Lethal allele

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Lethal alleles (also referred to as lethal 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. [1] Lethal alleles can be recessive, dominant, conditional, perinatal, or postnatal after an extended period of apparently normal development depending on the gene or genes involved.

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Lethal alleles may specifically refer to embryonically lethal alleles, in which the fetus will never survive to term. Such alleles are a cause of non-Mendelian patterns of inheritance, such as the observation of traits in a 2:1 ratio.

History

Punnett square for the agouti gene in mice, demonstrating a recessive lethal allele. Lethal alleles punnett square.svg
Punnett square for the agouti gene in mice, demonstrating a recessive lethal allele.

Lethal alleles were first discovered by Lucien Cuénot 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. [3] 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 wild-type 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 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 embryonic lethal allele.

Types of lethal allele

Lethal alleles can also refer to any allele that can result in a terminal condition.

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 traits, they are only fatal in the homozygous condition. Heterozygotes will sometimes display a form of diseased phenotype in addition to an apparently dominant phenotype, as yellow mice are particularly susceptible to diabetes and obesity. [4]

An example of a lethal allele in humans are the BRCA mutations; inheriting one defective BRCA allele results in a greatly increased risk of breast cancer and ovarian cancer, while inheriting both defective alleles is embryonically lethal in almost all cases. [5] For live cases, inheriting both mutations lead to a grave prognosis where survival almost never extends beyond childhood. [6] This is because the BRCA mutations also result in a severe subtype of Fanconi anemia (FA-S for BRCA1, FA-D1 for BRCA2), itself an extremely rare medical condition.

Another example of a recessive lethal allele occurs in the 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. [7]

A lethal allele may refer to any allele encoding the disease that results in a terminal condition only in the homozygous or biallelic state. The heterozygous and homozygous phenotype is still expressed in most cases if two different disease-causing alleles are present. Achondroplasia is a skeletal system disorder caused by a recessive allele that can still result in a live birth in the homozygous state. [8] One mutant allele for achondroplasia 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, as is the case for cystic fibrosis carriers. If two cystic fibrosis carriers have children, they have a 25 percent chance of producing offspring having two copies of the allele, eventually resulting in the death of the child without intensive treatment. [9]

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. As a result, few dominant embryonically lethal alleles are documented as they would never show up in the population.

[8] An example in humans of a dominant lethal allele is Huntington's disease, a rare neurodegenerative disorder that ultimately results in premature 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. [10]

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. [8]

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. [11] Thus genes employed in the repair of DNA damages were identified using ts mutants, [12] [13] as well as genes affecting genetic recombination. [14] [15] 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. [16] 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. [11] [17] [18] These mutants were also used to initially identify and characterize many of the phage T4 genes, including genes whose encoded proteins function in DNA repair, genetic recombination, DNA replication and molecular morphogenesis. In addition, it was found that an amber mutation produces a "nonsense codon" within a gene that causes polypeptide chain termination during translation. This finding provided insight into a significant aspect of the genetic code.

See also

Related Research Articles

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<span class="mw-page-title-main">ENU</span> Chemical compound

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<span class="mw-page-title-main">Equine coat color genetics</span> Genetics behind the equine coat color

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<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

Complementation refers to a genetic process when two strains of an organism with different homozygous recessive mutations that produce the same mutant phenotype have offspring that express the wild-type phenotype when mated or crossed. Complementation will ordinarily occur if the mutations are in different genes. Complementation may also occur if the two mutations are at different sites within the same gene, but this effect is usually weaker than that of intergenic complementation. When the mutations are in different genes, each strain's genome supplies the wild-type allele to "complement" the mutated allele of the other strain's genome. Since the mutations are recessive, the offspring will display the wild-type phenotype. A complementation test can test whether the mutations in two strains are in different genes. Complementation is usually weaker or absent if the mutations are in the same gene. The convenience and essence of this test is that the mutations that produce a phenotype can be assigned to different genes without the exact knowledge of what the gene product is doing on a molecular level. American geneticist Edward B. Lewis developed the complementation test.

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Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.

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Dominant white (W) is a group of genetically related coat color alleles on the KIT gene of the horse, best known for producing an all-white coat, but also able to produce various forms of white spotting, as well as bold white markings. Prior to the discovery of the W allelic series, many of these patterns were described by the term sabino, which is still used by some breed registries.

<span class="mw-page-title-main">International Mouse Phenotyping Consortium</span>

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The agouti gene, the Agouti-signaling protein (ASIP) is responsible for variations in color in many species. Agouti works with extension to regulate the color of melanin which is produced in hairs. The agouti protein causes red to yellow pheomelanin to be produced, while the competing molecule α-MSH signals production of brown to black eumelanin. In wildtype mice, alternating cycles of agouti and α-MSH production cause agouti coloration. Each hair has bands of yellow which grew during agouti production, and black which grew during α-MSH production. Wildtype mice also have light-colored bellies. The hairs there are a creamy color the whole length because the agouti protein was produced the whole time the hairs were growing.

