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.

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 Predicting transfer RNA gene activity from sequence and genome context

2019 ◽  
Author(s):  
Bryan Thornlow ◽  
Joel Armstrong ◽  
Andrew Holmes ◽  
Russell Corbett-Detig ◽  
Todd Lowe
Keyword(s):  
Gene Expression ◽  
Trna Gene ◽  
Gene Expression Regulation ◽  
Gene Families ◽  
Transfer Rna ◽  
Gene Activity ◽  
Comparative Genomic ◽  
Trna Genes ◽  
Genomic Context ◽  
High Sequence Identity

ABSTRACTTransfer RNA (tRNA) genes are among the most highly transcribed genes in the genome due to their central role in protein synthesis. However, there is evidence for a broad range of gene expression across tRNA loci. This complexity, combined with difficulty in measuring transcript abundance and high sequence identity across transcripts, has severely limited our collective understanding of tRNA gene expression regulation and evolution. We establish sequence-based correlates to tRNA gene expression and develop a tRNA gene classification method that does not require, but benefits from comparative genomic information, and achieves accuracy comparable to molecular assays. We observe that guanine+cytosine (G+C) content and CpG density surrounding tRNA loci is exceptionally well correlated with tRNA gene activity, supporting a prominent regulatory role of the local genomic context in combination with internal sequence features. We use our tRNA gene activity predictions in conjunction with a comprehensive tRNA gene ortholog set spanning 29 placental mammals to infer the frequency of changes to tRNA gene expression among orthologs. Our method adds an important new dimension to tRNA annotation and will help focus the study of natural tRNA variants. Its simplicity and robustness enables facile application to other clades and timescales, as well as exploration of functional diversification of tRNAs and other large gene families.

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.

scholarly journals Highly accelerated rates of heritable large-scale mutations under prolonged exposure to a metal mixture of copper and nickel

2018 ◽  
Author(s):  
Frédéric J.J. Chain ◽  
Jullien M. Flynn ◽  
James K. Bull ◽  
Melania E. Cristescu
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Prolonged Exposure ◽  
De Novo ◽  
Multiple Stressors ◽  
Copy Number Variations ◽  
Environmental Stressors ◽  
Mutation Rates ◽  
Rate Variation ◽  
Mutational Load

AbstractMutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies have focused on point mutations rather than large-scale deletions and duplications (copy number variations or “CNVs”). We estimated mutation rates inDaphnia pulexexposed to low levels of environmental stressors as well as the effect of selection onde novomutations. We conducted a mutation accumulation (MA) experiment in which selection was minimized, coupled with an experiment in which a population was propagated under competitive conditions in a benign environment. After an average of 103 generations of MA propagation, we sequenced 60 genomes and found significantly accelerated rates of deletions and duplications in MA lines exposed to ecologically relevant concentrations of metals. Whereas control lines had gene deletion and duplication rates comparable to other multicellular eukaryotes (1.8 × 10−6per gene per generation), a mixture of nickel and copper increased rates fourfold. The realized mutation rate under selection was reduced to 0.4x that of control MA lines, providing evidence that CNVs contribute to mutational load. Our CNV breakpoint analysis revealed that nonhomologous recombination associated with regions of DNA fragility is the primary source of CNVs, plausibly linking metal-induced DNA strand breaks with higher CNV rates. Our findings suggest that environmental stress, in particular multiple stressors, can have profound effects on large-scale mutation rates and mutational load of populations.

scholarly journals The impact of genetic modifiers on variation in germline mutation rates within and among human populations

2021 ◽  
Author(s):  
William R. Milligan ◽  
Guy Amster ◽  
Guy Sella
Keyword(s):  
Genetic Modifier ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Ancestral Population ◽  
Human Populations ◽  
Demographic Model ◽  
Genetic Modifiers ◽  
Genome Wide ◽  
Demographic Processes ◽  
The Impact

AbstractMutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, “mutator alleles”, increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes ≈ 1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes ≫ 1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g., 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes > 1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.

scholarly journals Cloning and nucleotide sequence analysis of transfer RNA genes from Mycoplasma mycoides

1985 ◽  
Vol 232 (1) ◽  
pp. 223-228 ◽  
Author(s):  
T Samuelsson ◽  
P Elias ◽  
F Lustig ◽  
Y S Guindy
Keyword(s):  
Sequence Analysis ◽  
Nucleotide Sequence ◽  
Trna Gene ◽  
Transfer Rna ◽  
Nucleotide Sequences ◽  
Transcriptional Unit ◽  
Nucleotide Sequence Analysis ◽  
Trna Genes ◽  
Mycoplasma Mycoides ◽  
Rna Genes

As part of an investigation of the tRNA genes of Mycoplasma mycoides, two HindIII fragments of mycoplasma DNA comprising 0.4 and 2.5 kilobases (kb), respectively, were cloned in pBR322 and their nucleotide sequences determined. Only one tRNA gene was found in the 0.4 kb fragment, the gene for tRNAArg with the anticodon TCT, while the 2.5 kb fragment contained nine different tRNA genes arranged in a cluster which presumably constitutes a transcriptional unit. The clustered tRNA genes, with their respective anticodons, were as follows: Arg (ACG), Pro (TGG), Ala (TGC), Met (CAT), Ile (CAT), Ser (TGA), fMet (CAT), Asp (GTC), and Phe (GAA).

