Understanding Gene Interactions and Mutations: Models of Dominance and Complementation

1. Gene Interaction

2. Mutations of haplosufficient genes are recessive

3. Two models for dominance of a mutation Figure 6-3

4. Incomplete dominance Figure 6-4

5. Tailless, a recessive lethal allele in cats Figure 6-9

6. Sickled and normal red blood cells Figure 6-5

7. Heterozygotes can have the protein of both alleles

8. The molecular basis of genetic complementation Figure 6-15

9. “Standard” interpretation of complementation test Complementation= mutations in 2 different genes Non-complementation= mutations in same gene Hawley & Gilliland (2006) Fig. 1

10. “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

11. Shared regions between genes

12. 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)

13. “False positive” of transgenic rescue • Ku and Dmblm genesboth 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)

14. 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)

15. Intragenic complementation in multi-domain proteins

16. 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)

17. Examples of body and wing yellow allele interactions Transvection (allele complementation) Fig. 2 Morris, et al. (1999) Genetics 151: 633–651.

18. Cis-preference enhancer model (Geyer, et al., 1990) W wing enhancer B body enhancer Br bristle enhancer T tarsal claw enhancer Y2is 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)

19. 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)

20. Example of a “Poisonous interaction” SSNC Non-complementation of non-allelic mutations Hawley & Gilliland (2006) Fig. 4 (after Stearns & Botstein (1988) Genetics119: 249–260)

21. A model for synthetic lethality Figure 6-23