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 phenotypewild-type phenotype fail to complementcomplement “Standard” interpretations: m1/m2m1/+ m2/+ (alleles)(different genes)

Transformation “rescue” is a variation of complementation test m1/m1 without transgenemutant phenotype m1/m1 with transgenemutant phenotype non-complement (transgene does not contain m+ gene) m1/m1 with transgenewild-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

upd YM55 os 1 upd3 d232a Df(1)os 1a upd YM55 LethalOSWTLethal upd3 d232a OS Df(1)os 1a 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 enhancer B body enhancer Br bristle enhancer T tarsal claw enhancer Y 2 is gypsy retrotransposon insertion at the yellow gene Y 1#8 780bp promoter deletion Y 1 ATG start codon → CTG y 2 complements y 1#8 (wing & body pigmented) y 2 fails to complement y 1 (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