Mutation

In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements.[1]

Mutations result from errors during DNA replication (especially during meiosis) or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair (especially microhomology-mediated end joining[2]), or cause an error during other forms of repair,[3][4] or else may cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.[5][6][7] Mutations may or may not produce discernible changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity.

The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double stranded (as in DNA) or single stranded. In some of these viruses (such as the single stranded human immunodeficiency virus) replication occurs quickly and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.

Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial.[8] Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.[5]

Darwin Hybrid Tulip Mutation 2014-05-01
A tulip flower exhibiting a partially yellow petal because of a mutation in its genes.

Description

Mutations can involve the duplication of large sections of DNA, usually through genetic recombination.[9] These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years.[10] Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology.[11] Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.[12][13]

Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties.[14] For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision; all four arose from a single ancestral gene.[15] Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function.[16][17] Other types of mutation occasionally create new genes from previously noncoding DNA.[18][19]

Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes.[20] In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.[21]

Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes.[22] For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression.[23] Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.[6]

Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation.[24] The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.

Prodryas
Prodryas persephone, a Late Eocene butterfly

For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.

Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness.[25][26] Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.

Beneficial mutations can improve reproductive success.[27][28]

History

Hugo de Vries (1848-1935), by Thérèse Schwartze (1851-1918)
Hugo de Vries, making a painting of an evening primrose, the plant which had apparently produced new forms by large mutations in his experiments, by Thérèse Schwartze, 1918

Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously,[29] in a sudden jump.[30] This was envisaged as driving evolution, which was limited by the supply of mutations.

Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation.[31] Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory.[32] In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie,[33][29] became a rival to Darwinism supported for a while by geneticists including William Bateson,[34] Thomas Hunt Morgan, and Reginald Punnett.[35][29]

Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher.[36][37][38][39] However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule,[40] and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.[37][38]

Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule.[41][42] In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited.[43] Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.[44]

Causes

Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.

One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited.[45]

Humans on average pass 60 new mutations to their children but fathers pass more mutations depending on their age with every year adding two new mutations to a child.[46]

Spontaneous mutation

Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:[47]

  • Tautomerism — A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication.
  • Depurination — Loss of a purine base (A or G) to form an apurinic site (AP site).
  • DeaminationHydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
  • Slipped strand mispairing — Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.
  • Replication slippage

Error-prone replication bypass

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats.[48] In mice, the majority of mutations are caused by translesion synthesis.[49] Likewise, in yeast, Kunz et al.[50] found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translation synthesis.

Errors introduced during DNA repair

Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations.[51]

Benzopyrene DNA adduct 1JDG
A covalent adduct between the metabolite of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA[52]

Induced mutation

Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.

Induced mutations on the molecular level can be caused by:

Gene structure eukaryote 2 annotated
This figure depicts the following processes of transcription, splicing, and translation of a eukaryotic gene.

Classification of types

By effect on structure

Chromosomes mutations-en
Five types of chromosomal mutations.
Notable mutations
Selection of disease-causing mutations, in a standard table of the genetic code of amino acids.[55]

The sequence of a gene can be altered in a number of ways.[56] Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Mutations in the structure of genes can be classified into several types.

Small-scale mutations

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:

  • Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element.
  • Deletions remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might in theory be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all.
  • Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.[57] These changes are classified as transitions or transversions.[58] Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mis-pairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). A point mutation are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.

Large-scale mutations

Large-scale mutations in chromosomal structure include:

  • Amplifications (or gene duplications) leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
  • Deletions of large chromosomal regions, leading to loss of the genes within those regions.
  • Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl).
  • Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
    • Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.
    • Chromosomal inversions: reversing the orientation of a chromosomal segment.
    • Non-homologous chromosomal crossover.
    • Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
  • Loss of heterozygosity: loss of one allele, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.

By effect on function

  • Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency).
  • Gain-of-function mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as dominant phenotypes. Several of Muller's morphs correspond to gain of function, including hypermorph and neomorph. In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses."[59]
  • Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53,[60] ATM,[61] CEBPA[62] and PPARgamma[63]). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix.[64] Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[65][66]
  • Hypomorphs, after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele.
  • Neomorphs are characterized by the control of new protein product synthesis.
  • Lethal mutations are mutations that lead to the death of the organisms that carry the mutations.
  • A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.[67]

By effect on fitness

In applied genetics, it is usual to speak of mutations as either harmful or beneficial.

