scholarly journals Evidence Concerning the Inadequacy of Mutation as an Explanation of the Frequency of the Sickle Cell Gene in the Belgian Congo

Blood ◽  
1955 ◽  
Vol 10 (4) ◽  
pp. 341-350 ◽  
Author(s):  
J. M. VANDEPITTE ◽  
WOLF W. ZUELZER ◽  
JAMES V. NEEL ◽  
J. COLAERT
Keyword(s):  
Natural Selection ◽  
Sickle Cell ◽  
Spontaneous Mutation ◽  
Genetic Modifier ◽  
Paper Electrophoresis ◽  
Preliminary Calculation ◽  
Spontaneous Mutation Rate ◽  
Balanced Polymorphism ◽  
Belgian Congo ◽  
Cell Gene

Abstract It is pointed out that there are two outstanding (and not mutually exclusive) possible explanations for the persistence of the sickle cell gene in the face of strong negative natural selection. These are (1) "balanced polymorphism," and (2) a high spontaneous mutation rate. In Léopoldville, Belgian Congo, approximately 25 per cent of the natives exhibit the sickling phenomenon. Over a two and one-half year period 261 patients with sickle cell disease, distributed among 243 families, were seen at the Institute of Tropical Medicine in Léopoldville. A total of 233 of the 243 mothers of the patients in this series was tested for the sickling phenomenon. Only two failed to sickle. Hemoglobin from these two women was normal on paper electrophoresis. The occurrence of these two exceptional mothers can be explained on the basis of mutation at some stage of oogenesis resulting in a sickle cell gene. Alternate possible explanations include (1) transmission by the mother of some other abnormal gene affecting hemoglobin synthesis, (2) occurrence in the mother of a genetic modifier of the effects of the sickle cell gene, (or its normal allele), and (3) unreported adoption. These data make possible a preliminary calculation of the extent to which mutation may be responsible for maintaining the sickle cell gene. Calculations based on the assumption that both these exceptional mothers indicate the occurrence of a mutation will lead to maximal estimates of the rate of mutation of the sickle cell gene. This maximal estimate is 1.7 x 10-3 per gene per generation. This rate, although very high by the usual standards of human mutation rates, is only approximately one-tenth that necessary to offset natural selection in a population with 25 per cent sickling.

scholarly journals Spontaneous mutations and the origin and maintenance of quantitative genetic variation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Wen Huang ◽  
Richard F Lyman ◽  
Rachel A Lyman ◽  
Mary Anna Carbone ◽  
Susan T Harbison ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Natural Selection ◽  
Quantitative Traits ◽  
Spontaneous Mutation ◽  
Natural Populations ◽  
Empirical Work ◽  
Stabilizing Selection ◽  
Spontaneous Mutation Rate ◽  
Evolutionary Forces ◽  
Quantitative Genetic

Mutation and natural selection shape the genetic variation in natural populations. Here, we directly estimated the spontaneous mutation rate by sequencing new Drosophila mutation accumulation lines maintained with minimal natural selection. We inferred strong stabilizing natural selection on quantitative traits because genetic variation among wild-derived inbred lines was much lower than predicted from a neutral model and the mutational effects were much larger than allelic effects of standing polymorphisms. Stabilizing selection could act directly on the traits, or indirectly from pleiotropic effects on fitness. However, our data are not consistent with simple models of mutation-stabilizing selection balance; therefore, further empirical work is needed to assess the balance of evolutionary forces responsible for quantitative genetic variation.

scholarly journals On the evolutionary adjustment of spontaneous mutation rates

1967 ◽  
Vol 9 (1) ◽  
pp. 23-34 ◽  
Author(s):  
Motoo Kimura
Keyword(s):  
Population Genetics ◽  
Natural Selection ◽  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Genetic Material ◽  
Genetic Load ◽  
Mutation Rates ◽  
Spontaneous Mutation Rate ◽  
Physiological Limit ◽  
Present Mode

Evolutionary factors which tend to decrease the mutation rate through natural selection and those which tend to increase the mutation rate are discussed from the standpoint of population genetics. The author's theory of optimum mutation rate based on the principle of minimum genetic load is re-examined, assuming that mutation rate is adjusted in the course of evolution in such a way that the sum of mutational and substitutional load is minimized. Another hypothesis is also examined that only selection toward lowering the mutation rate is effective and the present mutation rate in each organism represents the physical or physiological limit that may be attained by natural selection.The possibility cannot be excluded that the spontaneous mutation rate is near the minimum that may be attained under the present mode of organization of the genetic material, and at the same time is not very far from the optimum in the sense of minimizing the genetic load.

A Mutation in a Saccharomyces cerevisiae Gene (RAD3) Required for Nucleotide Excision Repair and Transcription Increases the Efficiency of Mismatch Correction

Genetics ◽  
1996 ◽  
Vol 144 (2) ◽  
pp. 459-466 ◽  
Author(s):  
Yingying Yang ◽  
Anthony L Johnson ◽  
Leland H Johnston ◽  
Wolfram Siede ◽  
Errol C Friedberg ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mismatch Repair ◽  
Excision Repair ◽  
Spontaneous Mutation ◽  
Surprising Result ◽  
Spontaneous Mutation Rate ◽  
Mismatch Correction ◽  
Nucleotide Excision ◽  
Repair Genes ◽  
Type Strains

