Modelling mitochondrial site polymorphisms to infer the number of segregating units and mutation rate.
Ontology highlight
ABSTRACT:
SUBMITTER: Hendy MD
PROVIDER: S-EPMC2679937 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:For over a century, inbred mice have been used in many areas of genetics research to gain insight into the genetic variation underlying traits of interest. The generalizability of any genetic research study in inbred mice is dependent upon all individual mice being genetically identical, which in turn is dependent on the breeding designs of companies that supply inbred mice to researchers. Here, we compare whole-genome sequences from individuals of four commonly used inbred strains that were procured from either the colony nucleus or from a production colony (which can be as many as ten generations removed from the nucleus) of a large commercial breeder, in order to investigate the extent and nature of genetic variation within and between individuals. We found that individuals within strains are not isogenic, and there are differences in the levels of genetic variation that are explained by differences in the genetic distance from the colony nucleus. In addition, we employ a novel approach to mutation rate estimation based on the observed genetic variation and the expected site frequency spectrum at equilibrium, given a fully inbred breeding design. We find that it provides a reasonable per nucleotide mutation rate estimate when mice come from the colony nucleus (~7.9 × 10-9 in C3H/HeN), but substantially inflated estimates when mice come from production colonies.
| S-EPMC7852876 | biostudies-literature
Project description:Segregation and mixing of size multidisperse granular materials remain challenging problems in many industrial applications. In this paper, we apply a continuum-based model that captures the effects of segregation, diffusion and advection for size tridisperse granular flow in quasi-two-dimensional chute flow. The model uses the kinematics of the flow and other physical parameters such as the diffusion coefficient and the percolation length scale, quantities that can be determined directly from experiment, simulation or theory and that are not arbitrarily adjustable. The predictions from the model are consistent with experimentally validated discrete element method (DEM) simulations over a wide range of flow conditions and particle sizes. The degree of segregation depends on the Péclet number, Pe, defined as the ratio of the segregation rate to the diffusion rate, the relative segregation strength ?ij between particle species i and j, and a characteristic length L, which is determined by the strength of segregation between smallest and largest particles. A parametric study of particle size, ?ij , Pe and L demonstrates how particle segregation patterns depend on the interplay of advection, segregation and diffusion. Finally, the segregation pattern is also affected by the velocity profile and the degree of basal slip at the chute surface. The model is applicable to different flow geometries, and should be easily adapted to segregation driven by other particle properties such as density and shape.
| S-EPMC5897752 | biostudies-literature
Project description:Direct estimation of the spontaneous mutation rate by short-term mutation accumulation lines in Chironomus riparius
| PRJEB18039 | ENA
Project description:PURPOSE: To investigate the genetic basis for autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family. METHODS: Patients underwent a detailed ophthalmic examination, including funduscopy, electroretinography (ERG), visual field testing, and optical coherence tomography. Genome-wide homozygosity mapping using a single nucleotide polymorphism array was performed to identify homozygous regions shared between the two affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico analysis was used to predict the effect of the mutation on splicing. RESULTS: The family included two affected individuals. Clinical findings included progressive deterioration of visual acuity, photophobia, defective color vision, loss of central visual fields, pigmentary deposits localized mainly in the peripheral retina, a thinned and atrophic macular region, retinal vessel attenuation, absent ERG cone responses, and reduced ERG rod responses. Homozygosity mapping revealed several homozygous intervals shared among the affected individuals. One, a 12Mb interval on chromosome 10, included the CDHR1 gene. Direct sequencing revealed a single base transversion, c.1485+2T>G, located in the conserved donor splice site of Intron 13. This mutation cosegregated with the disease in the family, and was not detected in 208 Israeli Christian Arab control chromosomes. In silico analysis predicted that this mutation eliminates the Intron 13 donor splice site. CONCLUSIONS: Only three distinct pathogenic mutations of CDHR1 have been reported to date in patients with autosomal recessive retinal degeneration. Here we report a novel splice site mutation of CDHR1, c.1485+2T>G, underlying autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family. This report expands the spectrum of pathogenic mutations of the CDHR1 gene.
| S-EPMC3519373 | biostudies-literature
Project description:ObjectivesLeber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON penetrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations.Data descriptionWe collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.