  • A harmful, or deleterious, mutation decreases the fitness of the organism.
  • A beneficial, or advantageous mutation increases the fitness of the organism. Mutations that promotes traits that are desirable, are also called beneficial. In theoretical population genetics, it is more usual to speak of mutations as deleterious or advantageous than harmful or beneficial.
  • A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level.
  • A nearly neutral mutation is a mutation that may be slightly deleterious or advantageous, although most nearly neutral mutations are slightly deleterious.

Distribution of fitness effects

Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation,[68] the rate of genomic decay,[69] the maintenance of outcrossing sexual reproduction as opposed to inbreeding[70] and the evolution of sex and genetic recombination.[71] In summary, the DFE plays an important role in predicting evolutionary dynamics.[72][73] A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.

  • Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant.[74][75][76][77] In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10.[78] In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput.[79] However, given that many mutations have effects too small to be detected[80] and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence data analysis can provide valuable information about these mutations.
DFE in VSV
The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.[74]
  • Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data.[81][82][83][84] By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations.[24] To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.

One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral.[85][25] Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations.[86] Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus.[74] Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast.[79] In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.

Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes.[87] Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie[88] and H. Allen Orr.[89] They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.[90][91][92]

In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species.[24] In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.[24]

By impact on protein sequence

  • A frameshift mutation is a mutation caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original.[93] The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
  • A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
    • A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.)
    • A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can in turn be classified as nonsense or missense mutations:
      • A missense mutation or changes a nucleotide is to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.[94] On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
      • A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different mutations, such as congenital adrenal hyperplasia. (See Stop codon.)

By inheritance

Portulaca grandiflora mutant1
A mutation has caused this moss rose plant to produce flowers of different colors. This is a somatic mutation that may also be passed on in the germline.

In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations),[95] which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

A germline mutation gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent.[96]

The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline. A new germline mutation not inherited from either parent is called a de novo mutation.

Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types.

  • A heterozygous mutation is a mutation of only one allele.
  • A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
  • Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.[97]

A wild type or homozygous non-mutated organism is one in which neither allele is mutated.

Special classes

  • Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).[98] These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.[99] The permissive conditions may be temperature,[100] certain chemicals,[101] light[101] or mutations in other parts of the genome.[99] In vivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand.[102] Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms.[101] DNA Recombinase systems like Cre-Lox Recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes.[101] Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss of function mutations at other temperatures.[103] Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan.[100]
  • Replication timing quantitative trait loci affects DNA replication.

Nomenclature

In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,[104] which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.

  • Nucleotide substitution (e.g., 76A>T) — The number is the position of the nucleotide from the 5' end; the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
    • If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that, for mutations in RNA, the nucleotide code is written in lower case.
  • Amino acid substitution (e.g., D111E) — The first letter is the one letter code of the wild-type amino acid, the number is the position of the amino acid from the N-terminus, and the second letter is the one letter code of the amino acid present in the mutation. Nonsense mutations are represented with an X for the second amino acid (e.g. D111X).
  • Amino acid deletion (e.g., ΔF508) — The Greek letter Δ (delta) indicates a deletion. The letter refers to the amino acid present in the wild type and the number is the position from the N terminus of the amino acid were it to be present as in the wild type.

Mutation rates

Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. Some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene. One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, this will probably be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial.[8] Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.[105]

If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision. On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism, and certain mutations can cause the cell to become malignant, and, thus, cause cancer.[106]

A DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired. DNA repair pathways can only recognize and act on "abnormal" structures in the DNA. Once a mutation occurs in a gene sequence it then has normal DNA structure and cannot be repaired.

Beneficial mutations

Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following:

HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes.[107] One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection; thus its frequency in the population increased.[108] This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.[109]

Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait).[110] Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.

Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection.[111] Obviously, such mutations are only beneficial for the bacteria but not for those infected.

Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is probably one of the most beneficial mutations in recent human evolution.[112]

Prion mutations

Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication.[113] The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

Somatic mutation

A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation.[95] Somatic mutations are not inherited because they do not affect the germline. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer.[114]

With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange.[115]

Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.[116]

Amorphic mutations

An amorph, a term utilized by Muller in 1932, is a mutated allele, which has lost the ability of the parent (whether wild type or any other type) allele to encode any functional protein. An amorphic mutation may be caused by the replacement of an amino acid that deactivates an enzyme or by the deletion of part of a gene that produces the enzyme.

Cells with heterozygous mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens all the time in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer.[117]

Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.

Hypomorphic and hypermorphic mutations

A hypomorphic mutation is a replacement of amino acids that would hinder enzyme activity, which would reduce the enzyme level but not to the point of complete loss. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant.

