In one quarter of their offspring, we would expect to observe individuals that are homozygous recessive for the nonfunctional allele. Because the gene is essential, these individuals might fail to develop past fertilization, die in utero, or die later in life, depending on what life stage requires this gene. An inheritance pattern in which an allele is only lethal in the homozygous form and in which the heterozygote may be normal or have some altered non-lethal phenotype is referred to as recessive lethal.
For crosses between heterozygous individuals with a recessive lethal allele that causes death before birth when homozygous, only wild-type homozygotes and heterozygotes would be observed.
The genotypic ratio would therefore be In other instances, the recessive lethal allele might also exhibit a dominant but not lethal phenotype in the heterozygote. For instance, the recessive lethal Curly allele in Drosophila affects wing shape in the heterozygote form, but is lethal in the homozygote.
Affected individuals may also develop anemia when administered therapeutic doses of antimalarial medications and other drugs Allison, Note, however, that the defective glucosephosphate dehydrogenase allele only causes death under certain conditions, which makes it a conditional lethal gene.
But why would this allele be so common? The interesting thing about individuals with the favism allele is that they are resistant to malaria, because it is more difficult for malaria parasites to multiply in cells with deficient amounts of glucosephosphate dehydrogenase.
Therefore, carrying the allele for favism confers an intrinsic genetic or adaptive advantage by protecting individuals from contracting malaria. Conditional lethal genes can also be expressed due to specific circumstances, such as temperature. Meanwhile, the wild-type protein is fully functional at both temperatures.
The condition in which the mutant phenotype is expressed is termed nonpermissive. Meanwhile, the condition in which the wild-type phenotype is expressed is called permissive. In order to study a conditional lethal mutant, the organism must be maintained under permissive conditions and then switched to the nonpermissive condition during the course of a specific experiment.
By developing a conditional lethal version of a dominant lethal gene, scientists can study and maintain organisms carrying dominant lethal alleles. Hemophilia is a hereditary disease caused by deficiencies in clotting factors, which results in impaired blood clotting and coagulation. Because the allele responsible for hemophilia is carried on the X chromosome , affected individuals are predominantly males, and they inherit the allele from their mothers.
Normally, clotting factors help form a temporary scab after a blood vessel is injured to prevent bleeding, but hemophiliacs cannot heal properly after injuries because of their low levels of blood clotting factors. Therefore, affected individuals bleed for a longer period of time until clotting occurs. This means that normally minor wounds can be fatal in a person with hemophilia.
The alleles responsible for hemophilia are thus called semilethal or sublethal genes, because they cause the death of only some of the individuals or organisms with the affected genotype. Scientists studying the fruit fly observed that pairwise combinations of some mutant alleles were not viable, whereas singly, the same mutant alleles did not cause death Boone et al.
In other words, some mutations are only lethal when paired with a second mutation. These genes are called synthetic lethal genes. When the functions of the two affected genes are not fully understood, scientists can create and study synthetic lethal mutants and their phenotypes to identify a gene's function.
Mechanisms can also be hypothesized from the known functions of pairs of mutated alleles. For instance, if both mutations occur in nonessential genes, a scientist could hypothesize that the two genes function in parallel pathways that share information with one another.
Each of the two pathways could compensate for a defect in the other, but when both pathways have a mutation, the combination results in synthetic lethality. Synthetic lethality can also indicate that two affected genes have the same role, and therefore, lethality only results when both copies are nonfunctional and one gene cannot substitute for the other. Additionally, both genes may function in the same essential pathway, and the pathway's function may be diminished by each mutation.
When an allele causes lethality, this is evidence that the gene must have a critical function in an organism. The discoveries of many lethal alleles have provided information on the functions of genes during development. Additionally, scientists can use conditional and synthetic lethal alleles to study the physiological functions and relationships of genes under specific conditions.
Full Screen. Allison, A. Glucosephosphate dehydrogenase deficiency in red blood cells of East Africans. Nature , — doi Baur, E. Berichte der Deutschen Botanischen Gesellschaft 25 , — Boone, C. Exploring genetic interactions and networks with yeast. Nature Reviews Genetics 8 , — doi Bowman, J. Action of Vicia faba on erythrocytes: Possible relationship to favism. Castle, W. On a modified Mendelian ratio among yellow mice.
Science 32 , — Les races pures et leurs combinaisons chez les souris. Archives de Zoologie Experimentale et Generale 4 , — Link, G. The role of genetics in etiological pathology. Quarterly Review of Biology 7 , — Paigen, K.
One hundred years of mouse genetics: An intellectual history. The classical period Genetics , 1—7 Chromosome Theory and the Castle and Morgan Debate. Discovery and Types of Genetic Linkage. In , W. Castle and C. Little demonstrated that when two heterozygotes were crossed, one-quarter of the offspring died during embryonic development.
The failed embryos were homozygous for the mutant agouti-allele suggesting that it is a recessive lethal allele.
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. The progeny never showed the phenotypic ratio expected from a monohybrid cross. Instead, they showed a phenotypic ratio of yellow to grey mice. 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. 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. 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.
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