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When Mendel's Laws were rediscovered, geneticists believed that mutations would only alter the appearance of a living organism. However, it was discovered that a mutant allele could cause death. When an essential gene is mutated, it can result in a lethal phenotype. If the mutation is caused by a dominant lethal genotype, the heterozygote for the allele will show the lethal phenotype, the homozygote dominant is impossible. If the mutation is caused by a recessive lethal genotype, the homozygote for the allele will have the lethal phenotype.
Lethal genes were first discovered by Lucien Cuénot while studying the inheritance of coat colour gene in mice. He expected a phenotype ratio from a heterozygote cross of 3 yellow:1 white, but the observed ratio was 2:1. By performing test crosses, he determined that all the yellow mice were heterozygotes and that the yellow colour coat was the dominant phenotypic trait. However, no homozygous yellow mice were obtained. In 1910, William Ernest Castle and C. C. Little reaffirmed Cuénot's discovery of a lethal gene by proving that a quarter of the offspring from crosses between heterozygotes died during embryonic development, due to failure to implant in the uterine lining. The quarter that died were the homozygous yellow mice that Cuénot did not see in his tests.
An example of lethal alleles in humans is achondroplasia, a genetic condition which causes dwarfism. Affected individuals are all heterozygotes, as the accumulation of two mutant alleles is lethal and results in the ovum not forming.
Another example of a lethal allele, this time in cats, is the Manx cat. Manx cats, if homozygotic, will not survive. Heterozygotic Manx cats have characteristically short tails.