Abstract RAD3 functions in DNA repair and transcription in Saccharomyces cerevisiae and particular rad3 alleles confer a mutator phenotype, possibly as a consequence of defective mismatch correction. We assessed the potential involvement of the Rad3 protein in mismatch correction by comparing heteroduplex repair in isogenic rad3-1 and wild-type strains. The rad3-1 allele increased the spontaneous mutation rate but did not prevent heteroduplex repair or bias its directionality. Instead, the efficiency of mismatch correction was enhanced in the rad3-1 strain. This surprising result prompted us to examine expression of yeast mismatch repair genes. We determined that MSH2, but not MLH1, is transcriptionally regulated during the cell-cycle like PMSl, and that rad3-1 does not increase the transcript levels for these genes in log phase cells. These observations suggest that the rad3-1 mutation gives rise to an enhanced efficiency of mismatch correction via a process that does not involve transcriptional regulation of mismatch repair. Interestingly, mismatch repair also was more efficient when error-editing by yeast DNA polymerase δ was eliminated. We discuss our results in relation to possible mechanisms that may link the rad3-1 mutation to mismatch correction efficiency.

scholarly journals Expression of the Sickle-cell Gene in Africa

BMJ ◽  
1955 ◽  
Vol 1 (4925) ◽  
pp. 1308-1311 ◽  
Author(s):  
G. M. Edington ◽  
H. Lehmann
Keyword(s):  
Sickle Cell ◽  
Cell Gene

scholarly journals Nature of Deleterious Mutation Load in Drosophila

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1993-1999 ◽  
Author(s):  
Peter D Keightley
Keyword(s):  
Deleterious Mutation ◽  
Spontaneous Mutation ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Mutation Load ◽  
Spontaneous Mutation Rate ◽  
A Minor ◽  
Chromosome I ◽  
Balancer Chromosomes ◽  
Balancer Chromosome

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila, frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

Gonad Temperature and Spontaneous Mutation-rate in Man

Nature ◽  
1957 ◽  
Vol 180 (4599) ◽  
pp. 1433-1434 ◽  
Author(s):  
LARS EHEENBERG ◽  
GÜNTER VON EHRENSTEIN ◽  
ARNE HEDGRAN
Keyword(s):  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Spontaneous Mutation Rate

Scope of action of the immunoglobulin mutator system

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 118-121 ◽  
Author(s):  
Matthias R. Wabl ◽  
Hans-Martin Jäck ◽  
R. C. von Borstel ◽  
Charles M. Steinberg
Keyword(s):  
B Cell ◽  
Mutation Rate ◽  
Heavy Chain ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Spontaneous Mutation ◽  
Cell Lineage ◽  
Variable Region ◽  
High Rate ◽  
Spontaneous Mutation Rate

The authors have developed a method to measure the rate of spontaneous mutations taking place in IgH, the gene encoding the immunoglobulin heavy chain. When an amber chain-termination codon mutates to a sense codon, translation of the polypeptide chain will be completed, and mutant cells producing the heavy chain can be detected with a fluorescent labelled antibody. The protocol used is the compartmentalization test which minimizes any effect of selection. In subclones of the pre-B lymphocyte line 18–81, the spontaneous mutation rate in the part of IgH encoding the variable region is somewhat greater than 10−5 mutations per base pair per generation. This supports the hypothesis that hypermutation is not dependent on cell stimulation by an antigen. In a hybrid between a cell of this line and a myeloma (which represents the terminal stage of the B-cell lineage), the mutation rate was too low to be determined by this test, less than 10−9. When the same loss to gain procedure system was used with an opal chain-terminating codon in the part of IgH encoding the constant region (Cμ), a high rate of reversion by deletion was found. Long (more than one exon) and short (less than one exon) deletions occurred at rates of 1.7 × 10−5 and 1.4 × 10−7 per generation, respectively. It is thought that the high rate of deletion is not related to somatic hypermutation but rather to DNA rearrangement during the heavy-chain class switch, which is occurring in these pre-B cell lines. The point mutation rate was too low to be detected above the background of deletion mutants, less than 5 × 10−8. The immunoglobulin mutator system works weakly, if at all, on two other, nonimmunoglobulin, genes tested: B2m (β2 microglobulin) and the gene for ouabain resistance.Key words: pre-B lymphocyte, B lymphocyte, spontaneous mutation rate, compartmentalization test, deletion mutation, hypermutation.

Screening for Sickle Cell Disease: A Hospital Based Study in Eastern Odisha, India

2012 ◽  
Vol 2 (2) ◽  
pp. 57-60
Author(s):  
Jayanti Mishra ◽  
Sanghamitra Pati ◽  
Mohammad Akhtar Hussain ◽  
Niraj Srivastava ◽  
Sindhubala Mishra
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Cell Disease ◽  
Medicine Department ◽  
Fetal Haemoglobin ◽  
Medical College ◽  
Rbc Indices ◽  
And Gender ◽  
Cell Gene

The highest frequency of sickle cell gene in India is reported in Odisha. The present study was taken up to assess the presence of sickle cell disease among febrile patients of a medical college of eastern Odisha. Patients referred from both pediatric and medicine department to the Hematology section of the department of Pathology, SCB Medical College, Cuttack were subjected to measurement of RBC indices, Sickling test, Haemoglobin Electrophoresis and Fetal Haemoglobin Estimation. Out of total 1000 referred patients 76(7.6%) were found to be positive for sickling. Two‐third of sicklingpositive patients had sickle cell trait with electrophoretic AS band. There was a significant association between age and positive sickling (χ2 = 24.357; df = 4, P = <0.0001). No significant association was observed between sickling and gender. Sickle cell positive cases are not uncommon in eastern Odisha. Our study demonstrated sickle cell trait to be more common among screened patients than other forms of sickle cell diseases.

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