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Andrew G Clark - One of the best experts on this subject based on the ideXlab platform.
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selection constrains high rates of tandem repetitive DNA Mutation in daphnia pulex
Genetics, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of Mutations in repeat 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 repeat sequences and evaluate the selective regime acting upon them. We found that Mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat 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 repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species.
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selection constrains high rates of satellite DNA Mutation in daphnia pulex
bioRxiv, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A 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.
Yauhuei Wei - One of the best experts on this subject based on the ideXlab platform.
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effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy encephalopathy lactic acidosis and stroke like episodes melas a3243g mitochondrial DNA Mutation
Biochemical Journal, 2005Co-Authors: Jagdeep K Sandhu, Yauhuei Wei, Caroline Sodja, Kevan Mcrae, Peter Rippstein, Boleslaw Lach, Fay Lee, Septimiu Bucurescu, Maryellen Harper, Marianna SikorskaAbstract:Reactive nitrogen and oxygen species (O2•−, H2O2, NO• and ONOO−) have been strongly implicated in the pathophysiology of neurodegenerative and mitochondrial diseases. In the present study, we examined the effects of nitrosative and/or nitrative stress generated by DETA-NO {(Z)-1-[2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate}, SIN-1 (3-morpholinosydnonimine hydrochloride) and SNP (sodium nitroprusside) on U87MG glioblastoma cybrids carrying wt (wild-type) and mutant [A3243G (Ala3243→Gly)] mtDNA (mitochondrial genome) from a patient suffering from MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The mutant cybrids had reduced activity of cytochrome c oxidase, significantly lower ATP level and decreased mitochondrial membrane potential. However, endogenous levels of reactive oxygen species were very similar in all cybrids regardless of whether they carried the mtDNA defects or not. Furthermore, the cybrids were insensitive to the nitrosative and/or nitrative stress produced by either DETA-NO or SIN-1 alone. Cytotoxicity, however, was observed in response to SNP treatment and a combination of SIN-1 and glucose-deprivation. The mutant cybrids were significantly more sensitive to these insults compared with the wt controls. Ultrastructural examination of dying cells revealed several characteristic features of autophagic cell death. We concluded that nitrosative and/or nitrative stress alone were insufficient to trigger cytotoxicity in these cells, but cell death was observed with a combination of metabolic and nitrative stress. The vulnerability of the cybrids to these types of injury correlated with the cellular energy status, which were compromised by the MELAS Mutation.
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mitochondrial DNA Mutation and depletion increase the susceptibility of human cells to apoptosis
Annals of the New York Academy of Sciences, 2004Co-Authors: Chunyi Liu, Yauhuei Wei, Chengfeng Lee, Chiunghui HongAbstract:Mitochondrial diseases, such as MELAS, MERRF, and CPEO syndromes, are associated with specific point Mutations or large-scale deletions of mitochondrial DNA (mtDNA), which impair mitochondrial respiratory functions and result in decreased production of ATP in affected tissues. Recently, mitochondria have been recognized to act as key players in the regulation of cell death. To investigate whether a pathogenic Mutation of mtDNA exerts any effect on the process of apoptosis of human cells, we constructed a series of cybrid human cells harboring different proportions of mtDNA with the A3243G or the A8344G transition, or with the 4,977-bp deletion, by cytoplasmic fusion of patients' skin fibroblasts with mtDNA-depleted rho(0) cells of an immortal human osteosarcoma cell line (143B). We observed that the decrease in cell viability upon staurosporine treatment or exposure to ultraviolet (UV) irradiation was more pronounced in the cybrids harboring high levels of mutated mtDNA compared with the control cybrids. Using DNA fragmentation analysis, we found that the cell death induced by treatment with 100 nM staurosporine or by exposure to UV irradiation at 20 J/m(2) was caused by apoptosis, not necrosis. Moreover, we demonstrated activation of caspase 3 by Western blot and enhanced release of cytochrome c after 100 nM staurosporine treatment or 20 J/m(2) UV irradiation of the cybrids harboring high levels of the three mtDNA Mutations. Furthermore, as compared with parental osteosarcoma 143B cells, the rho(0) cells were found to be more susceptible to apoptosis, which was accompanied by caspase 3 activation and cytochrome c release. This indicates that mtDNA plays an important role in the regulation of apoptosis in human cells. Taken together, these findings suggest that Mutation and depletion of mtDNA increase the susceptibility of human cells to apoptosis triggered by exogenous stimuli such as UV irradiation or staurosporine.
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oxidative stress mitochondrial DNA Mutation and impairment of antioxidant enzymes in aging
Experimental Biology and Medicine, 2002Co-Authors: Yauhuei Wei, Hsinchen LeeAbstract:Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as by-products of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA Mutations and defective antioxidant enzymes in human aging.
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biomarkers of DNA damage in patients with end stage renal disease mitochondrial DNA Mutation in hair follicles
Nephrology Dialysis Transplantation, 2001Co-Authors: Chin San Liu, Paik Seong Lim, Shu Huei Kao, Yauhuei WeiAbstract:Background. DNA damage was noted in patients with end-stage renal disease (ESRD). Mitochondrial DNA (mtDNA) Mutations have been proposed as a genomic biomarker in the process of human ageing, degenerative diseases and carcinogenesis. Methods. Polymerase chain reaction (PCR) techniques were applied to detect mtDNA deletions in hair follicles, an appendage of skin, from 162 patients with ESRD. Results. The incidences of the 4977 bp deletion of mtDNA in hair follicles were found to increase with age in normal control and ESRD patients. As compared with normal subjects, ESRD patients had 3.5, 2.3, 2.7, 2.3 and 1.4 times higher incidences of the 4977 bp deletion of mtDNA in the age groups of 20-30, 31-40, 41-50, 51-60 and 61-70 years, respectively. Moreover, the difference in the proportion of mtDNA with the 4977 bp deletion was statistically significant between ESRD patients and normal subjects >50 years of age. Conclusion. We suggest that the 4977 bp deletion of mtDNA in hair follicles may serve as one of the tissue biomarkers of genetic instability of the mitochondrial genome in ESRD patients.
Jullien M Flynn - One of the best experts on this subject based on the ideXlab platform.
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selection constrains high rates of tandem repetitive DNA Mutation in daphnia pulex
Genetics, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of Mutations in repeat 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 repeat sequences and evaluate the selective regime acting upon them. We found that Mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat 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 repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species.
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selection constrains high rates of satellite DNA Mutation in daphnia pulex
bioRxiv, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A 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.
Melania E Cristescu - One of the best experts on this subject based on the ideXlab platform.
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selection constrains high rates of tandem repetitive DNA Mutation in daphnia pulex
Genetics, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of Mutations in repeat 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 repeat sequences and evaluate the selective regime acting upon them. We found that Mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat 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 repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species.
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selection constrains high rates of satellite DNA Mutation in daphnia pulex
bioRxiv, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A 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.
Ian V Caldas - One of the best experts on this subject based on the ideXlab platform.
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selection constrains high rates of tandem repetitive DNA Mutation in daphnia pulex
Genetics, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of Mutations in repeat 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 repeat sequences and evaluate the selective regime acting upon them. We found that Mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat 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 repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species.
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selection constrains high rates of satellite DNA Mutation in daphnia pulex
bioRxiv, 2017Co-Authors: Jullien M Flynn, Ian V Caldas, Melania E Cristescu, Andrew G ClarkAbstract:A 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.