Status of our knowledge

 If a mutation affected gene, it was more likely to cause an amorphic or hypomorphic

allele than any of the gain function mutation. If you change a DNA sequence, you're
more likely to disrupt gene function rather than gain a new function
 Most loci in humans are happlosufficient, if you have 50% of the normal gene product
 We're all heterozygous for at least two mutations
 When a mutation affects gene function it is more likely to result in a loss-of-function
rather than a gain-in-function (much easier to randomly break something than
improve upon it)
 Because most loci are haplosufficient, most loss-of-function mutations will be
recessive to the wild-type (non-mutant allele). Investigation of variant alleles in
humans healthy populations suggests that each individual carries at least two
heterozygous premature stop alleles that could potentially lead to disease if present
as homozygotes.
 Most dominantly inherited diseases are caused by loss-of-function mutations in
haploinsufficient loci (e.g. Marfan’s syndrome).
 Marfan syndrome is caused a by lof mutation in a protein that's required for the
proper formation of connective tissue
 Most dominantly inherited diseases are caused by alleles that are semi-dominant to
the wild-type allele (D/D isn't the same as D/d)
 The most common gain-of-function is a Hypermorph (an increase in the functional
gene product)
 The most common type of neomorphic mutation causes a change in the pattern or
timing of gene expression (e.g. lactose tolerance)
 Expressed in tissue not normally expressed or time not normally expressed
 Normally lactose tolerance, the gene that produce lactase is normally produced
in infancy and early adolescence then shut off… several point mutations that
allow it to be expressed in the lifetime of an individual
 Antimorphic mutations antagonize the wild-type gene function. As such they act as
dominant negatives
 Mutant gene product antagonizes the funciton of the wt
 Reducing the ability of the wt copy of the gene product to function properly
 Activity drops below 50%, lower than a normal heterozygote
 Crossing a recessive mutation to a deficiency and look at the phenotype of
recessive/deficiency
 Deficiency: that region of DNA has been deleted from the chromosome, most
likely a deletion of a segment of a chromosome that contains multiple genes
 Cross b1/b1 homozygous mutant with b+/deficiency
 B+/deficiency is hemizygous for the wt allele bc there is no homologue
 What's the nature of the b1 allele? Is it a complete loss of b gene activity or a partial
loss of b gene activity
 What's the phenotype of the b1/deficiency?
 It could either be more severe or identical to the mutant phenotype?
 If it's identical to the mutant phenotype: b1 is a null allele, an amorph
 If it's a more severe phenotype, it's a hypomorphic mutation
 Hypomorphic mutation (similar to Muller's morphs, apricot… wa/wa x w1/w1 --> pale
apricot, more severe phenotype, more like the null phenotype
 the null is essentially like a deletion of the gene
 Deficiency is cleaner bc the gene is completely gone but messier bc a deficiency will
likley knock out multiple genes at once
 The deficiency has to be a null
 Null allele: there is no function at all
 Deficiency is a type of null allele where the DNA is completely deleted
  Manx cats: tailless cats, heterozygous for a mutation of a gene required for the
production of the vertebrate
 T/t= tailless t=null allele of the tailless gene
 Individuals that are t/t are dead
 T/t-hypomorphic = smaller tail
 Allelic series: from wt to null, and phenotypes in between
 Semi-dominant: can be semi dominant and have an allelic series of mutations but not
the same thing
 Ex: T/t = tailless
 t/t= dead
 This tells us that heterozygous phenotype is not equal to the homozygous
phenotype, so it means it's semidominant
 Homozygous is not the same as the heterozygous phenotype
 Allelic series: full array of different phenotypes when you have some alleles that
are null, some alleles that are null, and various hypomorphic alleles in between
 Those hypomorphic alleles could be semi-dominant

 If you're homozygous for a null mutation, you'll have a complete loss of that gene product