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HBIO4 > Inheritance

Genetic Counselling and Mendelian Inheritance

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)

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)

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)

ABO blood group is controlled by the immunoglobulin gene I
- There are 3 alleles I^A, I^B, 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
- I^AI^B is co-dominant
- I⁰ is recessive

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

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 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

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 (X^AX^B)
- 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

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