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Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells?
Durham SE, Samuels DC, Chinnery PF
(2006) Neuromuscul Disord 16: 381-6
MeSH Terms: Aged, 80 and over, Aging, Base Sequence, DNA Replication, DNA, Mitochondrial, Electron Transport Complex IV, Female, Genetic Drift, Humans, Mitosis, Muscle Fibers, Skeletal, Muscle, Skeletal, Point Mutation, Selection, Genetic, Sequence Analysis, DNA
Show Abstract · Added December 12, 2013
Mitochondrial DNA (mtDNA) mutations accumulate in the skeletal muscle of patients with mtDNA disease, and also as part of healthy ageing. Simulations of human muscle fibres suggest that, over many decades, the continuous destruction and copying of mtDNA (relaxed replication) can lead to dramatic changes in the percentage level of mutant mtDNA in non-dividing cells through random genetic drift. This process should apply to both pathogenic and neutral mutations. To test this hypothesis we sequenced the entire mitochondrial genome for 20 muscle fibres from a healthy elderly 85-year-old individual, chosen because of the low frequency of cytochrome c oxidase negative fibres. Phenotypically neutral single base substitutions were detected in 15% of the healthy fibres, supporting the hypothesis that positive selection is not essential for the clonal expansion of mtDNA point mutations during human life. Treatments that enhance mtDNA replication, such as vigorous excercise, could amplify this process, with potentially detrimental long-term consequences.
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15 MeSH Terms
The immunopathogenesis of sepsis in elderly patients.
Opal SM, Girard TD, Ely EW
(2005) Clin Infect Dis 41 Suppl 7: S504-12
MeSH Terms: Aged, Aging, Animals, B-Lymphocytes, Biological Evolution, Blood Coagulation, Clinical Trials as Topic, Cytokines, Disease Susceptibility, Humans, Immunity, Cellular, Immunity, Innate, Plasma Cells, Risk Factors, Selection, Genetic, Sepsis, Shock, Septic
Show Abstract · Added September 23, 2015
Prominent among the numerous events that contribute to the enhanced susceptibility of elderly patients to infection is the decline of immune function that accompanies aging. Elderly patients experience a marked decline in cell-mediated immune function and reduced humoral immune function. Age-dependent defects in T and B cell function are readily demonstrable in elderly patients, yet the essential elements of innate immunity are remarkably well preserved. The cytokine and chemokine signaling networks are altered in elderly patients and tends to favor a type 2 cytokine response over type 1 cytokine responses. The induction of proinflammatory cytokines after septic stimuli is not adequately controlled by anti-inflammatory mechanisms in elderly persons. This immune dysregulation is accompanied by a more pronounced procoagulant state in older patients. These molecular events function in concert to render elderly patients at excess risk for mortality from severe sepsis and septic shock.
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17 MeSH Terms
Haplotype structure and phylogenetic shadowing of a hypervariable region in the CAPN10 gene.
Clark VJ, Cox NJ, Hammond M, Hanis CL, Di Rienzo A
(2005) Hum Genet 117: 258-66
MeSH Terms: Animals, Calpain, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Linkage, Genetic Predisposition to Disease, Humans, Phylogeny, Polymorphism, Single Nucleotide, Primates, Selection, Genetic
Show Abstract · Added February 22, 2016
It has been proposed that variation in calpain 10 (CAPN10) contributes to the risk of type 2 diabetes (T2D). A previous survey of CAPN10 in ethnically diverse populations revealed an intronic region with a significant excess of polymorphism levels relative to inter-species sequence divergence, suggesting that this region was the target of long-standing balancing selection. Based on the thrifty genotype hypothesis, variation that increases risk to T2D in contemporary humans at one time conferred a survival advantage in ancestral populations. Thus, the signature of positive natural selection in a T2D candidate gene could identify a genomic region containing variation that influences disease susceptibility. Here, we investigate this hypothesis by re-sequencing the CAPN10 region with unusual polymorphism levels in T2D cases and controls (n=91) from a Mexican American (MA) population, and by using networks to infer the evolutionary relationships between the major haplotypes. Haplotype tag SNPs (htSNPs) were then selected in each population sample and in MA cases and controls. By placing the htSNPs on the haplotype network, we investigate how cross-population differences in CAPN10 genetic architecture may affect the detection of the disease association. Interestingly, despite the small scale of our case-control study, we observe a nearly significant signal of association between T2D and variation in the putative target of balancing selection. Finally, we use phylogenetic shadowing across 10 primate species to search for conserved non-coding elements that may affect the expression and function of CAPN10. These elements are postulated to be the targets of long-standing balancing selection.
