scholarly journals Effects of variable mutation rates and epistasis on the distribution of allele frequencies in humans

2016 ◽  
Author(s):  
Arbel Harpak ◽  
Anand Bhaskar ◽  
Jonathan K. Pritchard
Keyword(s):  
Demographic History ◽  
Mutation Rates ◽  
Substantial Variation ◽  
Genome Sequences ◽  
Sequence Context ◽  
Closely Related Species ◽  
Mutation Model ◽  
Local Sequence ◽  
Exome Aggregation Consortium ◽  
Sample Data

AbstractThe site frequency spectrum (SFS) has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the “phylogenetically-conditioned SFS” or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. We additionally find evidence for epistatic effects on the cSFS: namely, that parallel primate substitutions at nonsynonymous sites are more informative about constraint in humans when the parallel substitution occurs in a closely related species. In summary, we show that variable mutation rates and local sequence context are important determinants of the SFS in humans.

scholarly journals Base damage, local sequence context andTP53mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

2015 ◽  
Vol 43 (19) ◽  
pp. 9133-9146 ◽  
Author(s):  
Georgina E. Menzies ◽  
Simon H. Reed ◽  
Andrea Brancale ◽  
Paul D. Lewis
Keyword(s):  
Molecular Dynamics ◽  
Sequence Context ◽  
Base Damage ◽  
Local Sequence

scholarly journals Disruption of origin chromatin structure by helicase activation in the absence of DNA replication

2021 ◽  
Author(s):  
Rachel A. Hoffman ◽  
David M. MacAlpine
Keyword(s):  
Dna Replication ◽  
S Phase ◽  
Replication Initiation ◽  
Micrococcal Nuclease ◽  
Sequence Context ◽  
Α Subunit ◽  
Chromatin Dynamics ◽  
Conditional Mutant ◽  
Local Sequence ◽  
Efficient Replication

Prior to initiation of DNA replication, the eukaryotic helicase, Mcm2-7, must be activated to unwind DNA at replication start sites in early S-phase. To study helicase activation within origin chromatin, we constructed a conditional mutant of the polymerase α subunit Cdc17 (or Pol1) to prevent priming and block replication. Recovery of these cells at permissive conditions resulted in the generation of unreplicated gaps at origins, likely due to helicase activation prior to replication initiation. We used micrococcal nuclease (MNase)-based chromatin occupancy profiling under restrictive conditions to study chromatin dynamics associated with helicase activation. Helicase activation in the absence of DNA replication resulted in the disruption and disorganization of chromatin which extends up to one kilobase from early, efficient replication origins. The CMG holo-helicase complex also moves the same distance out from the origin, producing single-stranded DNA that activates the intra-S-phase checkpoint. Loss of the checkpoint did not regulate the progression and stalling of the CMG complex, but rather resulted in the disruption of chromatin at both early and late origins. Finally, we found that the local sequence context regulates helicase progression in the absence of DNA replication, suggesting that the helicase is intrinsically less processive when uncoupled from replication.

scholarly journals Rapid mutational declines of viability in Drosophila

2001 ◽  
Vol 77 (1) ◽  
pp. 53-60 ◽  
Author(s):  
JAMES D. FRY
Keyword(s):  
Environmental Changes ◽  
Deleterious Mutation ◽  
Sampling Error ◽  
Strain Differences ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Substantial Variation ◽  
Evolutionary Advantage ◽  
Neutral Genetic Variation ◽  
Assay Conditions

High rates of mildly deleterious mutation could cause the extinction of small populations, reduce neutral genetic variation and provide an evolutionary advantage for sex. In the first attempts to estimate the rate of mildly deleterious mutation, Mukai and Ohnishi allowed spontaneous mutations to accumulate on D. melanogaster second chromosomes shielded from recombination and selection. Viability of the shielded chromosomes appeared to decline rapidly, implying a deleterious mutation rate on the order of one per zygote per generation. These results have been challenged, however; at issue is whether Mukai and Ohnishi may have confounded viability declines caused by mutation with declines resulting from environmental changes or other extraneous factors. Here, using a method not sensitive to non-mutational viability changes, I reanalyse the previous mutation-accumulation (MA) experiments, and report the results of a new one. I show that in each of four experiments, including Mukai's two experiments, viability declines due to mildly deleterious mutations were rapid. The results give no support for the view that Mukai overestimated the declines. Although there is substantial variation in estimates of genomic mutation rates from the experiments, this variation is probably due to some combination of sampling error, strain differences and differences in assay conditions, rather than to failure to distinguish mutational and non-mutational viability changes.

