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					Basics of Molecular Genetics




김 종 일

(서울의대 생화학교실)
Genetics and Genetic
 Genetics
    - Science of inheritance
    - Concerned with differences/similarities of
      individuals resulting from the mechanisms of
      genetic material

 Genetic
    - Referring or relating to Genes
    - Inherited

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Confusing terms

 Familial
    - occurring in a family


 Sporadic
    - occurring from time to time, at irregular
      intervals; intermittent
    - said of a disease: occurring in isolated pockets;
      not epidemic


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Confusing terms
 Congenital
    -    said of a disease, defect or deformity: present at or
         before birth, and either inherited, or caused by injury,
         infection or the presence of certain drugs or chemicals
         in the mother’s body during pregnancy


 Hereditary
    -    descending or acquiring by inheritance
    -    passed down or transmitted genetically to offspring



2007-09-06                   의학유전학, 2007                            4
DNA and chromosome
                            • 46 chromosomes
                             = 23 from father
                               + 23 from mother
                             = 23 pairs of
                              chromosomes

                            • 22 pairs of
                              autosomes

                            • 1 pair of sex
                              chromosomes (X,Y)
                              XX or XY




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Mitosis

                  ..        .
                            .     .     . .      .
                  ..        .
                            .     .     . .      .
                  A-T
                 A-T       A-T
                           A-T   A-T     A-T
                                       A-T      2N
                                                4N
                                               A-T
                  G-C
                 G-C       G-C
                           G-C   G-C     G-C
                                       G-C     G-C
                  C-G
                 C-G       C-G
                           C-G   C-G     C-G
                                       C-G     C-G
                  T-A
                 T-A       T-A
                           T-A   T-A     T-A
                                       T-A     T-A
                  G-C
                 G-C       G-C
                           G-C   A-T     A-T
                                       A-T     A-T
                  G-C
                 G-C       G-C
                           G-C   G-C     G-C
                                       G-C     G-C
                  A-T
                 A-T       A-T
                           A-T   A-T     A-T
                                       A-T     A-T
                  C-G
                 C-G       C-G
                           C-G   C-G     C-G
                                       C-G     C-G
                  A-T
                 A-T       A-T
                           A-T   A-T     A-T
                                       A-T     A-T
                  G-C
                 G-C       G-C
                           G-C   G-C     G-C
                                       G-C     G-C
                  ..        .
                            .     .     . .      .
                  ..        .
                            .     .     . .      .

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Mitosis
                            .     .
                            .     .
                           A-T   A-T
                           G-C   G-C
                           C-G   C-G
                           T-A   T-A
                           G-C   A-T
                           G-C   G-C
                           A-T   A-T
                           C-G   C-G
                           A-T   A-T
                           G-C   G-C
                            .     .
                            .     .


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Meiosis
                          .       .
                 .      .       .      .
                          .       .
                 .      .       .      .
                        A-T    A-T
                A-T    A-T    A-T     A-T
                        G-C    G-C
                G-C    G-C    G-C     G-C
                        C-G    C-G
                C-G    C-G    C-G     C-G
                        T-A    T-A
                T-A    T-A    T-A     T-A
                        G-C    A-T
                G-C    G-C    A-T     A-T
                        G-C    G-C
                G-C    G-C    G-C     G-C
                        A-T    A-T
                A-T    A-T    A-T     A-T
                        C-G    C-G
                C-G    C-G    C-G     C-G
                        A-T    A-T
                A-T    A-T    A-T     A-T
                        G-C    G-C
                G-C    G-C    G-C     G-C
                          .       .
                 .      .       .      .
                          .       .
                 .      .       .      .

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Crossover, Chiasma and Recombination




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Meiosis




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Glossary : confusing terms
 (Genetic) Polymorphism
  Strictly, the existence of two or more variants
  (alleles, phenotypes, sequence variants,
  chromosomal structure variant) at significant
  frequencies in the population. Looser usages
  among molecular genecists include (1) any
  sequence variant present at a frequency >1% in a
  population, (2) any non-pathogenic sequence
  variant, regardless of frequency


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Glossary : confusing terms
 Locus
  A unique chromosomal location defining
  the position of an individual gene or DNA
  sequence

 Allele
  One of several alternative forms of a gene
  or DNA sequence at a specific
  chromosomal location (locus)
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Glossary : confusing terms

