Loss of Function Mutations

Types of Mutations and Their Effects

• Mutations can be understood by characterizing their effects on the function of encoded proteins.

Loss of Function Mutations

• Amorphic (null) mutations: Result in no protein production or yield a protein product that completely lacks function.
  • These mutations are usually recessive, as one wild-type copy of the gene is typically sufficient for normal function.
  • Example: CFTRΔ508 allele, associated with cystic fibrosis. The mutant CFTR protein doesn't exit the endoplasmic reticulum.
  • Wild-type CFTR is dominant because one copy can maintain the Chloride gradient
  • CFTRΔ508 is recessive because cystic fibrosis only appears if an individual is homozygous for the allele.
• Hypomorphic (leaky) mutations: Cause a reduction in protein function.
  • Due to less protein being made or the protein product having reduced activity.
  • Usually recessive because a wild-type copy often provides sufficient activity.
  • Example: Alleles of the Tyrosinase gene affect melanin production from tyrosine.
  • The wild-type allele (C) allows maximum tyrosinase activity and dark pigmentation.
  • The chinchilla allele (cch) reduces tyrosinase activity, making less pigment.

Gain of Function Mutations

• Hypermorphic mutations: Lead to an increase in protein activity, either by producing more protein or by enhancing the protein's activity.

  • Usually dominant because the presence of a hyperactive protein overshadows the normal protein.
  • Example: Hereditary pancreatitis (HP).
  • Trypsin-1, produced by the pancreas, prematurely activates and starts digesting the pancreas.
  • Normally, Trypsin-1 inactivates itself by cutting at Arginine117.
  • In HP, Arg117 is mutated to H117, preventing inactivation and causing acute pancreatitis.

• Antimorphic (dominant negative) mutations: Disturb the function of the protein encoded by the normal allele and usually occur when the protein operates as a hetero- or homo-multimer.

  • Occurs when a protein operates as a hetero- or homo-multimer.
  • Mutations in FBN1 lead to truncation of the protein and cause Marfan syndrome.
  • FBN1 encodes fibrillin-1, which assembles into long chains to form connective tissue fibers.
  • Results in unusually tall stature, long limbs, and arachnodactyly.

• Neomorphic mutations: Alter the protein function creating a 'new form', so they are usually dominant.

  • For example - Antennapedia in Drosophila, the gene is mutated, causing the development of legs where the eyes should be.

• Dominant lethal mutations: Cause the onset of the disease later in life due to the accumulation of the mutant product.

  • Huntington’s disease is caused by a triplet expansion in the HD locus giving a polyglutamine tract in the protein, leading to aggregation of protein into neurotoxic fibrils., typically beings at age 40.
  • Heterozygous individuals develop HD because the mutant polypeptide aggregates regardless of the presence of a wild-type copy
  • Appear in adult life because the accumulation of HD aggregates is slow.
  • Dominant lethal alleles are very rare; affected individuals must reproduce before dying.

Departure from Mendelian Ratios

• Mendelian ratios apply to traits controlled by dominant and recessive alleles, which is rare in nature.
• Incomplete dominance and co-dominance are recognized as departures from Mendelian genetics.
• These traits display non-Mendelian ratios at the level of the phenotype.

Incomplete (Partial) Dominance

• Results in a 'blend' of characteristics.
• Example: Four o'clock plants.
  • Crossing a wild-type red plant with a white plant results in all pink offspring.
  • The F2 generation has a 1:2:1 ratio of red:pink:white, not the 3:1 Mendelian ratio.

Co-dominance

• Presence of both alleles is detected equally.
• Example: ABO blood group system.
  • Locus I has three different alleles IA, IB, or i.
  • A person can have two of the three alleles.
  • IAIA or IAi results in blood type A
  • IBIB or IBi results in blood type B
  • IAIB results in blood type AB (co-dominance)
  • ii results in blood type O
  • The significance of ABO blood groups is highlighted during blood transfusions.
  • Individuals with blood type A make antibodies of type B.
  • Individuals with blood type B make antibodies of type A.
  • Individuals with blood type AB make neither antibody.
  • Individuals with blood type O make both A & B antibodies.

Lethal Alleles

• Can distort Mendelian segregation ratios.

• Normal wild-type mice have dark coats.

• The allele for yellow is dominant with respect to coat color.

• Crossing a yellow mouse with a wild type yields a 1:1 ratio of yellow to wild type mice.

• The allele for yellow is a recessive lethal with respect to viability

• Homozygous (AyAy) mice die before birth (lethal in utero).

• This homozygous combination is impossible to obtain.

• All Manx cats are heterozygous for a dominant allele that causes no tail.

• The allele interferes with normal spinal development in homozygous individuals.

• Homozygous Manx cats are never born because of the severe spinal deformity.

• In humans, a small percentage of miscarriages is due to homozygous lethal genes.

• The collection of lethal alleles in a population is referred to as the genetic load

• Around 85% of conceptions result in live births, and 15% are miscarried

• 7.5% owing to chromosomal abnormalities.

• The remaining 7.5% involves homozygous lethal genes, leading to lethal events in utero.

X-Linkage

• Genes present on the X chromosome exhibit unique inheritance patterns.
• Males inherit their X chromosome from their mother.
• Example: Hemophilia A (mutation in gene for blood clotting factor VIII on the X chromosome).
• Occurs most frequently in males.
• Cannot be passed from father to son.
• All daughters of affected fathers are carriers.
• Half the sons of a carrier will be affected, and half her daughters will be carriers, by probability.
• Examples of X-linked recessive traits: red-green color blindness, Duchenne muscular dystrophy, and X-linked ichthyosis.

Influence of Sex on Autosomal Traits

• Sex-limited traits: Phenotype is absolutely limited to one sex.
  • Example: Milk yield in dairy cattle. Number of eggs laid by poultry.
• Sex-influenced traits: Usually dependent on hormone constitution.
  • Example: Male pattern baldness.
  • The B allele is dominant in males (presence of high levels of testosterone) and recessive in females.
  • 2D:4D ratio - The 2nd digit is shorter than the 4th in males; the opposite is true for females.
  • Children with Asperger's syndrome have a high male:female ratio, indicating sex-influenced.

Maternal Inheritance

• Mitochondria and chloroplasts contain their own circular genome (e.g., mtDNA).
• Encodes 13 polypeptides plus rRNA and tRNA.
• Organelles are inherited exclusively from the maternal side of a cross.
• Mitochondria from sperm or pollen are excluded from the zygote.
• Mutations in mtDNA cause human diseases (mitochondrial cytopathies).
• Mainly affects organs that use high amount of energy, such as muscles and nerves.
  • MELAS (Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes).
• Follows matrilineal inheritance patterns, can only be passed on by the mother.
• Affected mothers transmit the disorder to all offspring.

Penetrance and Expressivity

• Mendelian ratios are observed when mutations are fully penetrant and show consistent expressivity.
• Few genes display these properties.
• They cause discrepancy between genotype and phenotype giving rise to non-Mendelian ratios.
• Incomplete penetrance occurs when the phenotype associated with a genotype fails to express in some cases.
  • In polydactyly, carrying the dominant mutant allele does not mean an individual will develop extra digits.
• Variable expressivity occurs when the phenotype varies in the degree of magnitude. Individuals with Wardenburg syndrome can display any all four of the principal features of the syndrome.
  • Hearing loss.
  • Differently colored eyes.
  • White forelock of hair.
  • Premature graying of hair.
• Such an allele is also pleotropic, since it affects more than one character.
• Penetrance and expressivity are controlled by factors like the genotype at other loci, and environmental factors.