A hypermorphic mutation changes the regulation of the gene and causes it to overproduce the gene produce causing a greater than normal enzyme levels. These type of alleles are dominant gain of function type of alleles.

See also

  • Portal-puzzle.svg Mutations portal

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.hack (video game series)

.hack () is a series of single-player action role-playing video games developed for the PlayStation 2 console by CyberConnect2 and published by Bandai. The series of four games, titled .hack//Infection, .hack//Mutation, .hack//Outbreak, and .hack//Quarantine, features a "game within a game"; a fictional massively multiplayer online role-playing game (MMORPG) called The World which does not require the player to connect to the Internet. Players may transfer their characters and data between games in the series. Each game comes with an extra DVD containing an episode of .hack//Liminality, the accompanying original video animation series which details fictional events that occur concurrently with the games.

The games are part of a multimedia franchise called Project .hack which explores the mysterious origins of The World. Set after the events of the anime series .hack//Sign, the games focus on a player named Kite and his quest to discover why some users have become comatose as a result of playing The World. The search evolves into a deeper investigation of The World and its effects on the stability of the Internet.

Critics gave the series mixed reviews. It was praised for its unique setting and its commitment to preserve suspension of disbelief, as well as the character designs. However, it was criticized for uneven pacing and a lack of improvement between games. The commercial success of the franchise led to the production of .hack//frägment—a remake of the series with online capabilities—and .hack//G.U., another video game trilogy.

Chromosome abnormality

A chromosome abnormality, disorder, anomaly, aberration, or mutation is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. The term "karyotype" refers to the full set of chromosomes from an individual; this can be compared to a "normal" karyotype for the species via genetic testing. A chromosome anomaly may be detected or confirmed in this manner. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies.

Deletion (genetics)

In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is lost during DNA replication. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome. The smallest single base deletion mutations are believed to occur by a single base flipping in the template DNA, followed by template DNA strand slippage, within the DNA polymerase active site. Deletions can be caused by errors in chromosomal crossover during meiosis, which causes several serious genetic diseases. Deletions that do not occur in multiples of three bases can cause a frameshift by changing the 3-nucleotide protein reading frame of the genetic sequence. The examples are given below of types and effects of deletions are representative of eukaryotic organisms, particularly humans, but are not relevant to prokaryotic organisms such as bacteria.

Evolution

Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes that are passed on from parent to offspring during reproduction. Different characteristics tend to exist within any given population as a result of mutation, genetic recombination and other sources of genetic variation. Evolution occurs when evolutionary processes such as natural selection (including sexual selection) and genetic drift act on this variation, resulting in certain characteristics becoming more common or rare within a population. It is this process of evolution that has given rise to biodiversity at every level of biological organisation, including the levels of species, individual organisms and molecules.The scientific theory of evolution by natural selection was proposed by Charles Darwin and Alfred Russel Wallace in the mid-19th century and was set out in detail in Darwin's book On the Origin of Species (1859). Evolution by natural selection was first demonstrated by the observation that more offspring are often produced than can possibly survive. This is followed by three observable facts about living organisms: 1) traits vary among individuals with respect to their morphology, physiology and behaviour (phenotypic variation), 2) different traits confer different rates of survival and reproduction (differential fitness) and 3) traits can be passed from generation to generation (heritability of fitness). Thus, in successive generations members of a population are more likely to be replaced by the progenies of parents with favourable characteristics that have enabled them to survive and reproduce in their respective environments. In the early 20th century, other competing ideas of evolution such as mutationism and orthogenesis were refuted as the modern synthesis reconciled Darwinian evolution with classical genetics, which established adaptive evolution as being caused by natural selection acting on Mendelian genetic variation.All life on Earth shares a last universal common ancestor (LUCA) that lived approximately 3.5–3.8 billion years ago. The fossil record includes a progression from early biogenic graphite, to microbial mat fossils, to fossilised multicellular organisms. Existing patterns of biodiversity have been shaped by repeated formations of new species (speciation), changes within species (anagenesis) and loss of species (extinction) throughout the evolutionary history of life on Earth. Morphological and biochemical traits are more similar among species that share a more recent common ancestor, and can be used to reconstruct phylogenetic trees.Evolutionary biologists have continued to study various aspects of evolution by forming and testing hypotheses as well as constructing theories based on evidence from the field or laboratory and on data generated by the methods of mathematical and theoretical biology. Their discoveries have influenced not just the development of biology but numerous other scientific and industrial fields, including agriculture, medicine and computer science.