<span class="mw-page-title-main">Balanced lethal systems</span>

In evolutionary biology, a balanced lethal system is a situation where recessive lethal alleles are present on two homologous chromosomes. Each of the chromosomes in such a pair carries a different lethal allele, which is compensated for by the functioning allele on the other chromosome. Since both these lethal alleles end up in the gametes in the same frequency as the functioning alleles, half of the offspring, the homozygotes, receive two copies of a lethal allele and therefore die during development. In such systems, only the heterozygotes survive.

References

  1. ↑ Gluecksohn-Waelsch, Salome (1963). "Lethal Genes and Analysis of Differentiation". Science. 142 (3597): 1269–76. Bibcode:1963Sci...142.1269G. doi:10.1126/science.142.3597.1269. PMID   14074837. S2CID   46113268.
  2. ↑ Mouse Genomes Informatic
  3. ↑ Hartwell, Leland; Hood, Leroy; Goldberg, Michael; Reynolds, Ann; Silver, Lee; Karagiannis, Jim; Papaconstantinou, Maria (2014). Genetics: From Genes to Genomes. Canada: McGraw-Hill Ryerson. pp. 39–42. ISBN   978-0-07-094669-9.
  4. ↑ Moussa NM, Claycombe KJ (1999). "The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity". Obes Res. 7 (5): 506-14. doi:10.1002/j.1550-8528.1999.tb00440.x. PMID   10509609.
  5. ↑ Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA (2014). "Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype". Cancer Discov. 5 (2): 135–42. doi:10.1158/2159-8290.CD-14-1156. PMC   4320660 . PMID   25472942.
  6. ↑ Maxwell, KN, Patel, V, Nead, KT, et al. (2013). "Fanconi anemia caused by biallelic inactivation of BRCA2 can present with an atypical cancer phenotype in adulthood". Clinical Genetics. 103 (1): 119–124. doi:10.1111/cge.14231. PMC   9742260 . PMID   36089892. S2CID   252198281.
  7. ↑ Robinson, R (1993). "Expressivity of the Manx Gene in Cats". J Hered. 84 (3): 170–2. doi:10.1093/oxfordjournals.jhered.a111311. PMID   8228170.
  8. 1 2 3 Lobo, I (2008). "Mendelian Ratios and Lethal Genes". Nature Education. 1 (1): 138.
  9. ↑ Ratjen, Felix; Döring, Gerd (February 2003). "Cystic fibrosis". Lancet. 361 (9358): 681–689. doi:10.1016/S0140-6736(03)12567-6. PMID   12606185. S2CID   24879334.
  10. ↑ Roos, Raymund AC (2010). "Huntington's disease: a clinical review". Orphanet Journal of Rare Diseases. 5 (1): 40. doi: 10.1186/1750-1172-5-40 . PMC   3022767 . PMID   21171977.
  11. 1 2 Edgar RS, Epstein RH (February 1965). "The genetics of a bacterial virus". Sci Am. 212: 70–8. doi:10.1038/scientificamerican0265-70. PMID   14272117.
  12. ↑ Baldy MW (February 1970). "The UV sensitivity of some early-function temperature-sensitive mutants of phage T4". Virology. 40 (2): 272–87. doi:10.1016/0042-6822(70)90403-4. PMID   4909413.
  13. ↑ Baldy MW, Strom B, Bernstein H (March 1971). "Repair of alkylated bacteriophage T4 deoxyribonucleic acid by a mechanism involving polynucleotide ligase". J Virol. 7 (3): 407–8. doi:10.1128/JVI.7.3.407-408.1971. PMC   356131 . PMID   4927528.
  14. ↑ Bernstein H (August 1967). "The effect on recombination of mutational defects in the DNA-polymerase and deoxycytidylate hydroxymethylase of phage T4D". Genetics. 56 (4): 755–69. doi:10.1093/genetics/56.4.755. PMC   1211652 . PMID   6061665.
  15. ↑ Bernstein H (1968). "Repair and recombination in phage T4. I. Genes affecting recombination". Cold Spring Harb Symp Quant Biol. 33: 325–31. doi:10.1101/sqb.1968.033.01.037. PMID   4891972.
  16. ↑ Scotti PD (1968). "A new class of temperature conditional lethal mutants of bacteriophage T4D". Mutat Res. 6 (1): 1–14. doi:10.1016/0027-5107(68)90098-5. PMID   4885498.
  17. ↑ Epstein RH, Bolle A, Steinberg CM, Stahl FW (March 2012). "Amber mutants of bacteriophage T4D: their isolation and genetic characterization". Genetics. 190 (3): 831–40. doi:10.1534/genetics.112.138438. PMC   3296251 . PMID   22518878.
  18. ↑ Epstein RH, Bolle A, Steinberg CM (March 2012). "Amber mutants of bacteriophage T4D: their isolation and genetic characterization". Genetics. 190 (3): 833–40. doi:10.1534/genetics.112.138438. PMC   3296251 . PMID   22419076.
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