Lethal allele

Last updated

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 may be recessive, dominant, or conditional depending on the gene or genes involved.

Contents

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 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 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 traits, they are only fatal in the homozygous condition.

Heterozygotes will sometimes display a form of diseased phenotype, as in the case of achondroplasia. [4] 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, 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 lethal allele, eventually resulting in the death of the child. [5] Another example 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 will result in a severe form of Fanconi anemia (FA-S for BRCA1, FA-D1 for BRCA2) that is embryonically lethal in most cases. Survivors of homozygous or biallelic BRCA mutations almost never survive to adulthood. [6] For live cases, inheriting both mutations lead to a grave prognosis where survival almost never extends beyond childhood. [7]

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. [8]

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. [4] 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. [9]

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. [4]

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. [10] Thus genes employed in the repair of DNA damages were identified using ts mutants, [11] [12] as well as genes affecting genetic recombination. [13] [14] 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. [15] 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. [10] [16] [17] 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

<span class="mw-page-title-main">Dominance (genetics)</span> One gene variant masking the effect of another in the other copy of the gene

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 and the second is called recessive. This state of having two different variants of the same gene on each chromosome is originally caused by a mutation in one of the genes, either new or inherited. The terms autosomal dominant or autosomal recessive are used to describe gene variants on non-sex chromosomes (autosomes) and their associated traits, while those on sex chromosomes (allosomes) are termed X-linked dominant, X-linked recessive or Y-linked; these have an inheritance and presentation pattern that depends on the sex of both the parent and the child. Since there is only one copy of the Y chromosome, Y-linked traits cannot be dominant or recessive. Additionally, there are other forms of dominance, such as incomplete dominance, in which a gene variant has a partial effect compared to when it is present on both chromosomes and co-dominance, in which different variants on each chromosome both show their associated traits.

Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.

<i>Escherichia virus T4</i> Species of bacteriophage

Escherichia virus T4 is a species of bacteriophages that infect Escherichia coli bacteria. It is a double-stranded DNA virus in the subfamily Tevenvirinae from the family Myoviridae. T4 is capable of undergoing only a lytic life cycle and not the lysogenic life cycle. The species was formerly named T-even bacteriophage, a name which also encompasses, among other strains, Enterobacteria phage T2, Enterobacteria phage T4 and Enterobacteria phage T6.

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

Equine coat color genetics determine a horse's coat color. Many colors are possible, but all variations are produced by changes in only a few genes. Bay is the most common color of horse, followed by black and chestnut. A change at the agouti locus is capable of turning bay to black, while a mutation at the extension locus can turn bay or black to chestnut.

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 be used to 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. The complementation test was developed by American geneticist Edward B. Lewis.

A null allele is a nonfunctional allele caused by a genetic mutation. Such mutations can cause a complete lack of production of the associated gene product or a product that does not function properly; in either case, the allele may be considered nonfunctional. A null allele cannot be distinguished from deletion of the entire locus solely from phenotypic observation.

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

Ethyl methanesulfonate (EMS) is a mutagenic, teratogenic, and carcinogenic organic compound with formula C3H8SO3. It produces random mutations in genetic material by nucleotide substitution; particularly through G:C to A:T transitions induced by guanine alkylation. EMS typically produces only point mutations. Due to its potency and well understood mutational spectrum, EMS is the most commonly used chemical mutagen in experimental genetics. Mutations induced by EMS exposure can then be studied in genetic screens or other assays.

Inbreeding depression is the reduced biological fitness which has the potential to result from inbreeding. Biological fitness refers to an organism's ability to survive and perpetuate its genetic material. Inbreeding depression is often the result of a population bottleneck. In general, the higher the genetic variation or gene pool within a breeding population, the less likely it is to suffer from inbreeding depression, though inbreeding and outbreeding depression can simultaneously occur.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive alleles in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive alleles. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

<span class="mw-page-title-main">Agouti-signaling protein</span> Protein-coding gene in the species Homo sapiens

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.

Balancer chromosomes are a type of genetically engineered chromosome used in laboratory biology for the maintenance of recessive lethal mutations within living organisms without interference from natural selection. Since such mutations are viable only in heterozygotes, they cannot be stably maintained through successive generations and therefore continually lead to production of wild-type organisms, which can be prevented by replacing the homologous wild-type chromosome with a balancer. In this capacity, balancers are crucial for genetics research on model organisms such as Drosophila melanogaster, the common fruit fly, for which stocks cannot be archived. They can also be used in forward genetics screens to specifically identify recessive lethal mutations. For that reason, balancers are also used in other model organisms, most notably the nematode worm Caenorhabditis elegans and the mouse.

