roth et al

According to the article, how do classical geneticists, population geneticists, and medical doctors each define "epistasis"?

Classical geneticist: one mutation masks or suppresses the effects of another allele at another locus (Bateson's original definition). Population geneticist: any genetic interaction, including aggravating/synthetic interactions where two mutations together yield a surprisingly deleterious phenotype. Medical doctor: a thin film on the surface of a urine specimen.

What is a genetic interaction?

When two mutations combined yield a surprising phenotype that cannot be explained simply by the independent effects observed for each mutation alone.

What is the difference between classical epistasis and population geneticist epistasis?

Classical epistasis only describes interactions where one mutant phenotype is masked or suppressed by the other. Population genetics includes classical epistasis plus aggravating/synthetic interactions (where two mutations together are much worse than either alone).

Why should we care about epistasis?

Classical epistasis provides a logical framework for inferring biological pathways and gene order. It is a key tool in functional genomics where systematic deletion of gene pairs reveals interactions.

What is an example of aggravating (non-classical) epistasis given in the paper?

Yeast genes BNI1 and BNR1 (formin proteins). Single mutants have polarity defects but are viable; double mutant is lethal (synthetic lethal phenotype).

What is an example of classical epistasis from C. elegans vulval development?

lin-26, lin-39, and let-23 control sequential steps: lin-26 mutants lack Pn.p cells; lin-39 mutants lack VPCs; let-23 mutants lack vulval cells. In double mutants, the upstream mutation masks the downstream one (lin-26 epistatic to lin-39, lin-39 epistatic to let-23).

In a positive regulatory or biosynthetic pathway, which gene is epistatic?

The upstream gene is epistatic to the downstream gene. The upstream mutation predominates and masks the downstream mutation's phenotype.

When would an epistatic mutation act downstream instead of upstream?

In a negative regulatory (switch regulation) pathway where the upstream gene represses the downstream gene. Then the downstream mutation is epistatic because it bypasses the need for upstream repression.

In the heffalump nose-tip fur example, what are the phenotypes of X and Y mutations?

X represses Y. X mutation: failure to repress Y → furry nose tip. Y mutation: no fur growth → bald nose tip. Double mutant (X Y) → bald (Y is epistatic, downstream).

In the C. elegans sex determination pathway, why is tra epistatic to her?

HER (secreted protein) represses TRA (membrane protein). her(lf) → feminized XO males; tra(lf) → masculinized XX hermaphrodites. Double mutant (tra her) looks like tra (masculinized), so tra is epistatic and downstream.

How can you order genes when loss-of-function mutations in two genes have the same phenotype?

Use a gain-of-function mutation in one gene that gives the opposite phenotype. Then do epistasis with the loss-of-function mutation in the other gene.

What is the Drosophila torso example of ordering genes with same loss-of-function phenotype?

torso(lf) and tailless(lf) both cause terminal cells to adopt central fates. torso(gf) causes all cells to adopt terminal fates. torso(gf); tailless(lf) double mutant looks like tailless(lf) (central fates), so tailless is downstream of torso.

What is a hypermorphic mutation (HJ Muller, 1932)?

A gain-of-function mutation that increases normal gene activity, often causing a phenotype opposite to loss-of-function alleles.

Why can hypomorphic (leaky) alleles cause problems in epistasis analysis?

Because they retain residual activity. In a double mutant with a null allele of a interacting gene, the residual activity can lead to mixed or unclear phenotypes instead of a clear epistatic relationship.

According to the article, does epistasis analysis only work if you already know the pathway?

No. The torso pathway was figured out genetically before either gene was cloned. Genetics and molecular biology complement each other.

What is an example of a microRNA pathway elucidated partly through epistasis?

lin-4 microRNA represses lin-14. lin-14 null mutation causes opposite phenotype to lin-4(lf) and is epistatic to lin-4(lf), establishing lin-14 as the downstream target.

What does a "co-equal" genetic interaction mean?

Neither mutation masks the other; the double mutant phenotype is not clearly epistatic. This may indicate genes working together as a cohesive unit (e.g., subunits of the same protein complex).

What was found when studying co-equal interactions among DNA repair genes?

Nine out of ten co-equal interactions corresponded to protein-protein interactions, including a "clique" of all pairs of four genes encoding the SHU complex.

How can systematic genetic interaction profiles be used?

Genes with similar profiles (same set of synthetic lethal partners) often encode components of the same protein complex or biochemical module, allowing prediction of function.

What was predicted for YMR299C (DYN3) based on genetic interaction profiling?

It was predicted to be part of the dynein-dynactin pathway (involved in spindle assembly, nuclear movement, and spindle orientation), a prediction later confirmed experimentally.

What is the final advice in the paper for someone who hates logic?

They may wish to consider alternatives such as a career in politics or, failing that, investment banking