Download y 1

Gene Interaction
Mutations of haplosufficient genes are recessive
Two models for dominance of a mutation
Figure 6-3
Incomplete dominance
Figure 6-4
Seven alleles and their interactions in leaf patterning of clover
Figure 6-7
A recessive lethal allele, yellow coat
Figure 6-8
Tailless, a recessive lethal allele in cats
Figure 6-9
Sickled and normal red blood cells
Figure 6-5
Heterozygotes can have the protein of both alleles
Figure 6-6
The molecular basis of genetic complementation
Figure 6-15
Testing complementation by using a heterokaryon
Complementation: a common, relatively simple allelism test
•Both mutations must be recessive, loss-of-function
•Can use leaky or null alleles; different phenotypes are permitted
Example:
m1/m1 has similar phenotype to m2/m2
Cross: m1/m1 X m2/m2
Results: mutant phenotype
fail to complement
wild-type phenotype
complement
“Standard”
interpretations:
m1/m2
(alleles)
m1/+ m2/+
(different genes)
Transformation “rescue” is a variation of complementation test
m1/m1 without transgene
mutant phenotype
m1/m1 with transgene
mutant phenotype non-complement
(transgene does not contain m+ gene)
m1/m1 with transgene
wild-type phenotype complement
(transgene contains the m+ gene)
“Standard” interpretation
of complementation test
Hawley & Gilliland (2006) Fig. 1
“Mutation” of a gene might be due to changes elsewhere!
•ald is Drosophila mps1 homolog; isolated four mutations (all rescued by ald+ transgene)
•two ald alleles cause meiotic and mitotic defects (ald sequence changes)
•two ald “mutations” cause only meiotic defects (normal ald sequence)
•both contain Doc element insertion into neighboring gene
(silences transcription of neighboring genes in germline cells)
Hawley & Gilliland (2006) Fig. 2
“False positive” of transgenic rescue
•Ku and Dmblm genes both involved in DNA repair and closely linked on the chromosome
•Old mutations of mus309 map to the region genetically
•DNA lesions of mus309 lie in Dmblm, but can be rescued with extra copies of Ku (provided on a
transgene)
Shared regions between genes
updYM55
upd3d232a
Df(1)os1a
updYM55
os1
upd3d232a
Df(1)os1a
Lethal
OS
WT
Lethal
OS
OS
Lethal
Exceptions to “Non-Complementation = Allelism”
Intragenic complementation (usually allele-specific)
•Multi-domain proteins (e.g., rudimentary)
•Transvection – pairing-dependent allelic complementation (stay tuned!)
Second-Site Non-Complementation (“SSNC”)
•“Poisonous interactions” – products interact to form a toxic product
(usually allele-specific)
•“Sequestration interactions” – product of one mutation sequesters the
other to a suboptimal concentration in the cell (usually one allelespecific)
•Combined haplo-insufficiency (allele non-specific)
Intragenic complementation in multi-domain proteins
Transvection:
synapsis-dependent allele complementation
E. Lewis (1954) among BX-C mutations in Drosophila
Numerous other genes in Drosophila and similar phenomena
observed in Neurospora, higher plants, mammals
Most due to enhancer elements functioning in trans (allele-specific)
Examples of body and wing yellow allele interactions
Transvection (allele complementation)
Fig. 2 Morris, et al. (1999) Genetics 151: 633–651.
Cis-preference enhancer model
(Geyer, et al., 1990)
W
B
Br
T
y2 complements y1#8 (wing & body pigmented)
wing enhancer
body enhancer
bristle enhancer
tarsal claw enhancer
Y2 is gypsy retrotransposon
insertion at the yellow gene
Y1#8 780bp promoter deletion
Y1 ATG start codon → CTG
y2 fails to complement y1 (wing & body pale)
Exceptions to “Non-Complementation = Allelism”
Intragenic complementation (usually allele-specific)
•Multi-domain proteins (e.g., rudimentary)
•Transvection – pairing-dependent allelic complementation
Second-Site Non-Complementation (“SSNC”)
•“Poisonous interactions” – products interact to form a toxic product
(usually allele-specific)
•“Sequestration interactions” – product of one mutation sequesters the
other to a suboptimal concentration in the cell (usually one allelespecific)
•Combined haplo-insufficiency (allele non-specific)
Example of a “Poisonous interaction” SSNC
Hawley & Gilliland (2006) Fig. 4
(after Stearns & Botstein (1988) Genetics 119: 249–260)
Non-complementation of
non-allelic mutations
A model for synthetic lethality
Figure 6-23