Lethal alleles (also referred to as lethal genes or lethals) are alleles that cause the death of the organism that carries them. They are usually a result of mutations in genes that are essential for growth or development. Lethal alleles may be recessive, dominant, or conditional depending on the gene or genes involved. Lethal alleles can be embryonically lethal, in which the fetus will never survive to term, or may be lethal perinatally or postnatally after an extended period of apparently normal development. Embryonically lethal alleles are a cause of non-

Mendelian Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later popularize ...

patterns of inheritance, such as the observation of traits in a 2:1 ratio.

History

Lethal alleles were first discovered by

Lucien Cuénot Lucien Claude Marie Julien Cuénot (; 21 October 1866 – 7 January 1951) was a French biologist. In the first half of the 20th century, Mendelism was not a popular subject among French biologists. Cuénot defied popular opinion and shirked the “ ...

in 1905 while studying the inheritance of coat colour in mice. The ''agouti'' gene in mice is largely responsible for determining coat colour. The wild-type allele produces a blend of yellow and black pigmentation in each hair of the mouse. This yellow and black blend may be referred to as 'agouti' in colour. One of the mutant alleles of the ''agouti'' gene results in mice with a much lighter, yellowish colour. When these yellow mice were crossed with

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

mice, a 1:1 ratio of yellow and dark grey offspring were obtained. This indicated that the yellow mutation is dominant, and all the parental yellow mice were heterozygotes for the mutant allele. By mating two yellow mice, Cuénot expected to observe a usual 1:2:1 Mendelian ratio of homozygous agouti to heterozygous yellow to homozygous yellow. Instead, he always observed a 1:2 ratio of agouti to yellow mice. He was unable to produce any mice that were homozygous for the yellow agouti allele. It was not until 1910 that

W. E. Castle William Ernest Castle (October 25, 1867 – June 3, 1962) was an early American geneticist. Early years William Ernest Castle was born on a farm in Ohio and took an early interest in natural history. He graduated in 1889 from Denison Universit ...

and C. C. Little confirmed Cuénot's work, further demonstrating that one quarter of the offspring were dying during embryonic development. This was the first documented example of a recessive lethal allele.

Types of lethal allele

Recessive lethals

A pair of identical alleles that are both present in an organism that ultimately results in death of that organism are referred to as recessive lethal alleles. Though recessive lethals may code for dominant or

recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

traits, they are only fatal in the homozygous condition. Heterozygotes will sometimes display a form of diseased phenotype, as in the case of

achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected ha ...

. One mutant lethal allele can be tolerated, but having two results in death. In the case of homozygous achondroplasia, death almost invariably occurs before birth or in the perinatal period. Not all heterozygotes for recessive lethal alleles will show a mutant

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

, as is the case for

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Ot ...

carriers. If two cystic fibrosis carriers have children, they have a 25 percent chance of producing offspring having two copies of the lethal allele, eventually resulting in the death of the child. Another example are the BRCA mutations; inheriting one defective BRCA allele results in a greatly increased risk of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

and

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

, while inheriting both defective alleles will result in a severe form of

Fanconi anemia Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of no ...

(FANCS for BRCA1, FANCD1 for BRCA2) that is embryonically lethal in most cases. Survivors of homozygous or biallelic BRCA mutations almost never survive to adulthood. For live cases, inheriting both mutations lead to a grave prognosis where survival almost never extends beyond childhood. Another example of a recessive lethal allele occurs in the

Manx cat The Manx cat (, in earlier times often spelled Manks) is a breed of domestic cat (''Felis catus'') originating on the Isle of Man, with a naturally occurring mutation that shortens the tail. Many Manx have a small stub of a tail, but Manx cat ...

. Manx cats possess a heterozygous mutation resulting in a shortened or missing tail. Crosses of two heterozygous Manx cats result in two-thirds of surviving offspring displaying the heterozygous shortened tail phenotype, and one-third of surviving offspring of normal tail length that is homozygous for a normal allele. Homozygous offspring for the mutant allele cannot survive birth and are therefore not seen in these crosses.

Dominant lethals

Alleles that need only be present in one copy in an organism to be fatal are referred to as dominant lethal alleles. These alleles are not commonly found in populations because they usually result in the death of an organism before it can transmit its lethal allele on to its offspring. An example in humans of a dominant lethal allele is Huntington's disease, a rare neurodegenerative disorder that ultimately results in death. However, because of its late-onset (i.e., often after reproduction has already occurred), it is able to be maintained in populations. A person exhibits Huntington's disease when they carry a single copy of a repeat-expanded Huntington allele on chromosome 4.

Conditional lethals

Alleles that will only be fatal in response to some environmental factor are referred to as conditional lethals. One example of a conditional lethal is favism, a sex-linked inherited condition that causes the carrier to develop hemolytic anemia when they eat fava beans. An infection of an '' E. coli'' host cell by a bacteriophage (phage) T4 temperature sensitive (ts) conditionally lethal mutant at a high restrictive temperature leads to lack of viable phage production. However growth of such mutants can still occur at a lower temperature. Such conditionally lethal ts mutants have been used to identify and characterize the function of many of the phage's genes.Edgar RS, Epstein RH. The genetics of a bacterial virus. Sci Am. 1965 Feb;212:70-8. doi: 10.1038/scientificamerican0265-70. PMID: 14272117. Thus genes employed in the repair of DNA damages were identified using ts mutants, as well as genes affecting

genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...

. For example, growing a ts DNA repair mutant at an intermediate temperature will allow some progeny phage to be produced. However, if that ts mutant is irradiated with UV light, its survival will be more strongly reduced compared to the reduction of survival of irradiated wild-type phage T4. In addition, cold sensitive conditional lethal mutants able to grow at high temperatures, but unable to grow at low temperatures, were also isolated in phage T4. These cold sensitive conditional lethal mutants also defined a set of phage genes. Another class of conditional lethal phage T4 mutants, called amber mutants, are able to grow on some strains of ''E. coli'' but not on others.Epstein RH, Bolle A, Steinberg CM. Amber mutants of bacteriophage T4D: their isolation and genetic characterization. Genetics. 2012 Mar;190(3):833-40. doi: 10.1534/genetics.112.138438. PMID: 22419076; PMCID: PMC3296251. These mutants were also used to initially identify and characterize many of the phage T4

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s, including genes whose encoded proteins function in

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritan ...

and molecular

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

. In addition, it was found that an amber mutation produces a "nonsense codon" within a gene that causes polypeptide chain termination during

translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

. This finding provided insight into a significant aspect of the

genetic code The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

. 4.Balanced lethals 6. Genetic lethals

References