Lethal yellow mice: Why two yellow mice give a 2:1 ratio

Level: High school to college · You’ll need: a monohybrid cross and dominant and recessive alleles · Part of mouse genetics

A lethal yellow mouse carries one copy of the agouti allele Ay. Ay is dominant for coat color, so one copy makes a yellow coat. But two copies are fatal: Ay/Ay embryos die very early in development. That’s why two yellow mice give 2 yellow pups to every 1 non-yellow pup, instead of the 3:1 ratio you’d expect from two carriers.

Assumptions for the crosses on this page: the agouti gene with the alleles below, other genes held the same, and enough pups for the ratios to show. Ratios are among pups that are born.

The agouti gene in mice

The agouti gene decides whether pigment cells make yellow pigment or black (or brown) pigment. In normal “wild-type” mice it switches between the two as each hair grows, giving banded hairs and the brownish agouti coat. The alleles taught in most courses are:

Because Ay/Ay never survives, every yellow mouse you meet is heterozygous: Ay/A or Ay/a.

Why two yellow mice give 2:1

Take two yellow mice, both Ay/a:

Four equally likely boxes, but one (Ay/Ay) never becomes a pup. Of the three boxes left, two are yellow and one is black:

⅔ yellow, ⅓ black among the pups that are born. About a quarter of the embryos are lost, so litters from two yellow parents tend to be smaller. Check it in the calculator.

The genotype ratio among live pups is 2 Ay/a : 1 a/a. Notice that it’s the same as the phenotype ratio here: every surviving genotype has its own coat.

A puzzle that took years to solve

The French biologist Lucien Cuénot was one of the first to show that Mendel’s laws apply to animals as well as plants, using mice. But his yellow mice wouldn’t behave. Crossing yellow with yellow never gave a true-breeding yellow line, and the ratio came out near 2:1 rather than 3:1. Cuénot realized yellow mice were always heterozygous, but explained the missing class another way.

In 1910, William Castle and Clarence Little showed that yellow × yellow litters were smaller than other litters. That supported the idea that homozygous yellow embryos do form and then die, rather than never forming at all. Later work found the dead embryos, and in 1994 researchers found the DNA change. Ay is a large deletion that joins the agouti gene to the start of a neighboring gene, Raly. Two copies remove Raly, which embryos need, so Ay/Ay embryos stop developing before they implant in the womb.

This is why the lethal yellow mouse is the classic textbook example of a recessive lethal allele: an allele that is dominant for one trait (coat color) but recessive for another (survival).

Lethal yellow is about more than color

The same deletion makes the agouti gene switch on all over the body instead of only in the skin. In the skin, that means yellow fur. Elsewhere, especially in the brain, the agouti protein interferes with signals that control appetite and weight, so lethal yellow mice tend to become obese and develop high blood sugar as adults. One gene with several effects like this is called pleiotropy.

Researchers use these mice to study obesity. This page describes the genetics only; it isn’t advice on keeping or breeding mice.

More worked crosses

Yellow × black: Ay/a × a/a

½ yellow, ½ black. No Ay/Ay boxes, so no embryos are lost and litters are normal size. Check it.

Yellow carrying agouti × yellow carrying non-agouti: Ay/A × Ay/a

The boxes are Ay/Ay (dies), Ay/a (yellow), Ay/A (yellow) and A/a (agouti). ⅔ yellow, ⅓ agouti. Check it.

Two genes: Ay/a B/b × Ay/a B/b

Use the product rule. Two-thirds of the pups are yellow, and the brown gene doesn’t change yellow fur. Among the third that are non-agouti (a/a), ¾ are black and ¼ brown:

Check it.

Common questions

Do two yellow mice give a 3:1 ratio?

No. Cross out the Ay/Ay box first, then count what’s left: 2 yellow to 1 non-yellow.

Can a yellow mouse be Ay/Ay?

No. No living mouse has that genotype; every yellow mouse is Ay/A or Ay/a.

Is Ay dominant or recessive?

Both, depending on the trait. It’s dominant for coat color but recessive for lethality, so say which trait you mean.

Are the fractions out of four boxes?

No. They’re out of the pups that are born. With two yellow parents, that’s three surviving boxes, so the denominator is 3.

Practice

1. Two yellow mice (Ay/a) have 12 pups. About how many would you expect to be yellow?
2. A yellow mouse is crossed with an agouti mouse (A/A). What are the expected pup colors and proportions?
3. Yellow-by-yellow crosses produce smaller litters than other crosses. Explain why.

Where the model stops

• There are more agouti alleles than the three here, including viable yellow (Avy), whose coat ranges from yellow to mottled to agouti depending on chemical marks on the DNA. That makes it a famous example in epigenetics; see the mouse methylation study for a different, more recent case.
• Real lethality isn’t always total or early. Some lethal alleles kill later in development or only in some genetic backgrounds.

Related

• Mouse coat color calculator: the 2:1 cross, with the lethal box crossed out
• White mouse genetics: albino and another kind of masking
• Mouse genetics: the mouse section overview
• Monohybrid cross calculator: the 3:1 cross this one breaks

Sources

• Michaud EJ, et al. “A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (A^y) mutation.” PNAS 91, 2562–2566 (1994). doi:10.1073/pnas.91.7.2562
• Castle WE, Little CC. “On a modified Mendelian ratio among yellow mice.” Science 32, 868–870 (1910). doi:10.1126/science.32.833.868
• Wolfe HG, Coleman DL. “Pigmentation.” In Biology of the Laboratory Mouse, Chapter 21. The Jackson Laboratory, via Mouse Genome Informatics. informatics.jax.org/greenbook