| 1. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
|
|
| 2. |
- Lin, Audrey T., et al.
(författare)
-
The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge
- 2023
-
Ingår i: Science. - 0036-8075 .- 1095-9203. ; 382:6676, s. 1303-1308
-
Tidskriftsartikel (refereegranskat)abstract
- Ancestral Coast Salish societies in the Pacific Northwest kept long-haired woolly dogs that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton", collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.
|
|
| 3. |
- Sinding, Mikkel-Holger S., et al.
(författare)
-
Arctic-adapted dogs emerged at the Pleistocene-Holocene transition
- 2020
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 368:6498
-
Tidskriftsartikel (refereegranskat)abstract
- Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an similar to 9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an similar to 33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.
|
|
| 4. |
- Bergström, Anders, et al.
(författare)
-
Grey wolf genomic history reveals a dual ancestry of dogs
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 607:7918, s. 313-320
-
Tidskriftsartikel (refereegranskat)abstract
- The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canis familiaris) lived. Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000–30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.
|
|
| 5. |
- Bouazza, Naim, et al.
(författare)
-
General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children
- 2022
-
Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 88:12, s. 4985-4996
-
Forskningsöversikt (refereegranskat)abstract
- Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.
|
|
| 6. |
- Fiddaman, Steven R., et al.
(författare)
-
Ancient chicken remains reveal the origins of virulence in Marek's disease virus
- 2023
-
Ingår i: Science (New York, N.Y.). - 1095-9203. ; 382:6676, s. 1276-1281
-
Tidskriftsartikel (refereegranskat)abstract
- The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.
|
|
| 7. |
- Mayama, Satoshi, et al.
(författare)
-
Subaru Near-infrared Imaging Polarimetry of Misaligned Disks around the SR 24 Hierarchical Triple System
- 2020
-
Ingår i: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 159:1
-
Tidskriftsartikel (refereegranskat)abstract
- The SR 24 multistar system hosts both circumprimary and circumsecondary disks, which are strongly misaligned with each other. The circumsecondary disk is circumbinary in nature. Interestingly, both disks are interacting, and they possibly rotate in opposite directions. To investigate the nature of this unique twin disk system, we present 01 resolution near-infrared polarized intensity images of the circumstellar structures around SR 24, obtained with HiCIAO mounted on the Subaru 8.2 m telescope. Both the circumprimary disk and the circumsecondary disk are resolved and have elongated features. While the position angle of the major axis and radius of the near-IR (NIR) polarization disk around SR 24S are 55° and 137 au, respectively, those around SR 24N are 110° and 34 au, respectively. With regard to overall morphology, the circumprimary disk around SR 24S shows strong asymmetry, whereas the circumsecondary disk around SR 24N shows relatively strong symmetry. Our NIR observations confirm the previous claim that the circumprimary and circumsecondary disks are misaligned from each other. Both the circumprimary and circumsecondary disks show similar structures in 12CO observations in terms of its size and elongation direction. This consistency is because both NIR and 12CO are tracing surface layers of the flared disks. As the radius of the polarization disk around SR 24N is roughly consistent with the size of the outer Roche lobe, it is natural to interpret the polarization disk around SR 24N as a circumbinary disk surrounding the SR 24Nb–Nc system.
|
|
| 8. |
- Meadows, Jennifer, et al.
(författare)
-
Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture
- 2023
-
Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 24
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 x data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function.Results: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection.Conclusions: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.
|
|
| 9. |
- Yang, Yi, et al.
(författare)
-
High-resolution Near-infrared Polarimetry and Submillimeter Imaging of FS Tau A : Possible Streamers in Misaligned Circumbinary Disk System
- 2020
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 889:2
-
Tidskriftsartikel (refereegranskat)abstract
- We analyzed the young (2.8 Myr-old) binary system FS Tau A using near-infrared (H-band) high -contrast polarimetry data from Subaru/HiCIAO and submillimeter CO (J = 2-1) line emission data from Atacama Large Millimeter/submillimeter Array (ALMA). Both the near-infrared and submillimeter observations reveal several clear structures extending to similar to 240 au from the stars. Based on these observations at different wavelengths, we report the following discoveries. One arm-like structure detected in the near-infrared band initially extends from the south of the binary with a subsequent turn to the northeast, corresponding to two bar-like structures detected in ALMA observations with an local standard of rest kinematic (LSRK) velocity of 1.19-5.64 km s(-1). Another feature detected in the near-infrared band extends initially from the north of the binary, relating to an arm-like structure detected in ALMA observations with an LSRK velocity of 8.17-16.43 km s(-1). From their shapes and velocities, we suggest that these structures can mostly be explained by two streamers that connect the outer circumbinary disk and the central binary components. These discoveries will be helpful for understanding the evolution of streamers and circumstellar disks in young binary systems.
|
|
| 10. |
- Burgert-Brucker, Clara R., et al.
(författare)
-
Risk factors associated with failing pre-transmission assessment surveys (pre-TAS) in lymphatic filariasis elimination programs : Results of a multi-country analysis
- 2020
-
Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 14:6
-
Tidskriftsartikel (refereegranskat)abstract
- Achieving elimination of lymphatic filariasis (LF) as a public health problem requires a minimum of five effective rounds of mass drug administration (MDA) and demonstrating low prevalence in subsequent assessments. The first assessments recommended by the World Health Organization (WHO) are sentinel and spot-check sites-referred to as pre-transmission assessment surveys (pre-TAS)-in each implementation unit after MDA. If pre-TAS shows that prevalence in each site has been lowered to less than 1% microfilaremia or less than 2% antigenemia, the implementation unit conducts a TAS to determine whether MDA can be stopped. Failure to pass pre-TAS means that further rounds of MDA are required. This study aims to understand factors influencing pre-TAS results using existing programmatic data from 554 implementation units, of which 74 (13%) failed, in 13 countries. Secondary data analysis was completed using existing data from Bangladesh, Benin, Burkina Faso, Cameroon, Ghana, Haiti, Indonesia, Mali, Nepal, Niger, Sierra Leone, Tanzania, and Uganda. Additional covariate data were obtained from spatial raster data sets. Bivariate analysis and multilinear regression were performed to establish potential relationships between variables and the pre-TAS result. Higher baseline prevalence and lower elevation were significant in the regression model. Variables statistically significantly associated with failure (p-value <= 0.05) in the bivariate analyses included baseline prevalence at or above 5% or 10%, use of Filariasis Test Strips (FTS), primary vector of Culex, treatment with diethylcarbamazine-albendazole, higher elevation, higher population density, higher enhanced vegetation index (EVI), higher annual rainfall, and 6 or more rounds of MDA. This paper reports for the first time factors associated with pre-TAS results from a multi-country analysis. This information can help countries more effectively forecast program activities, such as the potential need for more rounds of MDA, and prioritize resources to ensure adequate coverage of all persons in areas at highest risk of failing pre-TAS.
|
|
