Genetic Disorders

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Genetic Disorders

• Mitosis
• microscope mitosis
• Meiosis
• Crossing Over
• DNA replication
• Transcription and Translation

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Genetic Disorders

• Genetic disorders are extremely common with a
  lifetime frequency estimated at 670 per 1000.
• Genetic disorders can be classified as
• Mendelian disorders
• Multifactorial disorders
• Single- gene disorders with non-classic
  inheritance
• Chromosomal disorders

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Genetic Disorders

• The vast majority of genetic abnormalities do not
  result in a viable conceptus however 1 of all
  newborns have a gross chromosomal abnormality and
  5 of individuals younger than 25 have a serious
  disease with a significant genetic component.
• Only 2 of the human genome actually codes for
  proteins, more than 50 of the genome consists of
  blocks of repetitive nucleotides.
• This 2 consists of approximately 30,000 genes,
  with alternative splicing this can produces
  approximately 100,000 different proteins.

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Genetic Disorders

• On average 2 individuals share 99.9 of their DNA
  sequences, the panoply of human diversity is
  created by .1 of the genome (this is 3million
  base pairs).
• The most common variation is the single
  nucleotide polymorphism (SNP), SNPs occur
  normally throughout a persons DNA. They occur
  once in every 300 nucleotides on average, which
  means there are roughly 10 million SNPs in the
  human genome, lt 1 of these SNPs occur in coding
  regions and these may have a role in disease,
  however most SNPs represent markers inherited
  with a genetic locus.

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Mutations

• A permanent change in DNA, to be passed on to a
  subsequent generation (a heritable disorder) the
  mutation must occur in the germ cells.
• Mutations in somatic cells can cause disease but
  are not passed on to offspring.
• Mutations may occur in coding and/or non-coding
  regions.
• Non-coding region mutations may exert broad
  impact if they occur in an area of the genome
  involved in the control of gene expression.
• Most mutations cause no discernable effect.

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Mutations

• 3 types of mutations
• Genome mutations involve the loss or gain of a
  whole chromosome
• Chromosome mutations rearrangement, loss or gain
  of part of a chromosome resulting in a visible
  change in chromosome structure.
• Gene mutations a submicroscopic change in a gene
• 1. Point mutation a single nucleotide
  substitution
• 2. Frame-shift mutation a change in the
  reading frame of a gene due to an insertion or
  deletion of nucleotides.

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Mutations in coding regions

• Missence mutations point mutations in the coding
  sequence (one nucleotide for another) this may
  change the amino acid in the gene product. If
  the substituted amino acid still works its a
  conservative missence mutation. If the amino
  acid change results in a change in gene product
  activity its a non-conservative mutation, this
  can lead to a change in function.

A missence mutation in superoxide dismutase is
responsible for 20 of ALS cases (What does it
do?)
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Fig 5.2 p 748
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• Nonsense mutations point mutations in the coding
  sequence that results in the formation of a stop
  sequence for DNA directed RNA polymerase. The
  gene product is terminated early likely causing a
  loss of normal activity.

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Fig 5.5 p 149
Nonsense mutation causing ßo- Thalessemia
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• Frame-shift mutations insertions or deletions of
  multiples of three nucleotides may have no effect
  in the functioning gene product, frame shits of
  others numbers of nucleotides result in missence
  or nonsense mutations and result in a change in
  gene product function.

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Fig 5.4 p 148
Frameshift Mutation
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Fig 5.6 p 149
Triplet Deletion
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• Mutations in non-coding regions (Introns)
• Point mutations in enhancer or promoter regions
  may significantly affect the production of gene
  product.
• Point mutations may affect post transcriptional
  modification of mRNA interfering with proper
  translation.
• Tri-nucleotide Repeat Mutations
• These consist of amplification of 3 nucleotide
  sequences. Tri-nucleotide repeats are a common
  feature of normal genes, in this type mutation
  the 10 fold to 200 fold amplification of the
  repeats which results in abnormal gene
  expression. This type mutation is seen in
  fragile X syndrome Huntington disease.

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Mendelian Disorders

• Mendelian disorders result from mutations in
  single genes of large effect, the phenotypic
  expression of a mutated gene depends on the
  presence of compensatory genes and environmental
  factors.

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• It is only by chance that Mendel chose to study
  traits that were each located on the seven
  different genes of the garden pea (non-linked).

