Biochemical Approaches to Monitoring Human Populations for Germinal Mutation rates: I. Electrophoresis

1983 ◽  
pp. 71-93 ◽  
Author(s):  
James V. Neel ◽  
Harvey Mohrenweiser ◽  
Samir Hanash ◽  
Barnett Rosenblum ◽  
Stanley Sternberg ◽  
...  
Keyword(s):  
Mutation Rates ◽  
Human Populations ◽  
Germinal Mutation

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2018 ◽  
Vol 115 (36) ◽  
pp. 8996-9001 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Trna Gene ◽  
Gene Evolution ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Model Organisms ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Simple Method

Transfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between 7 and 10 times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution and indicates that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.

scholarly journals Changes in life history and population size can explain the relative neutral diversity levels on X and autosomes in extant human populations

2020 ◽  
Vol 117 (33) ◽  
pp. 20063-20069
Author(s):  
Guy Amster ◽  
David A. Murphy ◽  
William R. Milligan ◽  
Guy Sella
Keyword(s):  
Life History ◽  
Population Size ◽  
Mutation Rates ◽  
Human Populations ◽  
Effective Population ◽  
Mutation Bias ◽  
Female Ratio ◽  
Generation Times ◽  
Population Sizes ◽  
Male Mutation Bias

In human populations, the relative levels of neutral diversity on the X and autosomes differ markedly from each other and from the naïve theoretical expectation of 3/4. Here we propose an explanation for these differences based on new theory about the effects of sex-specific life history and given pedigree-based estimates of the dependence of human mutation rates on sex and age. We demonstrate that life history effects, particularly longer generation times in males than in females, are expected to have had multiple effects on human X-to-autosome (X:A) diversity ratios, as a result of male-biased mutation rates, the equilibrium X:A ratio of effective population sizes, and the differential responses to changes in population size. We also show that the standard approach of using divergence between species to correct for male mutation bias results in biased estimates of X:A effective population size ratios. We obtain alternative estimates using pedigree-based estimates of the male mutation bias, which reveal that X:A ratios of effective population sizes are considerably greater than previously appreciated. Finally, we find that the joint effects of historical changes in life history and population size can explain the observed X:A diversity ratios in extant human populations. Our results suggest that ancestral human populations were highly polygynous, that non-African populations experienced a substantial reduction in polygyny and/or increase in the male-to-female ratio of generation times around the Out-of-Africa bottleneck, and that current diversity levels were affected by fairly recent changes in sex-specific life history.

The Pool of Harmful Genes in Human Populations

1962 ◽  
Vol 11 (3) ◽  
pp. 284-287 ◽  
Author(s):  
G. R. Fraser
Keyword(s):  
Recurrent Mutation ◽  
Large Majority ◽  
Mutation Rates ◽  
Human Populations ◽  
Recessive Trait ◽  
Entire Spectrum ◽  
Geographical Variations ◽  
Pathological Conditions ◽  
Low Degree ◽  
Order Of Magnitude

The concepts of dominance and recessivity as applied to human genetical traits are losing their original connotations. It is better to speak of genes unconditionally deleterious in heterozygote form and those for which such disadvantage is doubtful. The classical dominant traits come into the first category and in the large majority they give rise to grossly pathological conditions and are ipso facto harmful-many in fact are lethal. In the case of these genes it is difficult to conceive that any agency other than recurrent mutation is instrumental in keeping them at their present frequency.Assuming that such mutation rates are of the same order of magnitude over the entire spectrum, the frequency of these traits will vary inversely with their severity and this is found to be approximately true-from an incidence of 3/million for an almost invariably lethal trait such as acrocephalosyndactyly to 1/1000 for a relatively innocuous trait such as ptosis.We would not expect genes even at the higher of these frequencies to be often seen and recognised in homozygote form with the low degree of inbreeding prevalent in human populations. This is in fact confirmed in practice and examples of possibly homozygous forms or dominant conditions are very rare. To be recognized as causing a recessive trait, with a few exceptions in inbred communities, a gene must be more common and often cannot therefore be maintained by recurrent mutation alone. Very wide geographical variations in the incidence of such traits also militate against such an interpretation. Phenylketonuria is an excellent example. The abnormal gene reaches a frequency of as much as 1% in some populations and it is unknown in others.

scholarly journals Appropriate Assignment of Fossil Calibration Information Minimizes the Difference between Phylogenetic and Pedigree Mutation Rates in Humans

Life ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 49 ◽  
Author(s):  
Renata Capellão ◽  
Elisa Costa-Paiva ◽  
Carlos Schrago
Keyword(s):  
Mutation Rate ◽  
Divergence Time ◽  
Mutation Rates ◽  
Human Populations ◽  
Fossil Calibration ◽  
Divergence Time Estimates ◽  
Time Estimates ◽  
The Mean ◽  
The Difference ◽  
Coalescent Time

Studies that measured mutation rates in human populations using pedigrees have reported values that differ significantly from rates estimated from the phylogenetic comparison of humans and chimpanzees. Consequently, exchanges between mutation rate values across different timescales lead to conflicting divergence time estimates. It has been argued that this variation of mutation rate estimates across hominoid evolution is in part caused by incorrect assignment of calibration information to the mean coalescent time among loci, instead of the true genetic isolation (speciation) time between humans and chimpanzees. In this study, we investigated the feasibility of estimating the human pedigree mutation rate using phylogenetic data from the genomes of great apes. We found that, when calibration information was correctly assigned to the human–chimpanzee speciation time (and not to the coalescent time), estimates of phylogenetic mutation rates were statistically equivalent to the estimates previously reported using studies of human pedigrees. We conclude that, within the range of biologically realistic ancestral generation times, part of the difference between whole-genome phylogenetic and pedigree mutation rates is due to inappropriate assignment of fossil calibration information to the mean coalescent time instead of the speciation time. Although our results focus on the human–chimpanzee divergence, our findings are general, and relevant to the inference of the timescale of the tree of life.

Approaches to Monitoring Human Populations for Mutation Rates and Genetic Disease

1973 ◽  
pp. 105-150 ◽  
Author(s):  
J. V. Neel ◽  
T. O. Tiffany ◽  
N. G. Anderson
Keyword(s):  
Genetic Disease ◽  
Mutation Rates ◽  
Human Populations

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2017 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Sequence Variation ◽  
Trna Gene ◽  
Purifying Selection ◽  
Transfer Rna ◽  
Mutation Rates ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Mutational Load

AbstractTransfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between seven and ten times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection, acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple new method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution, and implies that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.Significance StatementWhile transcription-associated mutagenesis (TAM) has been demonstrated for protein coding genes, its implications in shaping genome structure at transfer RNA (tRNA) loci in metazoans have not been fully appreciated. We show that cytosolic tRNAs are a striking example of TAM because of their variable rates of transcription, well-defined boundaries and internal promoter sequences. tRNA loci have a mutation rate approximately seven-to tenfold greater than the genome-wide average, and these mutations are consistent with signatures of TAM. These observations indicate that tRNA loci are disproportionately large contributors to mutational load in the human genome. Furthermore, the correlations between tRNA locus variation and transcription implicate that prediction of tRNA gene expression based on sequence variation data is possible.

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