| 1. |
- Andersson, Veronica, 1979, et al.
(författare)
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Enhancing protein disaggregation restores proteasome activity in aged cells
- 2013
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Ingår i: Aging-Us. - 1945-4589. ; 5:11, s. 802-812
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Tidskriftsartikel (refereegranskat)abstract
- The activity of the ubiquitin-proteasome system, UPS, declines during aging in several multicellular organisms. The reason behind this decline remains elusive. Here, using yeast as a model system, we show that while the level and potential capacity of the 26S proteasome is maintained in replicatively aged cells, the UPS is not functioning properly in vivo. As a consequence cytosolic UPS substrates, such as Delta ssCPY* are stabilized, accumulate, and form inclusions. By integrating a pGPD-HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. Remarkably, this elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age-associated aggregation obstructs UPS function. The data supports the existence of a negative feedback loop that accelerates aging by exacerbating proteostatic decline once misfolded and aggregation-prone proteins reach a critical level.
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| 2. |
- Dalen, Love, et al.
(författare)
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Ancient DNA reveals lack of postglacial habitat tracking in the arctic fox
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:16, s. 6726-6729
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Tidskriftsartikel (refereegranskat)abstract
- How species respond to an increased availability of habitat, for example at the end of the last glaciation, has been well established. In contrast, little is known about the opposite process, when the amount of habitat decreases. The hypothesis of habitat tracking predicts that species should be able to track both increases and decreases in habitat availability. The alternative hypothesis is that populations outside refugia become extinct during periods of unsuitable climate. To test these hypotheses, we used ancient DNA techniques to examine genetic variation in the arctic fox (Alopex lagopus) through an expansion/contraction cycle. The results show that the arctic fox in midlatitude Europe became extinct at the end of the Pleistocene and did not track the habitat when it shifted to the north. Instead, a high genetic similarity between the extant populations in Scandinavia and Siberia suggests an eastern origin for the Scandinavian population at the end of the last glaciation. These results provide new insights into how species respond to climate change, since they suggest that populations are unable to track decreases in habitat avaliability. This implies that arctic species may be particularly vulnerable to increases in global temperatures.
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| 3. |
- Hanzén, Sarah, et al.
(författare)
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Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins
- 2016
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 166:1, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.
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| 4. |
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| 5. |
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| 6. |
- Niemi, Marianna, et al.
(författare)
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Mitochondrial DNA and Y-chromosomal diversity in ancient populations of domestic sheep (Ovis aries) in Finland : comparison with contemporary sheep breeds
- 2013
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Ingår i: Genetics Selection Evolution. - : Springer Science and Business Media LLC. - 0999-193X .- 1297-9686. ; 45, s. 2-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several molecular and population genetic studies have focused on the native sheep breeds of Finland. In this work, we investigated their ancestral sheep populations from Iron Age, Medieval and Post-Medieval periods by sequencing a partial mitochondrial DNA D-loop and the 5'-promoter region of the SRY gene. We compared the maternal (mitochondrial DNA haplotypes) and paternal (SNP oY1) genetic diversity of ancient sheep in Finland with modern domestic sheep populations in Europe and Asia to study temporal changes in genetic variation and affinities between ancient and modern populations. Results: A 523-bp mitochondrial DNA sequence was successfully amplified for 26 of 36 sheep ancient samples i.e. five, seven and 14 samples representative of Iron Age, Medieval and Post-Medieval sheep, respectively. Genetic diversity was analyzed within the cohorts. This ancient dataset was compared with present-day data consisting of 94 animals from 10 contemporary European breeds and with GenBank DNA sequence data to carry out a haplotype sharing analysis. Among the 18 ancient mitochondrial DNA haplotypes identified, 14 were present in the modern breeds. Ancient haplotypes were assigned to the highly divergent ovine haplogroups A and B, haplogroup B being the major lineage within the cohorts. Only two haplotypes were detected in the Iron Age samples, while the genetic diversity of the Medieval and Post-Medieval cohorts was higher. For three of the ancient DNA samples, Y-chromosome SRY gene sequences were amplified indicating that they originated from rams. The SRY gene of these three ancient ram samples contained SNP G-oY1, which is frequent in modern north-European sheep breeds. Conclusions: Our study did not reveal any sign of major population replacement of native sheep in Finland since the Iron Age. Variations in the availability of archaeological remains may explain differences in genetic diversity estimates and patterns within the cohorts rather than demographic events that occurred in the past. Our ancient DNA results fit well with the genetic context of domestic sheep as determined by analyses of modern north-European sheep breeds.