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Mendelian Disorders

• Terms
• Codominance both alleles of a gene pair are
  expressed (blood type)
• Penetrance the percentage of individuals
  carrying a gene that express that trait, of those
  with the genetic trait the percentage who exhibit
  signs/symptoms of the mutation (genetic,
  environmental factors) e.g. Cancer related
  mutations (BRCA1 2), many have an oncogene but
  not all develop cancer
• Genetic heterogeneity the production of a given
  trait by different mutations at multiple foci (at
  least 16 different mutations associated with
  deafness).
• Pleiotropism multiple end effects of a single
  gene mutation
• Variable expressivity the variable expression
  of an autosomal dominant trait in affected
  individuals they all have the altered process
  but the signs and symptoms differ (genetic,
  environmental factors) e.g. Marfans syndrome.
• Polymorphism multiple allelic forms of a single
  gene (blood type)

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Fig 5.3 p 148
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Transmission patterns of single-gene disorders

• Autosomal dominant
• General features
• Mutations affect structural or regulatory
  proteins.
• In some instances the product of the mutant
  allele interferes with the function of the normal
  protein (dominant negative)
• Occasionally the abnormal gene product acquires
  properties not associated with the normal gene
  product, in Huntington disease the abnormal
  product is toxic to cells of the caudate and
  putamen.
• There is reduced penetrance and variable
  expressivity
• The onset of symptoms may be later than in
  autosomal recessive disorders.

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Stopped here Autosomal dominant

• Marfan syndrome is an autosomal dominant genetic
  disorder of the connective tissue characterized
  by disproportionately long limbs, long thin
  fingers, a typically tall stature, and a
  predisposition to cardiovascular abnormalities,
  specifically those affecting the heart valves and
  aorta. The disorder may also affect numerous
  other structures and organs including the
  lungs, eyes, dural sac surrounding the spinal
  cord, and hard palate.
• Estimates indicate that approximately 1 in 5000,
  or 0.02 of the American population have Marfan
  syndrome. Each parent with the condition has a
  50 chance of passing it on to a child due to its
  autosomal dominant nature. Most individuals with
  Marfan syndrome have another affected family
  member, but approximately 15-30 of all cases are
  due to de novo genetic mutations such
  spontaneous mutations occur in about 1 in 20 000
  births. Marfan syndrome is also an example of
  dominant negative mutation and haplo-insufficiency
  . It is associated with variable expressivity.
  Incomplete penetrance has not been definitively
  documented.

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• Marfan syndrome is caused by mutations in the
  FBN1 gene on chromosome 15 which codes a
  glycoprotein called fibrillin-1, a component of
  the extracellular matrix. The Fibrillin 1 protein
  is essential for the proper formation of the
  extracellular matrix including the biogenesis and
  maintenance of elastin fibers . Elastin fibers
  are found throughout the body but are
  particularly abundant in the aorta, ligaments and
  the ciliary zonules of the eye, consequently
  these areas are among the worst affected.

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Transmission patterns of single-gene disorders

• Autosomal Recessive
• General features
• Age of onset is frequently early in life
• Clinical features tend to be more uniform
• In many enzymes are affected (most inborn errors
  of metabolism) rather than structural proteins)
• Heterozygotes often unaffected

• Sickle Cell Disease

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Why does Sickle Cell Survive?

• Sickle-cell disease occurs more commonly in
  people (or their descendants) from parts of the
  world such as sub-Saharan Africa, where malaria
  is or was common, but it also occurs in people of
  other ethnicities. This is because those with one
  or two alleles of the sickle cell disease are
  resistant to malaria since the red blood cells
  are not conducive to the parasites - in areas
  where malaria is common there is a survival value
  in carrying the sickle cell genes.

Plasmodium parasites in RBCs
Endemic malaria
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• X-linked Disorders
• All sex-linked disorders are X-linked (no
  Y-linked) and almost all are recessive.
• They are fully expressed in males (no normal X)
  and partially expressed in heterozygous females
  because they are true mosaics with random
  inactivation of one X chromosome.
• Classically there are no affected females because
  they have one normal X chromosome (they are
  carriers) ½ the daughters will be carriers, and ½
  the sons will be affected (they get the abnormal
  X).
• All daughters of an affected male will be
  carriers, but as long as mom is normal no sons
  will be affected.
• Homozygous females may result from the offspring
  of an affected male and a carrier female.

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Sex-linked Disorders

• Hemophilia is the name of a family of hereditary
  genetic disorders that impair the body's ability
  to control blood clotting. In the most common
  form, hemophilia A. clotting factor VIII is
  absent. Hemophilia B, also known as factor IX
  deficiency, is the second most common type of
  hemophilia.
• The effects of this sex-linked, X chromosome
  disorder are manifested almost entirely in males,
  although the gene for the disorder is inherited
  from the mother. This is more common in males
  because the female has two X chromosomes while
  the male only has one, meaning that if a male's x
  chromosome is defective, there is not another to
  "cover up" the disorder like females have.
• In about 30 of cases of Hemophilia B, however,
  there is no family history of the disorder and
  the condition is the result of a spontaneous gene
  mutation.
• A mother who is a carrier also has a 50 chance
  of giving the faulty X chromosome to her
  daughter. That does not give the daughter the
  hemophilia disease, but it does result in the
  daughter becoming a hemophilia carrier.
• Females are almost exclusively asymptomatic
  carriers of the disorder and may have inherited
  it from either their mother or father.
• How could you have an affected female?

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Queen Victoria
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