Founder effect

In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall Wright. As a result of the loss of genetic variation, the new population may be distinctively different, both genotypically and phenotypically, from the parent population from which it is derived. In extreme cases, the founder effect is thought to lead to the speciation and subsequent evolution of new species.

In the figure shown, the original population has nearly equal numbers of blue and red individuals. The three smaller founder populations show that one or the other color may predominate (founder effect), due to random sampling of the original population. A population bottleneck may also cause a founder effect, though it is not strictly a new population.

The founder effect occurs when a small group of migrants that is not genetically representative of the population from which they came establish in a new area. In addition to founder effects, the new population is often a very small population, so shows increased sensitivity to genetic drift, an increase in inbreeding, and relatively low genetic variation.

Frameshift mutation

A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame (the grouping of the codons), resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted. A frameshift mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional.

Frameshift mutations are apparent in severe genetic diseases such as Tay–Sachs disease; they increase susceptibility to certain cancers and classes of familial hypercholesterolaemia; in 1997, a frameshift mutation was linked to resistance to infection by the HIV retrovirus. Frameshift mutations have been proposed as a source of biological novelty, as with the alleged creation of nylonase, however, this interpretation is controversial. A study by Negoro et al (2006) found that a frameshift mutation was unlikely to have been the cause and that rather a two amino acid substitution in the active site of an ancestral esterase resulted in nylonase.

Genetic disorder

A genetic disorder is a genetic problem caused by one or more abnormalities formed in the genome. Most genetic disorders are quite rare and affect one person in every several thousands or millions. The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying Amelogenesis imperfecta.Genetic disorders may be hereditary, meaning that they are passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations or changes to the DNA. In such cases, the defect will only be passed down if it occurs in the germline.

Some types of recessive gene disorders confer an advantage in certain environments when only one copy of the gene is present.

Haplogroup

A haplotype is a group of alleles in an organism that are inherited together from a single parent, and a haplogroup (haploid from the Greek: ἁπλούς, haploûs, "onefold, simple" and English: group) is a group of similar haplotypes that share a common ancestor with a single-nucleotide polymorphism mutation. More specifically, a haplogroup is a combination of alleles at different chromosomes regions that are closely linked and that tend to be inherited together. As a haplogroup consists of similar haplotypes, it is usually possible to predict a haplogroup from haplotypes. Haplogroups pertain to a single line of descent. As such, membership of a haplogroup, by any individual, relies on a relatively small proportion of the genetic material possessed by that individual.

Each haplogroup originates from, and remains part of, a preceding single haplogroup (or paragroup). As such, any related group of haplogroups may be precisely modelled as a nested hierarchy, in which each set (haplogroup) is also a subset of a single broader set (as opposed, that is, to biparental models, such as human family trees).

Haplogroups are normally identified by an initial letter of the alphabet, and refinements consist of additional number and letter combinations, such as (for example) A → A1 → A1a.

In human genetics, the haplogroups most commonly studied are Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups, each of which can be used to define genetic populations. Y-DNA is passed solely along the patrilineal line, from father to son, while mtDNA is passed down the matrilineal line, from mother to offspring of both sexes. Neither recombines, and thus Y-DNA and mtDNA change only by chance mutation at each generation with no intermixture between parents' genetic material.

List of cat breeds

The following list of cat breeds includes only domestic cat breeds and domestic × wild hybrids. The list includes established breeds recognized by various cat registries, new and experimental breeds, landraces being established as standardized breeds, distinct domestic populations not being actively developed and lapsed (extinct) breeds.

As of 2016, The International Cat Association (TICA) recognizes 58 standardized breeds, the Cat Fanciers' Association (CFA) recognizes 44, and Fédération Internationale Féline (FIFe) recognizes 43.Inconsistency in breed classification and naming among registries means that an individual animal may be considered different breeds by different registries (though not necessarily eligible for registry in them all, depending on its exact ancestry). For example, TICA's Himalayan is considered a colorpoint variety of the Persian by CFA, while the Javanese (or Colorpoint Longhair) is a color variation of the Balinese in TICA and CFA; both breeds are merged (along with the Colorpoint Shorthair) into a single "mega-breed", the Colourpoint, in the World Cat Federation (WCF), who have repurposed the name "Javanese" for the Oriental Longhair. Also, "Colo[u]rpoint Longhair" refers to multiple different breeds in some other registries. There are several examples of nomenclatural confusion of this sort. Furthermore, many geographical and cultural names for cat breeds are fanciful selections made by Western breeders to be "exotic"-sounding and bear no relationship to the actual origin of the breeds; The Balinese, Himalayan, and Javanese are all examples of this trend.