| S-EPMC6302380 | biostudies-literature
Project description:BackgroundMitochondrion is a small organelle inside the eukaryotic cells. It has its own genome (mtDNA) and encodes for proteins that are critical for energy production and cellular metabolism. Mitochondrial dysfunctions have been implicated in cancer progression and may be related to poor prognosis in cancer patients. In this study we hypothesized that genetic variations in mtDNA are associated with clinical outcome in colorectal cancer patients.MethodsWe tested the associations of six mtDNA polymorphisms [MitoT479C, MitoT491C, MitoT10035C, MitoA13781G, 10398 (A/G), and 16189 (T/C)] and the mtDNA copy number change with overall survival (OS) and disease-free survival (DFS) times. Two mtDNA polymorphisms were genotyped using the TaqMan(®) SNP genotyping technique and the genotypes for the remaining four mtDNA polymorphisms were obtained by the Illumina(®) HumanOmni1-Quad genome wide SNP genotyping platform in 536 patients. The mtDNA copy number change (in tumor tissues with respect to non-tumor tissues) was estimated using the quantitative real time polymerase chain reaction for 274 patients. Associations of these mtDNA variations with OS and DFS were tested using the Cox regression method.ResultsIn both univariate and multivariable analyses, none of the six mtDNA polymorphisms were associated with OS or DFS. 39.6 and 60.4% of the patients had increased and decreased mtDNA copy number in their tumor tissues when compared to their non-tumor rectum or colon tissues, respectively. However, in contrast to previous findings, the change in the mtDNA copy number was associated with neither OS nor DFS in our patient cohort.ConclusionsOur results suggest that the mitochondrial genetic markers investigated in this study are not associated with outcome in colorectal cancer.
| S-EPMC4482280 | biostudies-literature
Project description:Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have also been used to estimate the mutation rate, using sites that are thought to evolve neutrally. We directly estimated the mtDNA mutation rate by scanning the mitochondrial genome of Drosophila melanogaster lines that had undergone approximately 200 generations of spontaneous mutation accumulation (MA). We detected a total of 28 point mutations and eight insertion-deletion (indel) mutations, yielding an estimate for the single-nucleotide mutation rate of 6.2 x 10(-8) per site per fly generation. Most mutations were heteroplasmic within a line, and their frequency distribution suggests that the effective number of mitochondrial genomes transmitted per female per generation is about 30. We observed repeated occurrences of some indel mutations, suggesting that indel mutational hotspots are common. Among the point mutations, there is a large excess of G-->A mutations on the major strand (the sense strand for the majority of mitochondrial genes). These mutations tend to occur at nonsynonymous sites of protein-coding genes, and they are expected to be deleterious, so do not become fixed between species. The overall mtDNA mutation rate per base pair per fly generation in Drosophila is estimated to be about 10x higher than the nuclear mutation rate, but the mitochondrial major strand G-->A mutation rate is about 70x higher than the nuclear rate. Silent sites are substantially more strongly biased towards A and T than nonsynonymous sites, consistent with the extreme mutation bias towards A+T. Strand-asymmetric mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of the mitochondrial genome of Drosophila.
| S-EPMC2517619 | biostudies-literature
Project description:Although there are many methods available for inferring copy-number variants (CNVs) from next-generation sequence data, there remains a need for a system that is computationally efficient but that retains good sensitivity and specificity across all types of CNVs. Here, we introduce a new method, estimation by read depth with single-nucleotide variants (ERDS), and use various approaches to compare its performance to other methods. We found that for common CNVs and high-coverage genomes, ERDS performs as well as the best method currently available (Genome STRiP), whereas for rare CNVs and high-coverage genomes, ERDS performs better than any available method. Importantly, ERDS accommodates both unique and highly amplified regions of the genome and does so without requiring separate alignments for calling CNVs and other variants. These comparisons show that for genomes sequenced at high coverage, ERDS provides a computationally convenient method that calls CNVs as well as or better than any currently available method.
| S-EPMC3511991 | biostudies-literature
Project description:Estimation of the spontaneous mutation rate in Heliconius melpomene
| PRJEB7581 | ENA
Project description:Mitochondrial DNA (mtDNA) mutations underlie a variety of human genetic disorders and are associated with the aging process. mtDNA polymorphisms are widely used in a variety of evolutionary applications. Although mtDNA mutation spectra are known to differ between distantly related model organisms, the extent to which mtDNA mutation processes vary between more closely related species and within species remains enigmatic. We analyzed mtDNA divergence in two sets of 250-generation Caenorhabditis briggsae mutation-accumulation (MA) lines, each derived from a different natural isolate progenitor: strain HK104 from Okayama, Japan, and strain PB800 from Ohio, United States. Both sets of C. briggsae MA lines accumulated numerous large heteroplasmic mtDNA deletions, whereas only one similar event was observed in a previous analysis of Caenorhabditis elegans MA line mtDNA. Homopolymer length change mutations were frequent in both sets of C. briggsae MA lines and occurred in both intergenic and protein-coding gene regions. The spectrum of C. briggsae mtDNA base substitution mutations differed from the spectrum previously observed in C. elegans. In C. briggsae, the HK104 MA lines experienced many different base substitution types, whereas the PB800 lines displayed only C:G --> T:A transitions, although the difference was not significant. Over half of the mtDNA base substitutions detected in the C. briggsae MA lines were in a heteroplasmic state, whereas all those previously characterized in C. elegans MA line mtDNA were fixed changes, indicating a narrower mtDNA bottleneck in C. elegans as compared with C. briggsae. Our results show that C. briggsae mtDNA is highly susceptible to large deletions and that the mitochondrial mutation process varies between Caenorhabditis nematode species.
| S-EPMC2839355 | biostudies-literature