allelic variation and pleiotropy of a single gene

mutations in haplosufficient genes

recessive because protein product from wild type allele is sufficient to produce wild type phenotype

dominant mutations

having a single copy of the mutation produces a phenotype (disease), despite having a wild type copy of the gene

haploinsufficiency

having only one wild type allele does not produce sufficient protein product to result in the wild type phenotype

dominant negative mutations

mutant protein interferes with wild type protein function, altering the phenotype (not wild type phenotype)

p53 mutant alleles

• function as dominant negative

• mutation in the DNA binding domain of one of the two alleles produces mutant protein that cannot bind DNA

• mutant protein can still bind other p53 proteins and form homotetramer

• homotetramer containing mutant subunits cannot bind DNA, and thus cannot activate p53 target genes

incomplete or partial dominance

intermediate phenotype is produced (new visible phenotype)

codominance

both alleles are expressed/detected, both phenotypes present

blood type as example of codominance

• 3 alleles determine blood type: i, I^A, I^B

• gene encodes a glycosyltransferase, determines which sugar is present at the end of a sugar chain on red blood cells

• A and B are dominant over O, but codominant with each other

  • I^A/i → blood type A

  • I^A/I^B → blood type AB (both phenotypes detected)

conventional assay for blood type dominance

• blood coagulates when antibody binds specific sugar chain

• if blood coagulates in anti-B serum and anti-AB serum, but not anti-A serum, blood type is B

• if blood coagulates in all three serums, blood type is AB

• if blood does not coagulate in any serum, blood type is O

assay for anemia phenotype (Hb gene)

• Hb^A/Hb^A → no anemia

• Hb^S/Hb^S → anemia

• Hb^A/Hb^S → no anemia

• therefore, Hb^A is completely dominant to Hb^S

assay for blood cell shape phenotype (Hb gene)

• Hb^A/Hb^A → normal shape

• Hb^S/Hb^S → sickle shape

• Hb^A/Hb^S → slight sickle shape

• intermediate phenotype produced, indicating that Hb^S is incompletely dominant to Hb^A

assay for phenotype of presence of Hb^A and Hb^S at the protein level (Hb gene)

• Hb^A/Hb^A → Hb^A protein visible on gel

• Hb^S/Hb^S → Hb^S protein visible on gel

• Hb^A/Hb^S → both Hb^A and Hb^S proteins visible on gel

• both alleles can be clearly discerned, indicating that Hb^A and Hb^S are codominant

recessive lethal

homozygous mutations causing lethality (two copies of the mutation cause lethality), whether mutation is recessive or dominant

conditional alleles

expression of phenotype depends on certain conditions/environments (ex: temperature, stability of protein varies)

rabbit colouring as an example of conditional alleles

• rabbits reared at 20°C or less → black extremities

• rabbits reared at temperatures above 30°C → all white

• caused by tyrosine kinase that is active at a lower temperature

penetrance

percentage of individuals with a given allele who exhibit the phenotype of that allele

causes of penetrance

• environment

• interacting genes

• subtlety of mutant phenotype (difficult to diagnose)

expressivity

degree to which a given allele is expressed at the phenotypic level (intensity of the phenotype)