Some mutations in essential genes may not be compatible with life. These are called lethal alleles. In this section we will focus primarily on lethal alleles that cause a failure of embryonic development, since those can impact expected offspring ratios. Other lethal alleles may cause death in later stages of life and are discussed toward the end of this section.

Diploid organisms have two copies of each gene, so inheritance of one non-functional allele still allows for a backup. However, if both alleles of an essential gene are knocked out, this can block the development of a growing embryo. This happens due to mutations in genes whose functions are essential for the development or survival of the organism. These mutations are called recessive lethal alleles because lethality requires two (homozygous) alleles. Heterozygotes may or may not have a phenotype that is distinct from the homozygotes for the healthy allele, but they survive.

Recessive lethal alleles are common in a laboratory setting, where geneticists use model organisms like mice or fruit flies to study gene function. Recessive lethal alleles affect expected offspring ratios from controlled crosses. The offspring ratios of a monohybrid cross (Aa x Aa) that involves a recessive lethal allele differ from the expected 3:1 phenotypic ratio because there are no individuals homozygous for an embryonic lethal allele detected among offspring.

If the heterozygote has the same phenotype as individuals homozygous for the healthy allele, the offspring will all be of one phenotypic class (essentially, 3:0). In this case, offspring ratios could not predict the presence of a lethal allele. However, if the heterozygote shows a mutant phenotype, the offspring of a monohybrid cross may show a phenotypic ratio of 2 (mutant):1 (wild-type). A 2:1 phenotypic offspring ratio therefore often indicates the presence of a lethal allele.

Some lab studies studying model organisms suggest that about 10-30% of genes may be essential^[1], but naturally-occurring lethal alleles of these genes are rare outside of lab settings.

One example of a recessive lethal allele that is seen outside of the lab is the allele that causes the tail-less Manx phenotype in cats. Manx cats have no tails. A Manx cat is shown in Figure 10a.

All Manx cats are heterozygous for the Manx allele. There are no cats homozygous for the Manx allele, since homozygous embryos die early in development and are never born. There’s no such thing as a true-breeding Manx cat: if two Manx cats are bred together, about 2/3 of the kittens will have no tail and 1/3 of the kittens will have a tail. This illustrated by the Punnett square shown in Figure 10b.

Note: The mutant Manx allele confers a dominant tailless phenotype (heterozygotes have a mutant phenotype!) and is indicated by a capital letter in the Punnett square in Figure 10b. But it is called recessive lethal because lethality is recessive.

An example of recessive lethality in humans is a particular form of dwarfism called achondroplasia. People with achondroplasia have shortened limbs and several other characteristic traits. Achondroplasia is caused by a heterozygous mutation in the gene FGFR3. Although there may be some associated health complications, people with achondroplasia typically can expect a normal lifespan.

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Other examples of lethal alleles

The previous example focused on alleles that cause embryonic lethality, but other lethal alleles may be lethal later in an organism’s lifespan. Alleles that impact viability after birth or even later in life – reducing expected lifespan – can be considered lethal alleles, too, although they won’t affect offspring ratios in the same way that embryonic lethal alleles do.

There are also rare examples of dominant lethal alleles. Dominant alleles causing embryonic lethality do not exist: Although dominant lethal mutations might arise spontaneously as a parent produces egg or sperm, any embryo who carried such a mutation would fail to develop to birth, so such alleles are not maintained in a population. But there are rare examples of dominant lethal alleles that don’t impact viability until later in life, after reproductive maturity. In human populations, an example of dominant lethality allele is the allele that causes Huntington’s disease. Huntington’s disease is a rare neurological disorder resulting from the death of neurons in the brain with associated cognitive decline, psychiatric symptoms, and uncontrollable movements. The onset of symptoms is in middle age, after many patients have had children and passed the dominant allele to their offspring. There is no cure for Huntington’s disease, and patients ultimately die from the progressive degeneration of brain tissue.

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