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11 MeSH Terms
Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus.
Fullerton SM, Bartoszewicz A, Ybazeta G, Horikawa Y, Bell GI, Kidd KK, Cox NJ, Hudson RR, Di Rienzo A
(2002) Am J Hum Genet 70: 1096-106
MeSH Terms: Africa, Alleles, Animals, Calpain, Chromosomes, Human, Pair 2, Continental Population Groups, Diabetes Mellitus, Type 2, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Haplorhini, Haplotypes, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Selection, Genetic
Show Abstract · Added February 22, 2016
Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed.
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16 MeSH Terms
The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?
Chinnery PF, Thorburn DR, Samuels DC, White SL, Dahl HM, Turnbull DM, Lightowlers RN, Howell N
(2000) Trends Genet 16: 500-5
MeSH Terms: Animals, DNA, Mitochondrial, Female, Gene Frequency, Humans, Mice, Mutation, Polymorphism, Genetic, Selection, Genetic, Species Specificity
Show Abstract · Added December 12, 2013
The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.
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10 MeSH Terms
Construction of an alkaline phosphatase fusion-generating transposon, mTn10phoA.
McClain MS, Engleberg NC
(1996) Gene 170: 147-8
MeSH Terms: Alkaline Phosphatase, Bacterial Proteins, Base Sequence, Cloning, Molecular, DNA Transposable Elements, Escherichia coli, Kanamycin Resistance, Recombinant Fusion Proteins, Selection, Genetic
Show Abstract · Added May 20, 2014
We constructed a derivative of the mini-transposon mTn10 that generates translational fusions to the phoA gene from Escherichia coli and carries the KmR determinant from Tn5. This new transposon, mTn10phoA, is carried on a mobilizable plasmid with both selectable and counterselectable markers. The plasmid carrying mTn10phoA was introduced into Legionella pneumophila. Southern hybridization analysis indicated that the mTn10phoA insertions were randomly distributed.
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9 MeSH Terms
Body weight gain is correlated with serum cholesterol at 8 weeks of age in pigs selected for four generations for low or high serum cholesterol.
Pond WG, Mersmann HJ, Klein PD, Ferlic LL, Wong WW, Hachey DL, Schoknecht PA, Zhang S
(1993) J Anim Sci 71: 2406-11
MeSH Terms: Animals, Birth Weight, Cholesterol, Cholesterol, HDL, Female, Genotype, Male, Regression Analysis, Selection, Genetic, Sex Factors, Swine, Triglycerides, Weaning, Weight Gain
Show Abstract · Added March 20, 2014
We determined the relationship of BW at birth, weaning (4 wk of age), and 8 wk of age to serum total cholesterol (C), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (TG) at 8 wk of age in pigs, from the fourth generation that had been selected for low (10 litters, 75 pigs, LC) or high (10 litters, 63 pigs, HC) C at 8 wk of age. Mean C concentration at 8 wk of age was 81 +/- 30 mg/dL for LC groups and 136 +/- 19 mg/dL for HC groups. Serum C, HDL-C, and TG concentrations were not correlated with birth weight, suggesting that the physiological factors that may cause reduced weight gain in older animals are not operative in newborn pigs. All three constituents were correlated (P < .05) with BW at weaning and at 8 wk. However, only 4% of the variation in weight at weaning and 7% at 8 wk could be explained by a relationship with serum TG. There was a positive correlation between C and BW at 8 wk (r = .46, P < .05), which was apparent within the subgroups of LC and HC females and LC males (r = .46, .48, .68, respectively); the correlation was low (r = .26) in HC males.
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14 MeSH Terms