scholarly journals Comparative Genomics ofCryptosporidium

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Aurélien J. Mazurie ◽  
João M. Alves ◽  
Luiz S. Ozaki ◽  
Shiguo Zhou ◽  
David C. Schwartz ◽  
...  
Keyword(s):  
Genome Organization ◽  
Distinct Species ◽  
Genome Sequences ◽  
Cryptosporidium Hominis ◽  
Gene Deletions ◽  
Structural Alterations ◽  
Phenotypic Differences ◽  
Apicomplexan Parasites ◽  
Sequence Identity ◽  
Local Sequence

Until recently, the apicomplexan parasites,Cryptosporidium hominisandC. parvum, were considered the same species. However, the two parasites, now considered distinct species, exhibit significant differences in host range, infectivity, and pathogenicity, and their sequenced genomes exhibit only 95–97% identity. The availability of the complete genome sequences of these organisms provides the potential to identify the genetic variations that are responsible for the phenotypic differences between the two parasites. We compared the genome organization and structure, gene composition, the metabolic and other pathways, and the local sequence identity between the genes of these twoCryptosporidiumspecies. Our observations show that the phenotypic differences betweenC. hominisandC. parvumare not due to gross genome rearrangements, structural alterations, gene deletions or insertions, metabolic capabilities, or other obvious genomic alterations. Rather, the results indicate that these genomes exhibit a remarkable structural and compositional conservation and suggest that the phenotypic differences observed are due to subtle variations in the sequences of proteins that act at the interface between the parasite and its host.

scholarly journals Carcinogen-induced DNA structural distortion differences in the RAS gene isoforms; the importance of local sequence

BMC Chemistry ◽  
2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Georgina E. Menzies ◽  
Ian A. Prior ◽  
Andrea Brancale ◽  
Simon H. Reed ◽  
Paul D. Lewis
Keyword(s):  
Context Effects ◽  
Ras Gene ◽  
Sequence Context ◽  
Methyl Group ◽  
Lung Cancer Patients ◽  
Local Distortion ◽  
Mutational Pattern ◽  
Local Sequence ◽  
Modelling Techniques ◽  
Gene Isoforms

Abstract Background Local sequence context is known to have an impact on the mutational pattern seen in cancer. The RAS genes and a smoking carcinogen, Benzo[a]pyrene diol epoxide (BPDE), have been utilised to explore these context effects. BPDE is known to form an adduct at the guanines in a number of RAS gene sites, KRAS codons 12, 13 and 14, NRAS codon 12, and HRAS codons 12 and 14. Results Molecular modelling techniques, along with multivariate analysis, have been utilised to determine the sequence influenced differences between BPDE-adducted RAS gene sequences as well as the local distortion caused by the adducts. Conclusions We conclude that G:C > T:A mutations at KRAS codon 12 in the tumours of lung cancer patients (who smoke), proposed to be predominantly caused by BPDE, are due to the effect of the interaction methyl group at the C5 position of the thymine base in the KRAS sequence with the BPDE carcinogen investigated causing increased distortion. We further suggest methylated cytosine would have a similar effect, showing the importance of methylation in cancer development.

scholarly journals Blockwise Site Frequency Spectra for Inferring Complex Population Histories and Recombination

2016 ◽  
Author(s):  
Champak R. Beeravolu ◽  
Michael J. Hickerson ◽  
Laurent A.F. Frantz ◽  
Konrad Lohse
Keyword(s):  
Demographic History ◽  
Composite Likelihood ◽  
Model Organisms ◽  
Secondary Contact ◽  
Parameter Estimates ◽  
Genome Sequences ◽  
Frequency Spectra ◽  
Genome Wide ◽  
Complex Population ◽  
History Of

AbstractWe introduce ABLE (Approximate Blockwise Likelihood Estimation), a novel composite likelihood framework based on a recently introduced summary of sequence variation: the blockwise site frequency spectrum (bSFS). This simulation-based framework uses the the frequencies of bSFS configurations to jointly model demographic history and recombination and is explicitly designed to make inference using multiple whole genomes or genome-wide multi-locus data (e.g. RADSeq) catering to the needs of researchers studying model or non-model organisms respectively. The flexible nature of our method further allows for arbitrarily complex population histories using unphased and unpolarized whole genome sequences. In silico experiments demonstrate accurate parameter estimates across a range of divergence models with increasing complexity, and as a proof of principle, we infer the demographic history of the two species of orangutan from multiple genome sequences (over 160 Mbp in length) from each species. Our results indicate that the two orangutan species split approximately 650-950 thousand years ago but experienced a pulse of secondary contact much more recently, most likely during a period of low sea-level South East Asia (∼300,000 years ago). Unlike previous analyses we can reject a history of continuous gene flow and co-estimate genome-wide recombination. ABLE is available for download at https://github.com/champost/ABLE.