The domestic short-haired and domestic long-haired cat types are not breeds, but terms used (with various spellings) in the cat fancy to describe mongrel cats of a general type, by coat length, that do not belong to a particular breed. Some registries permit them to be pedigreed and they have been used as foundation stock in the establishment of some breeds. They should not be confused with standardized breeds with similar names, such as British Shorthair and Oriental Longhair.

Missense mutation

In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.

Mutant

In biology and especially genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. The term mutant is also applied to a virus with an alteration in its nucleotide sequence whose genome is RNA, rather than DNA. In multicellular eukaryotes, a DNA sequence may be altered in an individual somatic cell that then gives rise to a mutant somatic cell lineage as happens in cancer progression. Also in eukaryotes, alteration of a mitochondrial or plastid DNA sequence may give rise to a mutant lineage that is inherited separately from mutant genotypes in the nuclear genome. The natural occurrence of genetic mutations is integral to the process of evolution. The study of mutants is an integral part of biology; by understanding the effect that a mutation in a gene has, it is possible to establish the normal function of that gene.

Mutant (Marvel Comics)

In American comic books published by Marvel Comics, a mutant is a human being that possesses a genetic trait called the X-gene. It causes the mutant to develop superhuman powers that manifest at puberty. Human mutants are sometimes referred to as a human subspecies Homo sapiens superior, or simply Homo superior. Mutants are the evolutionary progeny of Homo sapiens, and are generally assumed to be the next stage in human evolution. The accuracy of this is the subject of much debate in the Marvel Universe.

Unlike Marvel's mutates, which are characters who develop their powers only after exposure to outside stimuli or energies (such as the Hulk, Spider-Man, The Fantastic Four, and Absorbing Man), mutants have actual genetic mutations.

Point mutation

A point mutation or substitution is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence of DNA or RNA. Point mutations have a variety of effects on the downstream protein product—consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from benign (e.g. synonymous mutations) to catastrophic (e.g. frameshift mutations), with regard to protein production, composition, and function.

Population genetics

Population genetics is a subfield of genetics that deals with genetic differences within and between populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and population structure.Population genetics was a vital ingredient in the emergence of the modern evolutionary synthesis. Its primary founders were Sewall Wright, J. B. S. Haldane and Ronald Fisher, who also laid the foundations for the related discipline of quantitative genetics. Traditionally a highly mathematical discipline, modern population genetics encompasses theoretical, lab, and field work. Population genetic models are used both for statistical inference from DNA sequence data and for proof/disproof of concept.What sets population genetics apart today from newer, more phenotypic approaches to modelling evolution, such as evolutionary game theory and adaptive dynamics, is its emphasis on genetic phenomena as dominance, epistasis, and the degree to which genetic recombination breaks up linkage disequilibrium. This makes it appropriate for comparison to population genomics data.

Propagation of grapevines

The propagation of grapevines is an important consideration in commercial viticulture and winemaking. Grapevines, most of which belong to the Vitis vinifera family, produce one crop of fruit each growing season with a limited life span for individual vines. While some centenarian old vine examples of grape varieties exist, most grapevines are between the ages of 10 and 30 years. As vineyard owners seek to replant their vines, a number of techniques are available which may include planting a new cutting that has been selected by either clonal or mass (massal) selection. Vines can also be propagated by grafting a new plant vine upon existing rootstock or by layering one of the canes of an existing vine into the ground next to the vine and severing the connection when the new vine develops its own root system.In commercial viticulture, grapevines are rarely propagated from seedlings as each seed contains unique genetic information from its two parent varieties (the flowering parent and the parent that provided the pollen that fertilized the flower) and would, theoretically, be a different variety than either parent. This would be true even if two hermaphroditic vine varieties, such as Chardonnay, cross pollinated each other. While the grape clusters that would arise from the pollination would be considered Chardonnay any vines that sprang from one of the seeds of the grape berries would be considered a distinct variety other than Chardonnay. It is for this reason that grapevines are usually propagated from cuttings while grape breeders will utilize seedlings to come up with new grape varieties including crossings that include parents of two varieties within the same species (such as Cabernet Sauvignon which is a crossing of the Vitis vinifera varieties Cabernet Franc and Sauvignon blanc) or hybrid grape varieties which include parents from two different Vitis species such as the Armagnac grape Baco blanc, which was propagated from the vinifera grape Folle blanche and the Vitis labrusca variety Noah.

