12.10 : Lethal Alleles

Agouti: A Lethal Allele

Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow mouse obesity syndrome, characterized by early onset of obesity and tumors.

In a breeding experiment, Cuénot crossed two yellow mice and observed that two offspring were yellow and one was gray. The progeny never showed the 3:1 phenotypic ratio expected from a monohybrid cross. Instead, they showed a 2:1 phenotypic ratio of yellow to grey mice.

In 1910, W.E. Castle and C.C. Little demonstrated that the missing yellow mice were dying in the embryonic stage. The embryo carried both recessive mutant alleles, a homozygous condition that affects the differentiation of both the inner cell mass (ICM) and trophectoderm, the outer layer of the blastocyst.

Lethal Alleles in Humans

Some recessive lethal alleles cause genetic disorders in humans. For example, achondroplasia is a genetic disorder that affects bone development resulting in short-limbed dwarfism. It is caused by a dominant allele, which means the presence of a single copy of the mutated allele causes the disorder. However, when the same allele is present in homozygous form, it becomes lethal and causes death during embryonic development. Even though the disease is caused by a dominant allele, the lethality is recessive; hence, it is called a recessive lethal allele.

Similarly, dominant lethal alleles can also cause genetic disorders in humans. Such lethal alleles cause death even if they are present in a single copy. Mostly, these alleles are hard to find in a population because it causes the early death of an organism. An example of a dominant lethal allele is Huntington’s disease, a fatal neurological disorder. The onset of this disease is slow, which allows heterozygotes to survive after birth. If the person survives until the reproductive age, the genes are passed on to their offspring. This way, the allele persists in the population.