scholarly journals Distance from sub-Saharan Africa predicts mutational load in diverse human genomes

2015 ◽  
Vol 113 (4) ◽  
pp. E440-E449 ◽  
Author(s):  
Brenna M. Henn ◽  
Laura R. Botigué ◽  
Stephan Peischl ◽  
Isabelle Dupanloup ◽  
Mikhail Lipatov ◽  
...  
Keyword(s):  
Purifying Selection ◽  
Allele Frequencies ◽  
Sub Saharan Africa ◽  
Human Populations ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
High Coverage ◽  
Deleterious Alleles ◽  
Out Of Africa ◽  
Sub Saharan

The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

scholarly journals A test of the hypothesis that variable mutation rates create signals that have previously been interpreted as evidence of archaic introgression into humans

2020 ◽  
Author(s):  
William Amos
Keyword(s):  
Mutation Rate ◽  
Alternative Model ◽  
Mutation Rates ◽  
Human Populations ◽  
Common Cause ◽  
Coalescent Simulations ◽  
Recurrent Mutations ◽  
Archaic Introgression ◽  
Excess Base ◽  
Human Specific

AbstractIt is widely accepted that non-African humans carry 1-2% Neanderthal DNA due to historical inter-breeding. However, inferences about introgression rely on a critical assumption that mutation rate is constant and that back-mutations are too rare to be important. Both these assumptions have been challenged, and recent evidence points towards an alternative model where signals interpreted as introgression are driven mainly by higher mutation rates in Africa. In this model, non-Africans appear closer to archaics not because they harbour introgressed fragments but because Africans have diverged more. Here I test this idea by using the density of rare, human-specific variants (RHSVs) as a proxy for recent mutation rate. I find that sites that contribute most to the signal interpreted as introgression tend to occur in tightly defined regions spanning only a few hundred bases in which mutation rate differs greatly between the two human populations being compared. Mutation rate is invariably higher in the population into which introgression is not inferred. I confirmed that RHSV density reflects mutation rate by conducting a parallel analysis looking at the density of RHSVs around sites with three alleles, an independent class of site that also requires recurrent mutations to form. Near-identical peaks in RHSV density are found, suggesting a common cause. Similarly, coalescent simulations confirm that, with constant mutation rate, introgressed fragments do not occur preferentially in regions with a high density of rare, human-specific variants. Together, these observations are difficult to reconcile with a model where excess base-sharing is driven by archaic legacies but instead provide support for a higher mutation rate inside Africa driving increased divergence from the ancestral human state.

scholarly journals Distance from Sub-Saharan Africa Predicts Mutational Load in Diverse Human Genomes

2015 ◽  
Author(s):  
Brenna M. Henn ◽  
Laura R Botigue ◽  
Stephan Peischl ◽  
Isabelle Dupanloup ◽  
Mikhail Lipatov ◽  
...  
Keyword(s):  
Purifying Selection ◽  
Allele Frequencies ◽  
Sub Saharan Africa ◽  
Human Populations ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
High Coverage ◽  
Deleterious Alleles ◽  
Out Of Africa ◽  
Sub Saharan

The Out-of-Africa (OOA) dispersal ~50,000 years ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from 7 geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

scholarly journals The demographic history and mutational load of African hunter-gatherers and farmers

2017 ◽  
Author(s):  
Marie Lopez ◽  
Athanasios Kousathanas ◽  
Hélène Quach ◽  
Christine Harmant ◽  
Patrick Mouguiama-Daouda ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Gene Flow ◽  
Demographic History ◽  
Purifying Selection ◽  
Human Populations ◽  
Mutational Load ◽  
Sequencing Data ◽  
Hunter Gatherers ◽  
African Populations ◽  
The Impact

AbstractThe distribution of deleterious genetic variation across human populations is a key issue in evolutionary biology and medical genetics. However, the impact of different modes of subsistence on recent changes in population size, patterns of gene flow, and deleterious mutational load remains unclear. Here, we report high-coverage exome sequencing data from various populations of rainforest hunter-gatherers and farmers from central Africa. We find that the recent demographic histories of hunter-gatherers and farmers differed considerably, with population collapses for hunter-gatherers and expansions for farmers, accompanied by increased gene flow. We show that purifying selection against deleterious alleles is of similar efficiency across African populations, in contrast with Europeans where we detect weaker purifying selection. Furthermore, the per-individual mutation load of rainforest hunter-gatherers is similar to that of farmers, under both additive and recessive models. Our results indicate that differences in the cultural practices and demographic regimes of African populations have not resulted in large differences in mutational burden, and highlight the beneficial role of gene flow in reshaping the distribution of deleterious genetic variation across human populations.

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