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| 7. |
- Niemi, Marianna, et al.
(författare)
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Temporal Fluctuation in North East Baltic Sea Region Cattle Population Revealed by Mitochondrial and Y-Chromosomal DNA Analyses
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Ancient DNA analysis offers a way to detect changes in populations over time. To date, most studies of ancient cattle have focused on their domestication in prehistory, while only a limited number of studies have analysed later periods. Conversely, the genetic structure of modern cattle populations is well known given the undertaking of several molecular and population genetic studies. Results Bones and teeth from ancient cattle populations from the North-East Baltic Sea region dated to the Prehistoric (Late Bronze and Iron Age, 5 samples), Medieval (14), and Post-Medieval (26) periods were investigated by sequencing 667 base pairs (bp) from the mitochondrial DNA (mtDNA) and 155 bp of intron 19 in the Y-chromosomal UTY gene. Comparison of maternal (mtDNA haplotypes) genetic diversity in ancient cattle (45 samples) with modern cattle populations in Europe and Asia (2094 samples) revealed 30 ancient mtDNA haplotypes, 24 of which were shared with modern breeds, while 6 were unique to the ancient samples. Of seven Y-chromosomal sequences determined from ancient samples, six were Y2 and one Y1 haplotype. Combined data including Swedish samples from the same periods (64 samples) was compared with the occurrence of Y-chromosomal haplotypes in modern cattle (1614 samples). Conclusions The diversity of haplogroups was highest in the Prehistoric samples, where many haplotypes were unique. The Medieval and Post-Medieval samples also show a high diversity with new haplotypes. Some of these haplotypes have become frequent in modern breeds in the Nordic Countries and North-Western Russia while other haplotypes have remained in only a few local breeds or seem to have been lost. A temporal shift in Y-chromosomal haplotypes from Y2 to Y1 was detected that corresponds with the appearance of new mtDNA haplotypes in the Medieval and Post-Medieval period. This suggests a replacement of the Prehistoric mtDNA and Y- chromosomal haplotypes by new types of cattle.
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| 8. |
- Norén, Karin, et al.
(författare)
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Farmed arctic foxes on the Fennoscandian mountain tundra : implications for conservation
- 2009
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Ingår i: Animal Conservation. - : Wiley. - 1367-9430 .- 1469-1795. ; 12:5, s. 434-444
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Tidskriftsartikel (refereegranskat)abstract
- Hybridization between wild and captive-bred individuals is a serious conservation issue that requires measures to prevent negative effects. Such measures are, however, often considered controversial by the public, especially when concerning charismatic species. One of the threats to the critically endangered Fennoscandian arctic fox Alopex lagopus is hybridization with escaped farm foxes, conveying a risk of outbreeding depression through loss of local adaptations to the lemming cycle. In this study, we investigate the existence of escaped farm foxes among wild arctic foxes and whether hybridization has occurred in the wild. We analysed mitochondrial control region sequences and 10 microsatellite loci in samples from free-ranging foxes and compared them with reference samples of known farm foxes and true Fennoscandian arctic foxes. We identified the farm fox specific mitochondrial haplotype H9 in 25 out of 182 samples, 21 of which had been collected within or nearby the wild subpopulation on Hardangervidda in south-western Norway. Genetic analyses of museum specimens collected on Hardangervidda (1897–1975) suggested that farm fox genotypes have recently been introduced to the area. Principal component analysis as well as both model- and frequency-based analyses of microsatellite data imply that the free-ranging H9s were farm foxes rather than wild arctic foxes and that the entire Hardangervidda population consisted of farm foxes or putative hybrids. We strongly recommend removal of farm foxes and hybrids in the wild to prevent genetic pollution of the remaining wild subpopulations of threatened arctic foxes.
