Jennifer Lake's Blog

August 11, 2009

MUTATION

Scientists sometimes say the scariest things, especially if one parallels the descriptions of one system (bacterial populations) to another (human populations). In a document about genetic mutation in bacterial populations, Joshua Lederberg wrote, straightforwardly enough in 1951:
“…mutation is the fundamental source of genetic variation, but in view of the smallness of spontaneous mutation rates, it is obvious that the occasional change of a cell from one genetic condition to another can make little impression upon the composition of bacterial populations. The forces that determine which genetic types will predominate in bacterial cultures are the subject of population dynamics. In diploid sexual organisms, population genetics is greatly complicated by recombination and by the concealment of genetic variation in the heterozygous condition, so that the most drastic culling may have to be carried out for a great many generations to have marked effect on the relative frequency of different gene forms.”
Here are excerpts from the link:
 
“The physiological study of mutant characters is known as phenogenetics, in contrast to formal or cryptogenetics which deals directly with the mechanism of hereditary transmission. One would resonably expect that a gene mutation would require a period of time to work its effects on the phenotype or outward behavior of the organism. This lag in bacterial mutation effects (phenotypic or phenomic lag) was first noticed directly with phage-resistance mutations induced by radiations….Phage resistant mutations play such a large part in genetic study because of the ease with which they can be selected out of large populations, simply by adding suspensions of the virus under appropriate conditions. This facility is shared by antibiotics…”
 
“Current interest in drug-resistance mutations is largely motivated by their importance in limiting the effectiveness of chemotherapy….In most cases, resistance may be developed in a series of individually small steps…evidence for this comes primarily from kinetic studies of increasing resistance under selection…”
 
“A more striking oddity is the mutation which over-adapts the cell to streptomycin so that the resistant mutant is dependent upon streptomycin for growth. The function of streptomycin is possibly to regulate an over-expanded enzyme system….Amino acids and vitamins are not commonly thought of as antibiotics but it has long been known that they sometimes interfere with, rather than promote, bacterial growth. The very ubiquity of these compounds imparts a special interest to them as possible natural regulators. Of equal interest is the correlation between sensitivity to amino acids and virulence in Salmonella and Brucella which may reflect a hitherto unsuspected general principle.”
 
“Auxotrophs have been used for the exploration of many biosynthetic pathways which are remarkably similar in bacteria, molds, and mammals….Mutations leading to catabolic defects have been especially useful in bacterial work, both as genetic markers and in the analysis of fermentation pathways….Most mutation rates are so low (of the order of one per million or billion cell divisions) that mutational equilibria would take too long for human observation, even if the necessary constancy of the environment were possible.”
 
“Induced mutations –Since Mullers announcement [Hermann J. Muller] in 1928 that X-rays would induce mutations in fruitflies an extensive segment of genetic research has concerned the discovery of mutagenic agents and the conditions of their effects. Higher organisms like Drosophila [fruitfly] and maize are indispensible in the finer analysis of the cytological
basis of induced genetic alterations, but microorganisms are very useful tools in the screening of new agents for mutagenic activity and in the study of the gross quantitative aspects of such activity….Dose-response data have been published for mutations induced by X-rays and by UV but their interpretation, especially for UV, is far from simple.
   It has been thought that radiations induced mutations by direct photo-chemical processes, i.e. that the gene itself might be activated by the absorption of a quantum of UV, or by collision with a secondary electron following an X-ray quantum absorption. Some revision of this concept is now necessary on the basis of recent research. The effectiveness of X-rays is potentiated by the presence of oxygen, and there may be a ten fold difference between the doses required for a given effect in oxygen, as against an inert atmosphere. This argues for a radiochemical intermediate, possibly some free radical (peroxide?) which depends upon oxygen for its production under the influence of X-radiation.
   Owing to the powerful penetrability of X-radiation, it has been used in Drosophila studies more extensively than UV which penetrates through living material so poorly that there are serious experimental difficulties in its application in the genetics of plants and animals…[but] UV is probably the most convenient and widely used mutagenic treatment in microbial experiments. The analysis of UV effects has been stimulated by the discovery of photoreactivation.”
 
“Chemical mutagens –A byproduct of research on chemical warfare agents during WWII [is] the realization of the possibility of mutagenic activity of chemicals. The nitrogen and sulfur “mustards” (p-chloro-alkylamines and sulfides) have been studied especially extensively and found to be potent mutagens for all organisms studied. In general their effects are similar to those of X-rays and UV….There is a wealth of further literature on this subject and it is likely to remain an active field….substances as diverse as formaldehyde, acriflavine, urethane, caffeine, hydrogen peroxide, and manganous ion are credibly reported as active in one or another system….and in general, the results of ,i.e., X-ray treatment would not be readily distinguishable from that of formaldehyde.”
 
“Spontaneous mutation– Evidence…is especially paradoxical….One interpretation is that spontaneous mutations are due not to intramolecular accidents or reproductive errors, but rather to the action of intracellular chemical mutagens formed by metabolic processes….but in view of the smallness of spontaneous mutation rates, it is obvious that the occasional change of a cell from one genetic condition to another can make little impression upon the composition of bacterial populations. In diploid sexual organisms, population genetics is greatly complicated by the recombination and by concealment of genetic variation in the heterozygous condition, so that the most drastic culling may have to be carried out for a great many generations to have a marked effect on the relative frequency of different gene forms.”
 
“Marker” mutant cells increased in proportion as mutations accumulated, but instead of increasing indefinitely, their ratio was subject to sporadic downward shifts. The same interpretation was independently formulated for each case: an adaptive mutation increasing the fit of the bacteria to their rather artificial in vitro environment. Owing to the overwhelming preponderance of the cells not carrying the marker, the adaptive mutation will usually occur in an unmarked cell, the descendents of which will then displace the rest of the population, markers and all. After the changeover, marker mutations accumulate again until a possible second changeover takes place to complete another cycle….genetic adaptations are often quite specific for the immediate environment….”
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[2004] “Mutation is the ultimate source of genetic novelty. As such, the rate at which new mutations arise is a central issue in genetics, with profound implications for both evolution and human health… The chief difficulty confronting experimentalists was the fact that [natural] mutations occur at a very low rate.
…”Haldane (1927) was the first to develop the formal theory for equilibrium frequencies of alleles in mutation-selection balance… This provided a straightforward way to estimate the mutation rate for deleterious alleles… In subsequent work, Haldane (1947) suggested that more mutations may come from the male germ line than from the female germ line, a result that has since been well supported by molecular studies.
…”single nucleotide substitutions are at least one order of magnitude more common than other types of mutations, such as insertions or deletions.
…”With the completion of the human genome sequence (International Human Genome Sequencing Consortium 2001) we can now estimate..that each individual harbours roughly 100-200 new mutations… most of these mutations will not occur in genes. However, one of the surprises of genomics has been the large numbers of noncoding sites that are conserved between species and therefore presumably have important functions… The mutations that occur in genes may therefore represent only a subset of the important mutations in humans.” http://www.eebweb.arizona.edu/nachman/pdfs/nachman_2004.pdf
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