Gene InteractionGene 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 wild-type phenotypefail to complement complement

“Standard” interpretations:

m1/m2 m1/+ m2/+(alleles) (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

•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)

“Mutation” of a gene might be due to changes elsewhere!

Hawley & Gilliland (2006) Fig. 2

•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)

“False positive” of transgenic rescue

updYM55 os1 upd3d232a Df(1)os1a

updYM55 Lethal OS WT Lethal

upd3d232a OS OS

Df(1)os1a Lethal

Shared regions between genes

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 allele-specific)

•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 wing enhancerB body enhancerBr bristle enhancerT tarsal claw enhancer

Y2 is gypsy retrotransposon insertion at the yellow gene

Y1#8 780bp promoter deletion

Y1 ATG start codon → CTG

y2 complements y1#8 (wing & body pigmented)

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 allele-specific)

•Combined haplo-insufficiency (allele non-specific)

Example of a “Poisonous interaction” SSNC

Non-complementation of non-allelic mutations

Hawley & Gilliland (2006) Fig. 4(after Stearns & Botstein (1988) Genetics 119: 249–260)

A model for synthetic lethality

Figure 6-23