye
  ratio, but only males had white eyes
• Morgan determined that the white-eyed mutant
  allele must be located on the X chromosome
• Morgans finding supported the chromosome theory
  of inheritance

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Sex linkage

• Sex chromosomes determine gender of individual
• XX in females, XY in males
• Each ovum contains an X chromosome, while a sperm
  may contain either an X or a Y chromosome
• The SRY gene on the Y chromosome codes for the
  development of testes
• X chromosome has genes for many traits NOT
  associated with sexual characteristics

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Sex-linked Inheritance

• A gene located on either sex chromosome is called
  a sex-linked gene
• In humans, sex-linked usually refers to a gene on
  the larger X chromosome
• If gene is on Y chromosome
• Sons will inherit from father
• Females dont get Y-linked traits
• Y-linked genes not common
• Example Hairy ears

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X-linked Inheritance

• If gene is on X chromosome
• Can inherit from either parent
• Sons always get X chromosome from mom and Y
  chromosome from dad

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X-linked traits

• Color blindness
• Hemophilia
• Duchene muscular dystrophy
• (SCID) Severe Combined Immunodeficiency Syndrome
• AKA Bubble boy disease

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X-linked recessive genes

• Sex-linked genes follow specific patterns of
  inheritance
• For a recessive sex-linked trait to be expressed
• A female needs two copies of the allele
• A male needs only one copy of the allele
• Sex-linked recessive disorders are much more
  common in males than in females

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Females X-linked

• In mammalian females, one of the two X
  chromosomes in each cell is randomly inactivated
  during embryonic development
• The inactive X condenses into a Barr body
• If a female is heterozygous for a particular gene
  located on the X chromosome, she will be a mosaic
  for that character

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Carriers

• Females can be carriers
• Have one copy of gene, but do not show trait
• Other X has normal dominant gene
• Males cannot be carriers, they either have it or
  they do not
• Males will give gene to all daughters, none to
  sons
• If he has the gene all his daughters will be
  carriers of trait

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Red-green color blindness

• X-linked disorder
• Cant differentiate these two colors
• Many people who have this are not aware of the
  fact
• First described in a boy who could not be trained
  to harvest only the ripe, red apples from his
  fathers orchard.
• Instead, he chose green apples as often as he
  chose red
• What serious consequence could result from this?

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Sex-Linked Traits
 1. Normal Color Vision A 29,  B 45,  C --,  D 26
 2. Red-Green Color-Blind A 70,  B --,  C 5,  D --
 3. Red Color-blind A 70,  B --,  C 5,  D 6
 4. Green Color-Blind A 70,  B --,  C 5,  D 2
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Hemophilia

• An X-linked disorder that causes a problem with
  blood clotting
• If your blood didnt have the ability to clot and
  you bruised yourself or scraped your knee, you
  would be in danger of bleeding to death
• Queen Victoria was a carrier and she passed the
  trait on to some of her children

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Hemophilia

• About 1 in every 10,000 males has hemophilia, but
  only about 1 in every 1 million females inherits
  the same disorder
• Why????
• Males only have one X chromosome
• A single recessive allele for hemophilia will
  cause the disorder
• Females would need two recessive alleles to
  inherit hemophilia
• Males inherit the allele for hemophilia on the X
  chromosome from their carrier or infected mothers

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Hemophilia
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Hemophilia

• Hemophilia can be treated with blood transfusions
  and injections of Factor VIII, the blood-clotting
  enzyme that is absent in people affected by the
  condition
• Both treatments are expensive
• New methods of DNA technology are being used to
  develop a safer and cheaper source of the
  clotting factor

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Sex-linked Questions

• Both the mother and the father of a male
  hemophiliac appear normal. From whom did the son
  inherit the allele for hemophilia? What are the
  genotypes of the mother, the father and the son?
• Mother
• Mother XNXn, Father XNY, Son XnY
• A woman is color blind. If she marries a man with
  normal vision, what are the chances that her
  daughter will be color blind? Will be carriers?
  What are her chances that her sons will be color
  blind?
• 0
• 100
• 100
• Is it possible for two normal parents to have a
  color blind daughter?
• No - mom would have to be at least carrier dad
  have it

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What is on our chromosomes?

