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Chapter 4: questions 52, 60, 49, 55

**** Hand in 52 and 60

Eye color pathway in flies


 Null alleles of the white gene --> white eye fly
 There are other genes that act with white to make the red pigment, called scarlet and
brown (ABC transporters)
 Transmembrane proteins that sit in the membrane and act as transport channels.
 Scarlet and white transport tryptophan and downstream compounds, the
tryptophan can be modified to make ommochromes (brown)
 Scarlet gene allows for the production of brown pigment, the loss of function
for scarlet is scarlet eyes
 Brown sits with white and forms a channel in which guanine can come in and
modified to drosopterin (scarlet)
 The brown gene allows for the production of scarlet pigment, the loss of
function for the brown phenotype --> brown
 Scarlet eyed flies with a new germ line mutation in a new gene (germ line mutation only in
one of the two homologs)
 We want to figure out what this gene does
 Out cross it to a scarlet fly and get flies that are either heterozygous for the
mutation or st/st;+/m
 Could have a mutation for brown which would give white eyed flies
 Could also have a mutation in white which would then give white eyed flies
 How do we figure this out?
 Brown and scarlet are parallel in the pathway and they're converging
 Take individuals that are white eyed and cross to wt and get flies that are
heterozygous to both of the mutations --> sibling cross
 If it's a mutation in brown (expectations)
 9 wt (+/st, +/b)
 3 st/st (B/+, or +/+, or +/b which all give scarlet)
 3 b/b ( st/+, +/+, +/st)
 1 additive st/st; b/b -white
 If it's a mutation in white (Expectations)
 9 wt
 3 st/st (w/+, +/+, +/w) --> scarlet
 3 w/w (st/+, +/+, +/w) --> white
 1 w/w;st/st --> white
 9: 4:3 recessive epistasis

Modifier Screens
 A way of exploring interactions between genes
 Enhancers
 Makes the phenotype more severe-less wild-type. Can be recessive enhancers (two
mutant copies required to enhance the mutant phenotype. Or dominant-one
mutant copy enhances the phenotype
 Genetic enhancers have nothing to do with enhancer elements in the genome
 Suppressors: make the mutant phenotype more like wild-type. Like enhancers they can be
recessive or dominant
 Revertants: uncommon type, mutation in a particular gene
 Intergenic suppressor bc the mutation is occuring in the same gene that was
mutated originally.
 Pseudorevertants
 Ex: insertion mutation (put in one, frameshift), insertion of 3, non frameshift-
restore coding template
 An allelic series of white alleles - using hypomorphs to find modifiers
 Often start screen with hypomorphs
 Ex: start with white cherry and identify modifiers that make it more like the wildtype
or look for things that make it more like white
 Start out with a hypomorphic allele of a gene that's functioning in the pathway,
partial loss of function at gene A, still activates gene B but not as it normally would.
If you have both hypomorphic mutations then it enhances the phenotype. Can say A
enhances B or B enhances A.
 Apricot eyed flies

Compensatory mutations
 Mutations in compensatory genes
 White is a gene in the genome that is activated by a transcriptional pathway that makes
the white gene that makes the protein that allows for the production of red eyes
 If we inhibit or knockout the gene that normally inhibits the transcription of white, we get
a darker apricot colored eye
 Interactions of repressors are very rare
 Compensatory change that then suppresses the mutant phenotype
 Allele specific, gene specific
 Bypass suppressor: common type
 Pathway specific, rescues null allele
 Mutant blocks one pathway, suppressor opens alternative pathway

Suppressors
 Unc 54 mutants homozygous for the myosin heavy chain, paralyzed phenotype
 Unc 54 worms were mutagenized and screened for suppressors
 Worms that are homozygous for sup3 mutation among with unc54 were able to move
 Sup3 encodes for myo3 which is a myosin heavy chain which is normally expressed at very
low levels but there's an upregulation of the pathway
 Sup3 is an allele of myo-3 which encodes a normally minor myosin heavy chain but its
expression is increased -3 fold in the myo-3sup3 allele

Screens for mutations that increase or decrease penetrance


 Commonly used for finding genes that interact in heritable cancers
 When researchers look for second site mutations that affect the development of cancer
 Lof mutation in the tumor suppressor and in the animals or in the cell lines, this results in
a cancerous phenotype less than a 100% of the time
 Lof mutation in a tumor suppressor that shows development of cancer with incomplete
penetrance --> mutaganize --> select for lines that show an increase or decrease in
penetrance
 Mutations that increase penetrance are enhancers
 Mutations that decrease penetrance are suppressors
 Often done with p53
 59% (incomplete penetrance) mutations in p53
 When Rb is mutated the penetrance is now 100%
 Can say that Rb is an enhancer of p53 because it enhances the penetrance of
osteosarcoma

Going forward in reverse


 Take a wt fly and express a mutant gene from humans in the fly
 Created a fly model of Huntingdon's disease by expressing in the eye of the fly a mutant
form of the Huntington
 When you take the human form of the Huntington allele and express it in the eyes, the
eye becomes disorganized at the surface when it's normally organized. Accumulation of
aggregates in the eye.

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