 Genotype
  The genetic constitution of an individual,
  either overall or at a specific locus

 Phenotype
  The observable characteristics of a cell or
  organism, including the result of any test
  that is not a direct test of the genotype
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Examples -
Locus, Allele, Genotype and Phenotype

Locus name     ABO Blood Type
               The gene for the enzyme called
Description
               glycosyltransferase
Chromosomal
               9q34
location
Alleles        A, B, O
Genotypes      AA, BB, OO, AB, AO, BO
Phenotypes     A형, B형, O형, AB형
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Genotype Frequency / Allele Frequency

 In a population of N persons, each with 2
  alleles at a particular locus, the total
  number of alleles is 2N

 (Relative) frequency of A1 allele
  = Number of A1 alleles / 2N



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Hardy-Weinberg Equilibrium

 Assume
        Normal locus segregation
        Equal allele frequencies for males and females
        No mutation, selection, migration
        Large population
        Random mating with respect to genotype of
         interest



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Hardy-Weinberg Equilibrium
    For an autosomal locus,
     if the frequecy of the allele Ai = qi

     Genotype                 Frequency
        AiAi                   qi2
        AiAj                   2qiqj

    For 2 alleles,
     if the frequency of the allele A1, A2 is q and 1-q, respectively

     Genotype                 Frequency
        A1A1                    q2
        A1A2                    2q(1-q)
        A2A2                    (1-q)2



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Dominance vs. Recessiveness
 Classically refer to situation in which the
  expression of one allele in a heterozygote masks
  the other at a particular locus
 The allele that is expressed in the phenotype is
  dominant with respect to that phenotype; the one
  that is masked is recessive
 Codominance refers to the situation in which both
  alleles are expressed in the heterozygote, or in
  which the heterozygote phenotypic expression
  differs from that of either homozygote
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Main symbols used in pedigrees




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 Autosomal Dominant Inheritance

        A/A               a/a



              A/a                a/a




                                               ?

a/a         A/a     a/a    A/a         A/a         a/a         a/a



      A/a                                                a/a

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Autosomal Dominant Inheritance
 An affected person usually has at least one
  affected parent
 Affect either sex
 Transmitted by either sex
 A child of an affected x unaffected mating
  has 50% chance of being affected (this
  assumes the affected person is
  heterozygous, which is usually true for rare
  conditions).
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Autosomal Recessive Inheritance




                          ?


2007-09-06      의학유전학, 2007       22
Autosomal Recessive Inheritance
 Affected people are usually born to unaffected
  parents
 Parents of affected people are usually
  asymptomatic carriers
 There is an increased incidence of parental
  consanguinity
 Affects either sex
 After the birth of an affected child, each
  subsequent child has a 25% chance of being
  affected (assuming both parents are
  phenotypically normal carriers)

2007-09-06            의학유전학, 2007                  23
X-linked recessive inheritance




                                 ?


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X-linked recessive inheritance
 Affects mainly males
 Affected males are usually born to unaffected
  parents; the mother is normally an asymptomatic
  carrier and may have affected male relatives
 Females may be affected if the father is affected
  and the mother is a carrier, or occasionally as a
  result of nonrandom X-inactivation
 There is no male-to-male transmission in the
  pedigree (but matings of an affected male and
  carrier female can give the appearance of male to
  male transmission)
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X-linked dominant inheritance




             ?


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X-linked dominant inheritance
 Affects either sex, but more females than
  males
 Females are often more mildly and more
  variably affected than males
 The child of an affected female, regardless
  of its sex, has a 50% chance of being
  affected
 For an affected male, all his daughters but
  none of his sons are affected
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More Definitions
 Penetrance
     Probability of disease given the genotype (i.e.
      not everyone with the genotype will be affected)
     Complete penetrance
     Incomplete penetrance
         -   Refers to the failure of a phenotype to be evident
             even though the genotype usually producing the
             phenotype is present
         -   Variable age of onset (e.g. Huntington’s disease),
             also called “age-dependent penetrance”


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More Definitions
 Variable expressivity
     Refers to variation in the expression of a trait, e.g., in
      severity
 Pleiotropy
     A occurrence of multiple diverse effects due to
      segregation at a single locus; effects on multiple traits
      due to a single “allele”, e.g., PKU
     If a single locus produces an effect on several traits,
      that locus is said to be pleiotropic (or have pleiotropic
      effects)
 Phenocopy
     A condition, not genetically caused, that mimics one
      that has a genetic causes