• Each chromosome has hundreds or thousands of
  genes
• Genes located on the same chromosome that tend to
  be inherited together are called linked genes
• Thomas Morgan found that body color and wing size
  of fruit flies are usually inherited together in
  specific combinations
• He noted that these genes do not assort
  independently, and reasoned that they were on the
  same chromosome
• However, nonparental phenotypes were also
  produced
• Understanding this result involves exploring
  genetic recombination

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Genetic Recombination

• Mendel observed that combinations of traits in
  some offspring differ from either parent
• Offspring with a phenotype matching one of the
  parental phenotypes are called parental types
• Offspring with nonparental phenotypes (new
  combinations of traits) are called recombinant
  types, or recombinants
• Morgan discovered that genes can be linked, but
  the linkage was incomplete, as evident from
  recombinant phenotypes
• Morgan proposed that some process must sometimes
  break the physical connection between genes on
  the same chromosome
• Mechanism was the crossing over of homologous
  chromosomes

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Genetic map

• Alfred Sturtevant, one of Morgans students,
  constructed a genetic map, an ordered list of the
  genetic loci along a particular chromosome
• Sturtevant predicted that the farther apart two
  genes are, the higher the probability that a
  crossover will occur between them and therefore
  the higher the recombination frequency

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Genetic map

• A linkage map is a genetic map of a chromosome
  based on recombination frequencies
• Distances between genes can be expressed as map
  units one map unit, or centimorgan, represents a
  1 recombination frequency (max value 50)
• Map units indicate relative distance and order,
  not precise locations of genes

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Human Genome Project

• The most ambitious mapping project to date has
  been the sequencing of the human genome
• Officially begun as the Human Genome Project in
  1990, the sequencing was largely completed by
  2003
• The project had three stages
• Genetic (or linkage) mapping
• Physical mapping
• DNA sequencing

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Human Genome Project

• A physical map expresses the distance between
  genetic markers, usually as the number of base
  pairs along the DNA
• It is constructed by cutting a DNA molecule into
  many short fragments and arranging them in order
  by identifying overlaps
• Sequencing was then done on the chromosomes

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Gene Manipulation

• DNA sequencing has depended on advances in
  technology, starting with making recombinant DNA
• In recombinant DNA, nucleotide sequences from two
  different sources, often two species, are
  combined in vitro into the same DNA molecule
• Methods for making recombinant DNA are central to
  genetic engineering, the direct manipulation of
  genes for practical purposes

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Biotechnology

• DNA technology has revolutionized biotechnology,
  the manipulation of organisms or their genetic
  components to make useful products
• One benefit of DNA technology is identification
  of human genes in which mutation plays a role in
  genetic diseases
• Scientists can diagnose many human genetic
  disorders by using molecular biology techniques
  to look for the disease-causing mutation
• Genetic disorders can also be tested for using
  genetic markers that are linked to the
  disease-causing allele

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Transgenics

• Advances in DNA technology and genetic research
  are important to the development of new drugs to
  treat diseases
• Transgenic animals are made by introducing genes
  from one species into the genome of another
  animal
• Transgenic animals are pharmaceutical
  factories, producers of large amounts of
  otherwise rare substances for medical use
• Pharm plants are also being developed to make
  human proteins for medical use
• This is useful for the production of insulin,
  human growth hormones, and vaccines

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Gene Therapy

• Gene therapy is the alteration of an afflicted
  individuals genes
• Gene therapy holds great potential for treating
  disorders traceable to a single defective gene
• Vectors are used for delivery of genes into
  specific types of cells (example bone marrow)
• Gene therapy raises ethical questions, such as
  whether human germ-line cells should be treated
  to correct the defect in future generations

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Causes of Genetic Disorders

• Meiosis usually functions accurately, but
  problems may arise at times
• Large-scale chromosomal alterations often lead to
  spontaneous abortions (miscarriages) or cause a
  variety of developmental disorders
• In nondisjunction, pairs of homologous
  chromosomes do not separate normally during
  meiosis
• May occur in Meiosis I or II
• One gamete receives two of the same type of
  chromosome
• Another gamete receives no copy of the chromosome

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Fertilization after nondisjunction

• Nondisjunction results in gametes with an extra
  or missing chromosome
• If the other gamete is normal, the zygote will
  have 2n 1 (47 in humans) or 2n - 1 (45 in
  humans)
• Most of the time an extra chromosome prevents
  development from occurring
• Aneuploidy results from the fertilization of
  gametes in which nondisjunction occurred
• Offspring with this condition have an abnormal
  number of a particular chromosome

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Fertilization after nondisjunction

• Monosomy occurs when the zygote has only one copy
  of a particular chromosome (2n -1)
• Trisomy occurs when the zygote has three copies
  of a particular chromosome (2n1)
• Polyploidy is a condition in which an organism
  has more than two complete sets of chromosomes
• Triploidy (3n) is three sets of chromosomes
• Tetraploidy (4n) is four sets of chromosomes
• Polyploidy is common in plants, but not animals
• Polyploids are more normal in appearance than
  aneuploids

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Nondisjunction animation Animation 2
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Human Disorders due to chromosome alterations

