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Genetic Counselling and Mendelian Inheritance

Terms

  • Phenotype: observable characteristic or trait (appearance, behaviour) expressed by genotype
  • Genotype: makeup of alleles (AA or Aa or aa)
  • Dominant: allele always expressed (Aa)
  • Recessive: allele expressed if both copies are identical (aa)
  • Genes are expressed simultaneously by two alleles
    • One allele from each homologous chromosome
    • Homozygous: two identical alleles (AA or aa)
    • Heterozygous: different alleles (Aa)

Monohybrid Inheritance

  • Inheritance of a single characteristic
    • Controlled by different alleles of the same gene
  • Autosomal recessive
    • Example: Cystic Fibrosis, Phenylketonuria
      • Normal allele is dominant
      • To develop the disease, two abnormal alleles are required (homozygous)
      • Carriers carry an abnormal allele but are not affected (heterozygous)
    • Both parents are heterozygous carriers (Aa + Aa)
      • 25% unaffected (AA)
      • 50% carrier (Aa)
      • 25% affected (aa)
    • Affected (aa) + unaffected (AA)
      • All offspring will be carriers
    • Affected (aa) + Carrier (Aa)
      • 50% carriers and 50% affected
  • Autosomal dominant
    • Examples: Huntington's
      • Abnormal allele is dominant
      • To develop the disease, only one abnormal allele is required
      • No unaffected carriers possible
    • Aa + aa → 50:50
    • Aa + Aa → 3:1 (75% affected and 25% unaffected)

Codominance

  • Example: Sickle-cell anaemia
    • Mutation in β-globin chain of haemoglobin
    • This forms haemoglobin S (HbS)
    • Red blood cells become sickle shaped in low oxygen levels
      • Reduces their flexibility
      • Cannot deform to pass through capillaries
      • May get stuck in small blood vessels
      • Causes organ damage and ischaemia
    • Abnormal red cells are destroyed by the spleen → anaemia
  • Heterozygous allele is neither dominant nor recessive
    • Both alleles are expressed to determine phenotype
    • Normal allele still produces 50% of normal haemoglobin (no symptoms)
    • People are carriers and have a sickle-cell trait
  • Malaria
    • Sickle-cell anaemia is more common in Africa due to malaria
    • Those with sickle-cell trait are more resistant to malaria
    • Red cells start to sickle when infected by malaria and rupture
    • Malaria plasmodium is unable to reproduce in red cells
  • Inheritance
    • Sickle-cell anaemia (SS) + Sickle-cell trait (AS)
      • 50% carriers (AS)
      • 50% affected (SS)
    • Both parents have sickle-cell trait (AS)
      • 25% unaffected (AA)
      • 50% carrier (AS)
      • 25% affected (SS)

Multiple Alleles

  • ABO blood group is controlled by the immunoglobulin gene I
    • There are 3 alleles IA, IB, and I0 for that gene
    • These alleles code for antigens A, B and neither A/B, respectively
  • Only 2 alleles can be present in a diploid cell
    • IAIB is co-dominant
    • I0 is recessive

Rhesus Blood Groups

  • Rhesus (Rh) positive
    • Presence of antigen D on red cells
    • Allele is dominant
  • Rh negative mother AND Rh positive baby
    • First pregnancy
      • Red cells CANNOT cross the placenta
      • But mixing of blood does occur when giving birth
      • Mother develops antibodies to antigen D (sensitisation)
    • Second pregnancy
      • Antibodies CAN cross the placenta
      • Attack baby's red blood cells
      • Causes haemolytic disease of the newborn (anaemia + jaundice, stillbirth)
  • Prevention
    • Rh negative + not sensitized → give anti-D injection
    • Anti-D destroys Rh positive cells before antibodies develop
    • Given during pregnancy and after birth

Chi-Squared Test (x2)

  • Observed Expected value
    • IMG
    • degree of freedom = n - 1
  • Shows if differences between sets of data are significant or not
  • Null hypothesis states that there are no significant differences between sets of data
  • Small value / probability higher than the level of significance 0.05/5%
    • Little difference between observed and expected value
    • Likely to be extremes of the same population
    • Null hypothesis accepted
  • Large value / probability is less than the level of significance 0.05/5%
    • Significant difference between observed and expected data
    • Likely to be two distinct populations
    • Null hypothesis rejected

Genetic Counselling

  • Genetic screening
    • Detect whether person is a carrier for an inherited disease
    • Done by searching extracted DNA for the base-sequence of the gene
  • Chorionic villus sampling (CVS)
    • Small sample of the placenta
    • Performed after 10wks of pregnancy
    • Thin needle through wall of abdomen or through vagina and opening of womb
  • Amniocentesis
    • Small sample of amniotic fluid (fluid that surrounds foetus in womb)
    • Performed between 15-22wks
    • Passing needle through abdomen and womb
    • Amniotic fluid is drawn out through a syringe
    • Cells in fluid are cultured and DNA is extracted
  • Karyotyping
    • Arrangement of chromosomes into homologous pairs
    • Detect abnormal chromosomes (not genes)
  • Embryo screening
    • Only allowed for severe genetic diseases
    • Embryos are cultured using IVF
    • Single cell is taken with a pipette and its DNA extracted
    • (-) Produces many embryos which are not used
    • (-) Long-term side effects for the embryo used are not known

Sex-linked Inheritance

  • Inheritance of sex in humans
    • Females are homogametic sex (X: or XX)
    • Males are heterogametic sex (XY) / Y chromosome is shorter
    • Involves whole chromosomes instead of individual genes
  • Phenotypic characteristic is inherited on X, not on Y chromosome
    • Characteristic is more common in males → females can be heterozygous (XAXB)
    • Sex linked characteristic is never passed from father to son
  • Example: Duchenne muscular dystrophy (DMD)
    • Faulty gene prevents production of dystrophin
    • The protein is normally found in muscles and holds cells together
    • Lack of dystrophin causes progressive muscle weakness
    • Muscle is eventually replaced by fat and connective tissue
  • X-linked recessive
    • Normal allele is dominant (X)
    • Female carrier (Xx) + Unaffected male (YX)
      • Offspring phenotype and genotype
        • 25% affected son (Yx)
        • 25% unaffected son (YX)
        • 25% female carrier (Xx)
        • 25% unaffected daughter (XX)
      • Therefore
        • 50% affected male
        • 50% female carrier
        • Only males can be affected
        • All daughters of affected male will be carrier
        • All sons of affected male are unaffected
    • Female carrier (Xx) + Affected male (Yx)
      • 25% healthy son, female carrier, affected son and affected daughter
    • Female unaffected (XX) + Affected male (Yx)
      • 50% healthy (YX) and 50% carrier (Xx)
      • No male to male transmission
      • Females are always carriers

Pedigrees

  • Interpretation
    • Autosomal dominant: vertical transmission of disease
    • Autosomal recessive: horizontal transmission
    • X-linked recessive: no male-male transmission
    • X-linked dominant: affected males have unaffected sons!
  • X-linked vs Recessive
    • Sex linked: only seen in males, not in females
    • Recessive: unaffected parents