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Our high school genetics chapter has some extra information about L.Cuenot. It only covered his research, and the fact that mice homozygous for yellow coat color would die before birth. It was an example of a lethal allele.

We have learned about sickle cell anemia, thalassemia, and hemophilia. All of them had a specific reason/mechanism which caused damage. For example, it's not the shape of the red blood cell in itself which is problematic, it is the fact that it can't carry enough oxygen. Therefore the cell will die off much quicker than normal cells.

I asked few of the biology teachers why the yellow coat color was lethal, but they couldn't provide any answer.

My question is, what causes the mice to die before birth?

Links to relevant articles or excerpts from them are highly appreciated.

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    $\begingroup$ Good question! Minor quibble: the shape of red blood cells is very problematic because it can cause sickle cell crisis, the prevention of which is, unhelpfully, "live a life free of physical and mental stressors, have perfect hydration habits, and don't exercise in non-ideal conditions" $\endgroup$ – Punintended Oct 13 '20 at 20:03
  • $\begingroup$ @Punintended Wow! I didn't know about this angle of the clogging of small blood vessels due to their shape. I guess there's only so much they teach you in high school. $\endgroup$ – Amarylis Vaselaar Oct 14 '20 at 4:33
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Really interesting question: The lethal yellow mutation (also abbreviated Ay) affects the agouti signalling protein which plays a major role in pigmentation. Heterozygous expression of it leads to the dominant expression of pheomelanin (which is yellow), causing the mice to express this color (among other effects). To understand why it is homozygous embryonic lethal, we need to take a further look at the gene and its organisation.

Agouti is located on chromosome 2 of the mouse genome and downstream of a gene called "Raly" (synonymous also MERC)(Image from NCBI Genes)

enter image description here

The Ay mutation now deletes a large chunk of DNA, removing about 170kb between these genes. This removes parts of the coding sequence of the Raly gene and the complete promoter and (non-coding) exon1 of the Agouti gene and results in a fusion protein in which the agouti gene is put under the control of the Raly promoter. This leads to the expression of Agouti every time when Raly should be turned on. Schematically, this looks like this (figure 4 from reference 2):

enter image description here

Raly is an RNA binding protein, which is highly expressed in embryonic tissues. The mutation leads to the expressing of Agouti there instead. According to reference 3 this leads to embryos which do not develop further than the blastocyst stage leading to premature death of the embryo.

So in short, the deletion removes the expression of Raly, a protein important for embryonic development. Im homozygous mice this is embryonical lethal, in heterozygous mice this can obviously be compensated. However, these mice tend to be obese and are more susceptible for certain tumors (reference 4).

References:

  1. The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein
  2. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation.
  3. Pleiotropic effects of the mouse lethal yellow (Ay) mutation explained by deletion of a maternally expressed gene and the simultaneous production of agouti fusion RNAs
  4. The molecular basis for dominant yellow agouti coat color mutations
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  • $\begingroup$ It looks like Eif2s2 on the opposite strand would also be deleted in Ay mice. Do you know if this has any effect on the phenotype? It would be interesting to see if researchers knocked in Eif2s2 somewhere else and looked to see if there were any confounding effects. $\endgroup$ – MattDMo Oct 13 '20 at 19:28
  • $\begingroup$ @MattDMo I don't know, but I'll have a look into it tomorrow when I have access to journals again. $\endgroup$ – Chris Oct 13 '20 at 20:01
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    $\begingroup$ In other words, the yellow color is just one obvious manifestation of a more significant syndrome, which under 2 copies becomes massively worse and causes complete failure of the organism? $\endgroup$ – The_Sympathizer Oct 14 '20 at 22:49

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