• Alterations of chromosome number are associated
  with some serious disorders
• Some types of aneuploidy appear to upset the
  genetic balance less than others, resulting in
  individuals surviving to birth and beyond
• These surviving individuals have a set of
  symptoms, or syndrome, characteristic of the type
  of aneuploidy

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Down Syndrome

• Down syndrome is an aneuploid condition that
  results from three copies of chromosome 21
• Trisomy 21
• Most common serious birth defect
• 1 in 700 births
• Varying degrees of mental retardation
• Due to Gart gene on 21st chromosome
• 1/2 eggs of female will carry extra 21 and 1/2
  will be normal
• Risk increases with age of mother

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Incidence of Down Syndrome
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Klinefelter Syndrome

• Klinefelter syndrome is the result of an extra X
  chromosome in a male, producing XXY individuals
• Trisomy 23 (XXY)
• 1 in every 2,000 births
• Could be from nondisjunction in either parent

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Turner Syndrome

• Turner syndrome produces XO females, who are
  sterile
• Monosomy 23 (XO)
• 1 in every 5,000 births
• It is the only known viable monosomy in humans
• Girls with Turner Syndrome do not develop
  secondary sex characteristics such as breast
  tissue and underarm or pubic hair

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Mutation types

• Alterations of chromosome structure may also lead
  to genetic disorders
• Breakage of a chromosome can lead to four types
  of changes in chromosome structure
• Deletion removes a chromosomal segment
• Duplication repeats a chromosomal segment
• Inversion reverses a segment within a chromosome
• Translocation moves a segment from one chromosome
  to another

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Mutation types
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Cri du chat

• The syndrome cri du chat (cry of the cat),
  results from a specific deletion in chromosome 5
• A child born with this syndrome is mentally
  retarded and has a catlike cry
• Individuals usually die in infancy or early
  childhood

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Chronic Myelogenous Leukemia

• Certain cancers, including chronic myelogenous
  leukemia (CML), are caused by translocations of
  chromosomes
• Occurs with the exchange of a large portion of
  chromosome 22 with a small fragment from the tip
  of chromosome 9
• Shortened, easily recognizable chromosome 22 is
  called the Philadelphia chromosome

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Genomic imprinting

• There are two normal exceptions to Mendelian
  genetics
• One exception involves genes located in the
  nucleus, and the other exception involves genes
  located outside the nucleus
• Genes marked in gametes as coming from mom or dad
• Genes inherited from father expressed differently
  than genes inherited from mother
• For a small fraction of mammalian traits, the
  phenotype depends on which parent passed along
  the alleles for those traits
• Such variation in phenotype is called genomic
  imprinting
• Example Insulin-like growth factor in mice

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Organelle genes

• Extranuclear genes (or cytoplasmic genes) are
  genes found in organelles in the cytoplasm
• Mitochondria, chloroplasts, and other plant
  plastids carry small circular DNA molecules
• Extranuclear genes are inherited maternally
  because the zygotes cytoplasm comes from the egg

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Organelle genes

• The first evidence of extranuclear genes came
  from studies on the inheritance of yellow or
  white patches on leaves of an otherwise green
  plant
• Some defects in mitochondrial genes prevent cells
  from making enough ATP and result in diseases
  that affect the muscular and nervous systems
• For example, mitochondrial myopathy and Lebers
  hereditary optic neuropathy

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Review Questions

1. State the 2 basic ideas behind the chromosomal
   theory of inheritance.
2. Explain Morgans experiment and how it gave
   evidence that genes are located on chromosomes.
3. Explain sex linkage and sex-linked inheritance.
4. Name and describe characteristics of 4 genetic
   diseases that are known to be X-linked.
5. Explain the idea of a carrier for an X-linked
   genetic disease.
6. Carry out a monohybrid cross of an X-linked trait
   using a Punnett square.
7. Explain the idea of linked genes.
8. Explain the result of genetic recombination.
9. Identify the significance of genetic maps and
   linkage maps
10. Describe the Human Genome Project and
    differentiate between its 3 main stages.
11. Discuss the advantages of gene manipulation and
    biotechnology.
12. Describe various uses of transgenic animals.
13. Explain the purpose and use of gene therapy.
14. Explain how errors in meiosis can cause genetic
    syndromes.

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Review Questions

1. Define nondisjunction.
2. Differentiate between aneuploidy, monosomy,
   trisomy, and polyploidy.
3. Explain the cause, frequency, and problems
   associated with the following genetic syndromes
   Down syndrome, Klinefelter syndrome, Turner
   syndrome.
4. Describe the effect of mutations on genes.
5. Differentiate between deletion, duplication,
   inversion, and translocation mutations.
6. Explain cri du chat syndrome.
7. Explain chronic myelogenous leukemia as an
   example of a disease-causing mutation.
8. Explain genomic imprinting and the effects of
   extranuclear genes.