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| 9. |
- Nyström, Veronica, et al.
(författare)
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Genetic consequences of a demographic bottleneck in the Scandinavian arctic fox
- 2006
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Ingår i: Oikos. - : Wiley. - 0030-1299 .- 1600-0706. ; 114:1, s. 84-94
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Tidskriftsartikel (refereegranskat)abstract
- Demographic bottlenecks can result in a loss of genetic variation due to the bottleneck effect and subsequent genetic drift. The arctic fox population in Scandinavia went through a severe demographic bottleneck in the early 20th century, and is today classified as critically endangered. In this study, we investigated the pre-bottleneck genetic variation in Scandinavia and compared it to modern samples from Scandinavia and North Russia. Variation in the mtDNA control region and five microsatellite loci was examined through ancient DNA analysis on museum specimens. The microsatellite data from the museum specimens was further used to simulate the expected effect of the bottleneck. The arctic foxes in Scandinavia have lost approximately 25% of the microsatellite alleles and four out of seven mtDNA haplotypes. The results also suggest that the genetic differentiation between North Russia and Scandinavia has doubled over the last 100 years. However, the level of heterozygosity was significantly higher than expected from the simulations. This highlights both the advantage of using museum specimens and the importance of generating specific predictions in conservation genetics.
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| 10. |
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| 11. |
- Nyström, Veronica, et al.
(författare)
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Microsatellite genotyping reveals end-Pleistocene decline in mammoth autosomal genetic variation
- 2012
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Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 21:14, s. 3391-3402
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Tidskriftsartikel (refereegranskat)abstract
- The last glaciation was a dynamic period with strong impact on the demography of many species and populations. In recent years, mitochondrial DNA sequences retrieved from radiocarbon-dated remains have provided novel insights into the history of Late Pleistocene populations. However, genotyping of loci from the nuclear genome may provide enhanced resolution of population-level changes. Here, we use four autosomal microsatellite DNA markers to investigate the demographic history of woolly mammoths (Mammuthus primigenius) in north-eastern Siberia from before 60 000 years ago up until the species final disappearance c. 4000 years ago. We identified two genetic groups, implying a marked temporal genetic differentiation between samples with radiocarbon ages older than 12 thousand radiocarbon years before present (ka) and those younger than 9 ka. Simulation-based analysis indicates that this dramatic change in genetic composition, which included a decrease in individual heterozygosity of approximately 30%, was due to a multifold reduction in effective population size. A corresponding reduction in genetic variation was also detected in the mitochondrial DNA, where about 65% of the diversity was lost. We observed no further loss in genetic variation during the Holocene, which suggests a rapid final extinction event.
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| 12. |
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| 13. |
- Nyström, Veronica, 1979-
(författare)
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Studies of declining populations - temporal genetic analyses of two arctic mammals
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many populations and species are threatened with extinction today. Understanding the extinction process and the factors behind population decline is therefore important. In this thesis, genetic analyses were performed on temporally spaced samples to investigate the demographic history and genetic effects of population reduction of two species: the arctic fox (Vulpes lagopus) and the woolly mammoth (Mammuthus primigenius). We used ancient DNA techniques to measure genetic variation in both mitochondrial DNA and microsatellites. In paper I, we investigated the genetic consequences of a human-induced demographic bottleneck in the Scandinavian arctic fox population. By comparing genetic data from museum specimens with genetic data from the contemporary population, we found a loss of genetic variation. However, the loss was less than expected, probably due to gene flow from North Russia. Using the same approach, we also found that Pleistocene arctic foxes from midlatitude Europe do not seem to have contributed to the genetic composition of contemporary populations (paper II). This suggests that they went extinct rather than track their habitat when it shifted northwards at the end of Pleistocene. Further, by analysing genetic data from radiocarbon dated fossils, we also found that the woolly mammoth lost genetic variation in connection to a marked decline in population size at the end of Pleistocene (paper III and IV). However, no further losses were detected during the time that mammoths were isolated on Wrangel Island, which suggests a rapid extinction process possibly caused by the arrival of humans or a short-term change in climate (paper III and IV). The results in this thesis demonstrate the usefulness of temporal genetic analyses for identifying population decline and evaluating its consequences.