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More Definitions
 Phenotypic traits of interest may be
    - Discrete or continuous
 Discrete (discontinuous) traits are categorical and
  can by dichomous or polytomous
        affected vs unaffected
        no disease, mild disease, severe disease
        Blood group
        Number of children
 Continuous (quantitative) traits are measured on
  at least interval scale
     e.g. blood pressure, anthropometric measures,
      lipoprotein levels

2007-09-06                 의학유전학, 2007                30
An example for autosomal recessive
disease




2007-09-06      의학유전학, 2007          31
An example for autosomal recessive
disease - albinism




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An example for autosomal recessive
disease




2007-09-06      의학유전학, 2007          33
An example for autosomal recessive
disease - alkaptonuria

 Inborn error of
  metabolism




2007-09-06          의학유전학, 2007      34
An example for autosomal recessive
disease – cystic fibrosis
 Marked thickening of
  secretions, especially in the
  lung and in ducted glands
  such as pancreas
 Mutation in a gene that
  encodes a chloride channel
 Deficient Cl transport
  across the cell membrane
  leads to a reduction in the
  water content of
  extracellular fluid
2007-09-06            의학유전학, 2007    35
An example for X-linked recessive disease
– Duchenne muscular dystrophy (DMD)

 Progressive loss of muscle strength
 1 in 3300 live-born males
 A mutation in a gene that encodes
  dystrophin




2007-09-06        의학유전학, 2007           36
An example for autosomal dominant
disease




2007-09-06      의학유전학, 2007         37
An example for autosomal dominant
disease – achondroplasia

 A form of dwarfism due to mutation in the
  fibroblast growth factor type 3 receptor
 A specific mutation in the gene for the
  receptor constitutively activates the system,
  causing premature conversion of the
  growth plate into bone, severely stunting
  growth
 Gain-of-function mutation

2007-09-06         의학유전학, 2007               38
An example for autosomal dominant
disease – Huntington’s disease
 a rare inherited neurological disorder
  affecting up to almost 8 people per
  100,000.
 most obvious symptoms are abnormal
  body movements called chorea and a lack
  of coordination, but it also affects a
  number of mental abilities and some
  aspects of personality
 caused by a trinucleotide repeat
  expansion in the Huntingtin (Htt) gene
 This expansion produces an altered form
  of the Htt protein, mutant Huntingtin
  (mHtt), which results in neuronal cell
  death in select areas of the brain.


2007-09-06              의학유전학, 2007         39
An example for autosomal dominant
disease




2007-09-06      의학유전학, 2007         40
An example for autosomal dominant
disease




2007-09-06      의학유전학, 2007         41
An example for autosomal dominant
disease – Marfan’s syndrome

 A defect in the protein fibrillin, which is a
  component of connective tissue
 Heterozygotes show reduction of fibrillin by
  50% leading to weakening of connective
  tissue and signs of mild Marfan syndrome.
  (Haploinsufficiency)



2007-09-06          의학유전학, 2007               42
An example for autosomal dominant
disease




2007-09-06      의학유전학, 2007         43
An example for autosomal dominant disease
- osteogenesis imperfecta

 A disorder in which there is abnormal bone
  matrix, leading to brittle bones and frequent
  fractures
 Mutation in the gene that encodes
  components of type I collagen
 Mutation in one allele can lead to disruption
  of 75% of collagen triple helices due to the
  polymeric nature of the mature molecule
 An example of a dominant negative effect
2007-09-06         의학유전학, 2007               44
An example for autosomal dominant
disease – retinoblastoma




2007-09-06      의학유전학, 2007         45
An example for autosomal dominant
disease – retinoblastoma
 A mutation in Rb1
  gene
 Two-hit model for
  retinoblastoma




2007-09-06            의학유전학, 2007   46
Glomus tumor family (Heutink et al., 1992)




                 4



4       3



             4           2         5   2   2


2007-09-06           의학유전학, 2007             47
A family with hearing loss
(Prezant et al., 1993)




             6


                                6

2007-09-06        의학유전학, 2007       48
A family with hearing loss - modified




             6


                                 6

2007-09-06        의학유전학, 2007           49
                    핵 (Nucleus)



                   미토콘드리아 (Mitochondria)




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