Sex linkage

Sex linkage describes the patterns of inheritance and presentation when a mutated gene (an allele) is present on a sex chromosome (an allosome) rather than a non-sex chromosome (an autosome). They are characteristically different from the autosomal forms of dominance and recessiveness.

Since humans have several times as many genes on the female X chromosome than on the male Y chromosome, X-linked traits are much more common than Y-linked traits. Additionally, there are more X-linked recessive conditions than X-linked dominant, and X-linked recessive conditions affect males much more commonly, due to males only having the one X chromosome required for the condition to present.

In humans, X-linked traits are inherited from a carrier or affected mother or from an affected father. In X-linked recessive conditions, a son born to an unaffected father and a carrier mother has a 50% chance of inheriting the mother's X chromosome carrying the mutant allele and presenting with the condition. A daughter on the other hand has a 50% chance of being a carrier, however a fraction of carriers may display a milder (or even full) form of the condition due to their body's normal X-inactivation process preferably inactivating a certain parent's X chromosome (the father's in this case), a phenomenon known as skewed X-inactivation. If the condition is dominant, or if the father is also affected, the daughter has a 50% chance of being affected, with an additional 50% chance of being a carrier in the second case. A son born to an affected father and a non-carrier mother will always be unaffected due to not inheriting the father's X chromosome. A daughter on the other hand will always be a carrier (some of which may present with symptoms due to aforementioned skewed X-inactivation), unless the condition is dominant, in which case she will always be affected. There are a few Y-linked traits; these are inherited by sons from their father and are always expressed.

The incidence of X-linked recessive conditions in females is the square of that in males: for example, if 1 in 20 males in a human population are red-green color blind, then 1 in 400 females in the population are expected to be color-blind (1/20)*(1/20).

The inheritance patterns are different in animals which use different sex-determination systems. In the ZW sex-determination system used by birds, the mammalian pattern is reversed, since the male is the homogametic sex (ZZ) and the female is heterogametic (ZW).

In classical genetics, a mating experiment called a reciprocal cross is performed to test if an animal's trait is sex-linked.

Single-nucleotide polymorphism

A single-nucleotide polymorphism, often abbreviated to SNP (; plural ), is a substitution of a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g. > 1%).For example, at a specific base position in the human genome, the C nucleotide may appear in most individuals, but in a minority of individuals, the position is occupied by an A. This means that there is a SNP at this specific position, and the two possible nucleotide variations – C or A – are said to be alleles for this position.

SNPs underlie differences in our susceptibility to a wide range of diseases (e.g. – sickle-cell anemia, β-thalassemia and cystic fibrosis result from SNPs). The severity of illness and the way the body responds to treatments are also manifestations of genetic variations. For example, a single-base mutation in the APOE (apolipoprotein E) gene is associated with a lower risk for Alzheimer's disease.A single-nucleotide variant (SNV) is a variation in a single nucleotide without any limitations of frequency and may arise in somatic cells. A somatic single-nucleotide variation (e.g., caused by cancer) may also be called a single-nucleotide alteration.

Stop codon

In the genetic code, a stop codon (or termination codon) is a nucleotide triplet within messenger RNA that signals a termination of translation into proteins. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA (from DNA) correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein. Stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain. While start codons need nearby sequences or initiation factors to start translation, a stop codon alone is sufficient to initiate termination.

X-linked recessive inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily hemizygous for the gene mutation because they have one X and one Y chromosome) and in females who are homozygous for the gene mutation, see zygosity.

X-linked inheritance means that the gene causing the trait or the disorder is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. Carrier females who have only one copy of the mutation do not usually express the phenotype, although differences in X chromosome inactivation can lead to varying degrees of clinical expression in carrier females since some cells will express one X allele and some will express the other. The current estimate of sequenced X-linked genes is 499 and the total including vaguely defined traits is 983.Some scholars have suggested discontinuing the terms dominant and recessive when referring to X-linked inheritance due to the multiple mechanisms that can result in the expression of X-linked traits in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism.

Mutation
Mechanisms of mutation
Mutation with respect to structure
Mutation with respect to overall fitness
Chromosome abnormalities (Q90–Q99, 758)
Autosomal
X/Y linked
Translocations
Other
Evolution
Population genetics
Development
Of taxa
Of organs
Of processes
Tempo and modes
Speciation
History
Philosophy
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