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| 14. |
- Nyström, Veronica, et al.
(författare)
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Temporal genetic change in the last remaining population of woolly mammoth
- 2010
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 277:1692, s. 2331-2337
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Tidskriftsartikel (refereegranskat)abstract
- During the Late Pleistocene, the woolly mammoth (Mammuthus primigenius) experienced a series of local extinctions generally attributed to human predation or environmental change. Some small and isolated populations did however survive far into the Holocene. Here, we investigated the genetic consequences of the isolation of the last remaining mammoth population on Wrangel Island. We analysed 741 bp of the mitochondrial DNA and found a loss of genetic variation in relation to the isolation event, probably caused by a demographic bottleneck or a founder event. However, in spite of ca 5000 years of isolation, we did not detect any further loss of genetic variation. Together with the relatively high number of mitochondrial haplotypes on Wrangel Island near the final disappearance, this suggests a sudden extinction of a rather stable population.
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| 15. |
- Palkopoulou, Eleftheria, et al.
(författare)
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Holarctic genetic structure and range dynamics in the woolly mammoth
- 2013
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 280:1770, s. 20131910-
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Tidskriftsartikel (refereegranskat)abstract
- Ancient DNA analyses have provided enhanced resolution of population histories in many Pleistocene taxa. However, most studies are spatially restricted, making inference of species-level biogeographic histories difficult. Here, we analyse mitochondrial DNA (mtDNA) variation in the woolly mammoth from across its Holarctic range to reconstruct its history over the last 200 thousand years (kyr). We identify a previously undocumented major mtDNA lineage in Europe, which was replaced by another major mtDNA lineage 32-34 kyr before present (BP). Coalescent simulations provide support for demographic expansions at approximately 121 kyr BP, suggesting that the previous interglacial was an important driver for demography and intraspecific genetic divergence. Furthermore, our results suggest an expansion into Eurasia from America around 66 kyr BP, coinciding with the first exposure of the Bering Land Bridge during the Late Pleistocene. Bayesian inference indicates Late Pleistocene demographic stability until 20-15 kyr BP, when a severe population size decline occurred.
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| 16. |
- Pilheden, Mattias, et al.
(författare)
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Duplex sequencing uncovers recurrent low-frequency cancer-associated mutations in infant and childhood KMT2A-rearranged acute leukemia
- 2022
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Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3D835H or NRASG13D/G12S mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.
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| 17. |
- Tison, Jean-Luc, 1985-, et al.
(författare)
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Signature of post-glacial expansion and genetic structure at the northern range limit of the speckled wood butterfly
- 2014
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Ingår i: Biological Journal of the Linnean Society. - : Oxford University Press. - 0024-4066 .- 1095-8312. ; 113:1, s. 136-148
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Tidskriftsartikel (refereegranskat)abstract
- The post-glacial recolonisation of northern Europe has left distinct signatures in the genomes of many organisms, both due to random demographic processes and divergent natural selection. However, information on differences in genetic variation in conjunction with patterns of local adaptations along latitudinal gradients is often lacking. In this study, we examine genetic diversity and population structure in the speckled wood butterfly Pararge aegeria in northern Europe to investigate the species post-glacial recolonisation history and discuss how this may have affected its life-history evolution. We collected 209 samples and analysed genetic variation in nine microsatellite loci. The results demonstrated a more pronounced population structure in northern Europe compared with populations further south, as well as an overall decrease in genetic diversity with latitude, likely due to founder effects during the recolonisation process. Coalescent simulations coupled with approximate Bayesian computation suggested that central Scandinavia was colonised from the south, rather than from the east. In contrast to further south, populations at the northern range margin are univoltine expressing only one generation per year. This suggests either that univoltinism evolved independently on each side of the Baltic Sea, or that bivoltinism evolved in the south after northern Europe was recolonised.
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