| 1. |
- Ameur, Adam, et al.
(författare)
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Ultra-deep sequencing of mouse mitochondrial DNA : Mutational patterns and their origins
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1002028-
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice) have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.
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| 2. |
- Engelmark, Malin, et al.
(författare)
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Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis
- 2008
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 123:5, s. 437-443
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Tidskriftsartikel (refereegranskat)abstract
- Cervical cancer is a multifactorial disease influenced by both environmental and genetic factors. We have previously found linkage to 9q32 in a genomewide scan of affected sib-pairs (ASPs) with cervical cancer and to the thymic stromal co-transporter (TSCOT), a candidate gene in this region. Here we examined the contribution of 9q32 and TSCOT to cervical cancer susceptibility using at larger material of 641 ASPs, 278 of which were included in the earlier genome-scan. Since heritable forms of cancer frequently show stronger genetic effects in families with early onset of disease, we stratified the ASPs into two groups based on mean age at diagnosis (MAAD) within sib-pairs. Surprisingly, ASPs with high MAAD (30.5-47.5 years) showed increased sharing at all microsatellite markers at 9q31.1-33.1 and linkage signals of up to MLS = 2.74 for TSCOT SNPs, while ASPs with low MAAD (19-30 years) showed no deviation from random genetic sharing (MLS = 0.00). The difference in allelic sharing between the two MAAD strata was significant (P < 0.005) and is not likely to be explained by the HLA haplotype, a previously known genetic susceptibility factor for cervical cancer. Our results indicate locus heterogeneity in the susceptibility to cervical cancer between the two strata, with polymorphisms in the 9q32 region mainly showing an effect in women with high MAAD.
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| 3. |
- Ingman, Max, et al.
(författare)
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A recent genetic link between Sami and the Volga-Ural region of Russia
- 2007
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 15:1, s. 115-120
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Tidskriftsartikel (refereegranskat)abstract
- The genetic origin of the Sami is enigmatic and contributions from Continental Europe, Eastern Europe and Asia have been proposed. To address the evolutionary history of northern and southern Swedish Sami, we have studied their mtDNA haplogroup frequencies and complete mtDNA genome sequences. While the majority of mtDNA diversity in the northern Swedish, Norwegian and Finnish Sami is accounted for by haplogroups V and U5b1b1, the southern Swedish Sami have other haplogroups and a frequency distribution similar to that of the Continental European population. Stratification of the southern Sami on the basis of occupation indicates that this is the result of recent admixture with the Swedish population. The divergence time for the Sami haplogroup V sequences is 7600 YBP (years before present), and for U5b1b1, 5500 YBP amongst Sami and 6600 YBP amongst Sami and Finns. This suggests an arrival in the region soon after the retreat of the glacial ice, either by way of Continental Europe and/or the Volga-Ural region. Haplogroup Z is found at low frequency in the Sami and Northern Asian populations but is virtually absent in Europe. Several conserved substitutions group the Sami Z lineages strongly with those from Finland and the Volga-Ural region of Russia, but distinguish them from Northeast Asian representatives. This suggests that some Sami lineages shared a common ancestor with lineages from the Volga-Ural region as recently as 2700 years ago, indicative of a more recent contribution of people from the Volga-Ural region to the Sami population.
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| 4. |
- Ingman, Max, et al.
(författare)
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Analysis of the complete human mtDNA genome : methodology and inferences for human evolution
- 2001
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Ingår i: Journal of Heredity. - 0022-1503 .- 1465-7333. ; 92:6, s. 454-61
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of mitochondrial DNA (mtDNA) sequences has been a potent tool in our understanding of human evolution. However, almost all studies of human evolution based on mtDNA sequencing have focused on the control region, which constitutes less than 7% of the mitochondrial genome. The rapid development of technology for automated DNA sequencing has made it possible to study the complete mtDNA genomes in large numbers of individuals, opening the field of mitochondrial population genomics. Here we describe a suitable methodology for determining the complete human mitochondrial sequence and the global mtDNA diversity in humans. Also, we discuss the implications of the results with respect to the different hypotheses for the evolution of modern humans.
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| 5. |
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| 6. |
- Ingman, Max, 1970-
(författare)
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Mitochondria and Human Evolution
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondrial DNA (mtDNA) has been a potent tool in studies of the evolution of modern humans, human migrations and the dynamics of human populations over time. The popularity of this cytoplasmic genome has largely been due to its clonal inheritance (in Man) allowing the tracing of a direct genetic line. In addition, a comparatively high rate of nucleotide substitution facilitates phylogenetic resolution among relatively closely related individuals of the same species.In this thesis, a statistically supported phylogeny based on complete mitochondrial genome sequences is presented which, for the first time, unambiguously places the root of modern human mitochondrial lineages in Africa in the last 200 thousand years. This conclusion provides strong support for the “recent African origin” hypothesis. Also, the complete genome data underline the problematic nature of traditional approaches to analyses of mitochondrial phylogenies.The dispersal of anatomically modern humans from the African continent is examined through single nucleotide polymorphism (SNP) and sequence data. These data imply an expansion from Africa about 57 thousand years ago and a subsequent population dispersal into Asia. The dispersal coincides with a major population division that may be the result of multiple migratory routes to East Asia.Also investigated is the question of a common origin for the indigenous peoples of Australia and New Guinea. Previous studies have been equivocal on this question with some presenting evidence for a common genetic origin and other proposing separate histories. Our data reveals an ancient genetic link between Australian Aborigines and the peoples of the New Guinea highlands.
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| 7. |
- Ingman, Max, et al.
(författare)
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Mitochondrial genome variation and evolutionary history of Australian and New Guinean aborigines
- 2003
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 13:7, s. 1600-6
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Tidskriftsartikel (refereegranskat)abstract
- To study the evolutionary history of the Australian and New Guinean indigenous peoples, we analyzed 101 complete mitochondrial genomes including populations from Australia and New Guinea as well as from Africa, India, Europe, Asia, Melanesia, and Polynesia. The genetic diversity of the Australian mitochondrial sequences is remarkably high and is similar to that found across Asia. This is in contrast to the pattern seen in previously described Y-chromosome data where an Australia-specific haplotype was found at high frequency. The mitochondrial genome data indicate that Australia was colonized between 40 and 70 thousand years ago, either by a single migration from a heterogeneous source population or by multiple movements of smaller groups occurring over a period of time. Some Australian and New Guinea sequences form clades, suggesting the possibility of a joint colonization and/or admixture between the two regions.
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