scholarly journals Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

2019 ◽  
Author(s):  
Allison N. Catizone ◽  
Gizem Karsli Uzunbas ◽  
Petra Celadova ◽  
Sylvia Kuang ◽  
Daniel Bose ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Mrna Levels ◽  
Sequence Context ◽  
Endogenous Expression ◽  
Damage Repair ◽  
Local Sequence ◽  
Element Activity ◽  
Massively Parallel Reporter Assay

AbstractThe master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CRE), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors (TFs). Although the role of p53 as a strong trans-activator of gene expression is well known, the co-regulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. We identified a SP1/KLF family motif located in an intronic p53 CRE that is required for the endogenous expression of the p53-dependent gene CCNG1. We also identified ATF3 as a factor that co-regulates the expression of the p53-dependent gene GDF15 through binding with p53 in an upstream CRE. Loss of either p53 or ATF3 severely reduces CRE activity and alters endogenous GDF15 mRNA levels in the cell. Our data suggests that p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that p53 activity is guarded against loss of any one regulatory partner allowing for dynamic and redundant control of p53-mediated transcription.

scholarly journals Evolutionary Patterns in the Genus Homo

2021 ◽  
Vol 21 (01) ◽  
Author(s):  
Nisar A. Shar
Keyword(s):  
Related Species ◽  
Homo Sapiens ◽  
Demographic History ◽  
Human Intelligence ◽  
Evolutionary Patterns ◽  
Closely Related Species ◽  
Genus Homo ◽  
Wide Range ◽  
History Of

ABSTRACT The demographic history of Homo sapiens is complex; it involves a wide range of migrations and genetic adaptations. One of the closely related species to Homo sapiens is Neanderthals, which became extinct about 30,000 years ago. The aim of this research is to compare Homo sapiens with Neanderthals and chimpanzees to understand the patterns of inheritance and survival instincts of Homo sapiens. Results show that out of all selected groups of genes in this study, metabolism, and language genes are found to be the most evolving group of genes. This shows that these most evolving genes are contributing to the advancement of Homo sapiens. However, after comparing human intelligence genes with the primates, it is found that exonic regions are contributing more to the evolution of human intelligence hence, making Homo sapiens unique in terms of intelligence.

scholarly journals Selection constrains high rates of satellite DNA mutation in Daphnia pulex

2017 ◽  
Author(s):  
Jullien M. Flynn ◽  
Ian Caldas ◽  
Melania E. Cristescu ◽  
Andrew G. Clark
Keyword(s):  
Satellite Dna ◽  
Related Species ◽  
Rapid Evolution ◽  
Daphnia Pulex ◽  
Selective Constraint ◽  
Mutation Rates ◽  
Stabilizing Selection ◽  
Closely Related Species ◽  
Dna Mutation ◽  
Evolutionary Forces

AbstractA long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated satellite DNA whose composition varies greatly among even closely related species. To elucidate the evolutionary forces governing satellite dynamics, quantification of the rates and patterns of mutations in satellite DNA copy number and tests of its selective neutrality are necessary. Here we used whole-genome sequences of 28 mutation accumulation (MA) lines of Daphnia pulex in addition to six isolates from a non-MA population originating from the same progenitor to both estimate mutation rates of abundances of satellite sequences and evaluate the selective regime acting upon them. We found that mutation rates of individual satellite sequence “kmers” were both high and highly variable, ranging from additions/deletions of 0.29 – 105 copies per generation (reflecting changes of 0.12 - 0.80 percent per generation). Our results also provide evidence that new kmer sequences are often formed from existing ones. The non-MA population isolates showed a signal of either purifying or stabilizing selection, with 33 % lower variation in kmer abundance on average than the MA lines, although the level of selective constraint was not evenly distributed across all kmers. The changes between many pairs of kmers were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that kmer sequences can experience extremely rapid evolution in abundance, which can lead to high levels of divergence in genome-wide satellite DNA composition between closely related species.

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