Genetic interactions: epistasis - AndersenLab/Genetic-Analysis GitHub Wiki

Lecture 6

What is Epistasis?

Epistasis ("standing upon") occurs when the expression of an allele of one gene masks the expression of the allele of another gene. We say that gene A is epistatic to gene B when gene A masks the phenotype of gene B.

Epistasis occurs in different contexts

Determining epistasis requires some understanding of the nature of the genetic pathway being analyzed. Is the pathway a biosynthetic (i.e. metabolic) pathway or a regulatory pathway?

Metabolic/biosynthetic vs. regulatory

  • Biosynthetic/Metabolic pathways produce a product. Each gene (usually coding for an enzyme) modifies a precursor to produce a product.
  • Regulatory Pathways involve a series of genes that either activate (+) or inactivate (-) downstream members of the pathway.

In a biosynthetic pathway, two distinct phenotypes can be followed:

  1. Deficiency in pathway function:
    • A double mutant has the pathway deficiency phenotype of the most downstream gene.
    • For example: In the pathway above, a gene A;gene C double mutant will have the pathway deficiency phenotype of the gene C single mutant.
      • If you supply extra W to a gene A mutant, Z will be produced as in the wild type.
      • If you supply extra Y to a gene C mutant, Z will be produced as in the wild type.
      • If you supply extra W to a gene A;gene C mutant, Z will not be produced as in the wild type because gene C is mutant and the pathway still gets "stuck" at the transition from X to Y.
      • If you supply extra Y to a gene A;gene C mutant, Z will be produced as in the wild type.
    • Regardless of the gene action of the upstream gene, a mutation in the downstream gene will halt the pathway at a more downstream step anyway.
    • We would say that the downstream gene is epistatic to the upstream gene
  2. Accumulation of a precursor:
    • A double mutant accumulates the precursor of the most upstream gene.
    • For example: In the pathway above,
      • A gene A mutant accumulates precursor Q.
      • A gene C mutant accumulates precursor X.
      • A gene A;geneC double mutant accumulates precursor Q.
    • Regardless of the action of the downstream gene, a mutation in the upstream gene causes a build up of that precursor.

In a regulatory pathway, downstream genes can mask (or be epistatic to) upstream genes if they negate the input of earlier genes.

In any epistatic relationship, one must always consider that the genes could be acting in parallel. It is difficult to differentiate between downstream/upstream action and parallel action because gene inputs into a pathway or process could be stronger than other gene inputs.

Question to consider:

In a double mutant, you find that gene A is epistatic to gene B. Why can you not differentiate between (i) A acting downstream of B and (ii) A acting in parallel to B?

Further Resources

  • Epistasis - Excellent overview and explanation of biosynthetic (metabolic) vs. regulatory pathways.