The Yellow Agouti Conundrum: Mendelian Genetics Meets Molecular Biology
(AA; also represented as A+/A+)
(AAy; also represented as A+/Ay)
Figure sources: http://www.informatics.jax.org/greenbook/figures/figure21-1.shtml, part of The Jackson Laboratory's "Biology of the Laboratory Mouse," 2nd Edition (online version: http://www.informatics.jax.org/greenbook/)
Agouti is the common name for some animals of the genus Dasiprocta. The term "agouti" is also used to describe the fur color of other mammals, such as mice and horses, if they show a banded fur color reminiscent of Dasiprocta. Very importantly, the agouti gene (a) may be associated with obesity. Overexpression of the murine agouti gene in cultured human adipocytes prevents degradation of fats.
In a cross yellow doe (♀) X yellow buck (♂), a litter will be comprised of 2/3 yellow mice, 1/3 agouti (see genotypes above; A+ indicates the wild type allele). Since by now you are more familiar with transmission genetics, you notice that the proportion is not right. You will find in the formal scientific literature that Ay (yellow) is a recessive lethal allele, i.e., a homozygous AyAy does not develop after fertilization or perishes early in pre-natal development. Phenotypes are analyzed only in living offspring, hence recessive lethal alleles are considered when considering genotypes and discrepancies between the genotypic proportions vs. phenotypic proportions.
This seemingly incongruous relation between lethality and fur color has been explained at the molecular level. See article (posted on Blackboard) by Michaud EJ, Bultman SJ, Stubbs LJ, and Woychik RP (1993) Genes Dev 7:1203-1213. The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of an RNA-binding protein. You may obtain more information in Silvers WK (1979) The Coat Colors of Mice, Springer Verlag, Chapter 2. Remember to cite bibliographic or Internet sources if you happen to use any.
You may not need this information, but just to give you an idea of the complexity of the alleles A/a, and its relationship with obesity. According to Hollander WF and Gowen JW (1956) J Hered 47:221-224, other fur color alleles at the agouti locus and their phenotypes in the mouse (Mus musculus) are:
a "black," non-agouti, yellow hair in the ears and around the perineum
ae extreme non-agouti
at "black-and-tan" (belly yellowish, rest of the body black)
A+ wild type (uniformly agouti)
Aw "white-bellied," or yellow-bellied agouti
Ay "yellow," lethal if homozygous; the heterozygote is obese
To enter your answer, double click and type where indicated:
1) Explain why is there a non-Mendelian 2:1 yellow/agouti phenotypic ratio in this cross.
2) From your reading of the paper by Michaud et al., at what stage in the organism's development does the AyAy genotype establishes lethality?
3) What is the reason for the lethality of the AyAy genotype? [Hint: Check the Michaud et al. (1993) paper posted in the Minicourse 2 folder.]
4) What is the Raly gene? What does encode? How does it relate to the lethality of Ay?
5) A heterozygous animal AAy does not produce enough pigment and it is yellow. Homozygous individuals die during development, but AAy heterozygous do not. Why? You may use any graphic aid to explain this, if necessary (this means that you may use a Punnett square, a forking segregation diagram), or computations with fractions.
6) Give four examples of lethal alleles in humans, other animals or plants and a brief molecular explanation (i.e., why are they lethal).