A nonsense suppressor is a factor which can inhibit the effect of the nonsense mutation. Nonsense suppressors can be generally divided into two classes: a) a mutated tRNA which can bind with a termination codon on mRNA; b) a mutation on ribosomes decreasing the effect of a termination codon. It is believed that nonsense suppressors keep a low concentration in the cell and do not disrupt normal translation most of the time. In addition, many genes do not have only one termination codon, and cells commonly use ochre codons as the termination signal, whose nonsense suppressors are usually inefficient.

Temperature-sensitive mutants are variants of genes that allow normal function of the organism at low temperatures, but altered function at higher temperatures. Cold sensitive mutants are variants of genes that allow normal function of the organism at higher temperatures, but altered function at low temperatures.

The phage group was an informal network of biologists centered on Max Delbrück that contributed heavily to bacterial genetics and the origins of molecular biology in the mid-20th century. The phage group takes its name from bacteriophages, the bacteria-infecting viruses that the group used as experimental model organisms. In addition to Delbrück, important scientists associated with the phage group include: Salvador Luria, Alfred Hershey, Seymour Benzer, Charles Steinberg, Gunther Stent, James D. Watson, Frank Stahl, and Renato Dulbecco.

The T4 rII system is an experimental system developed in the 1950s by Seymour Benzer for studying the substructure of the gene. The experimental system is based on genetic crosses of different mutant strains of bacteriophage T4, a virus that infects the bacteria Escherichia coli.

The term proofreading is used in genetics to refer to the error-correcting processes, first proposed by John Hopfield and Jacques Ninio, involved in DNA replication, immune system specificity, enzyme-substrate recognition among many other processes that require enhanced specificity. The proofreading mechanisms of Hopfield and Ninio are non-equilibrium active processes that consume ATP to enhance specificity of various biochemical reactions.

<span class="mw-page-title-main">Zygosity</span> Degree of similarity of the alleles in an organism

Zygosity 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.

Robert Stuart Edgar was a geneticist.

Charles 'Charley' M. Steinberg was an immunobiologist and permanent member of the Basel Institute for Immunology. He was a former student of Max Delbrück. Notably he hosted Richard Feynman at Caltech when Feynman studied molecular biology, leading Feynman to remark that Charlie was “...the smartest guy I know”. He was instrumental in the discovery of V(D)J recombination, bacteriophage genetics as part of the phage group and co-discoverer of the amber-mutant of the T4 bacteriophage that led to the recognition of stop codons.

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.

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. 1 2 3 Lobo, I (2008). "Mendelian Ratios and Lethal Genes". Nature Education. 1 (1): 138.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Robinson, R (1993). "Expressivity of the Manx Gene in Cats". J Hered. 84 (3): 170–2. doi:10.1093/oxfordjournals.jhered.a111311. PMID   8228170.
  9. ↑ 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.
  10. 1 2 Edgar RS, Epstein RH. The genetics of a bacterial virus. Sci Am. 1965 Feb;212:70-8. doi: 10.1038/scientificamerican0265-70. PMID: 14272117.
  11. ↑ Baldy MW. The UV sensitivity of some early-function temperature-sensitive mutants of phage T4. Virology. 1970 Feb;40(2):272-87. doi: 10.1016/0042-6822(70)90403-4. PMID: 4909413.
  12. ↑ Baldy MW, Strom B, Bernstein H. Repair of alkylated bacteriophage T4 deoxyribonucleic acid by a mechanism involving polynucleotide ligase. J Virol. 1971 Mar;7(3):407-8. doi: 10.1128/JVI.7.3.407-408.1971. PMID: 4927528; PMCID: PMC356131.
  13. ↑ Bernstein H. The effect on recombination of mutational defects in the DNA-polymerase and deoxycytidylate hydroxymethylase of phage T4D. Genetics. 1967 Aug;56(4):755-69. PMID: 6061665; PMCID: PMC1211652.
  14. ↑ Bernstein H. Repair and recombination in phage T4. I. Genes affecting recombination. Cold Spring Harb Symp Quant Biol. 1968;33:325-331. doi:10.1101/sqb.1968.033.01.037
  15. ↑ Scotti PD. A new class of temperature conditional lethal mutants of bacteriophage T4D. Mutat Res. 1968 Jul-Aug;6(1):1-14. doi: 10.1016/0027-5107(68)90098-5. PMID: 4885498.
  16. ↑ Epstein RH, Bolle A, Steinberg CM, Stahl FW. Amber mutants of bacteriophage T4D: their isolation and genetic characterization. Genetics. 2012 Mar;190(3):831-40. doi: 10.1534/genetics.112.138438. PMID: 22518878.
  17. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.