| 1. |
- McCarthy, Shane, et al.
(författare)
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A reference panel of 64,976 haplotypes for genotype imputation
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
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Tidskriftsartikel (refereegranskat)abstract
- We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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| 2. |
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| 3. |
- Castensson, Anja, et al.
(författare)
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Serotonin Receptor 2C (HTR2C) and Schizophrenia : Examination of Possible Medication and Genetic Influences on Expression Levels
- 2005
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Ingår i: American Journal of Medical Genetics. - : Wiley. - 0148-7299 .- 1096-8628. ; 134B, s. 84-89
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Tidskriftsartikel (refereegranskat)abstract
- The serotonin receptor 2C (HTR2C) gene is of interest in schizophrenia due to its involvement in regulation of dopamine activity in the prefrontal cortex. We have previously reported a decreased expression of HTR2C mRNA levels in the prefrontal cortex of schizophrenia patients. The variability in mRNA expression levels is evaluated here more closely in relation to promoter haplotypes and neuroleptic treatment received by the patients. The decrease in HTR2C mRNA was present in neuroleptic treated individuals and in patients untreated at death, indicating that the lower expression is not a short-term medication effect. Three promoter polymorphisms were used to construct haplotypes. No SNP displayed genotypic or haplotypic association with the disease. Gene expression of HTR2C was not affected by haplotype and the expression decrease in schizophrenia patients was similar in all haplotype combinations (diplotypes). We conclude that the decrease in HTR2C expression in schizophrenia may be related to the disease mechanism rather than to drug treatment. The disease related changes in HTR2C expression are not related to the promoter variants typed in our sample, but could be due to other regulatory variants or trans-acting factors.
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| 4. |
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| 5. |
- Gauthier, Jérémy, et al.
(författare)
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First chromosome scale genomes of ithomiine butterflies (Nymphalidae: Ithomiini) : Comparative models for mimicry genetic studies
- 2023
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Ingår i: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 23:4, s. 872-885
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Tidskriftsartikel (refereegranskat)abstract
- The ithomiine butterflies (Nymphalidae: Danainae) represent the largest known radiation of Müllerian mimetic butterflies. They dominate by number the mimetic butterfly communities, which include species such as the iconic neotropical Heliconius genus. Recent studies on the ecology and genetics of speciation in Ithomiini have suggested that sexual pheromones, colour pattern and perhaps hostplant could drive reproductive isolation. However, no reference genome was available for Ithomiini, which has hindered further exploration on the genetic architecture of these candidate traits, and more generally on the genomic patterns of divergence. Here, we generated high-quality, chromosome-scale genome assemblies for two Melinaea species, M. marsaeus and M. menophilus, and a draft genome of the species Ithomia salapia. We obtained genomes with a size ranging from 396 to 503 Mb across the three species and scaffold N50 of 40.5 and 23.2 Mb for the two chromosome-scale assemblies. Using collinearity analyses we identified massive rearrangements between the two closely related Melinaea species. An annotation of transposable elements and gene content was performed, as well as a specialist annotation to target chemosensory genes, which is crucial for host plant detection and mate recognition in mimetic species. A comparative genomic approach revealed independent gene expansions in ithomiines and particularly in gustatory receptor genes. These first three genomes of ithomiine mimetic butterflies constitute a valuable addition and a welcome comparison to existing biological models such as Heliconius, and will enable further understanding of the mechanisms of adaptation in butterflies.
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| 6. |
- Green, Richard E., et al.
(författare)
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Three crocodilian genomes reveal ancestral patterns of evolution among archosaurs
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1335-
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Tidskriftsartikel (refereegranskat)abstract
- To provide context for the diversification of archosaurs-the group that includes crocodilians, dinosaurs, and birds-we generated draft genomes of three crocodilians: Alligator mississippiensis (the American alligator), Crocodylus porosus (the saltwater crocodile), and Gavialis gangeticus (the Indian gharial). We observed an exceptionally slow rate of genome evolution within crocodilians at all levels, including nucleotide substitutions, indels, transposable element content and movement, gene family evolution, and chromosomal synteny. When placed within the context of related taxa including birds and turtles, this suggests that the common ancestor of all of these taxa also exhibited slow genome evolution and that the comparatively rapid evolution is derived in birds. The data also provided the opportunity to analyze heterozygosity in crocodilians, which indicates a likely reduction in population size for all three taxa through the Pleistocene. Finally, these data combined with newly published bird genomes allowed us to reconstruct the partial genome of the common ancestor of archosaurs, thereby providing a tool to investigate the genetic starting material of crocodilians, birds, and dinosaurs.
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| 7. |
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| 8. |
- McCarthy, Shane
(författare)
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Comparative sequencing of candidate genes in complex disease
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Complex multi-factorial diseases such as cardiovascular, metabolic, neurological and respiratory disorders affect a great number of people across the world. In the post-Human Genome Sequencing era, genome wide association studies are increasingly viable alternatives to linkage approaches in locating disease genes. In addition, positional and hypothesis-driven candidate genes can be assessed for their role in susceptibility to sporadic common diseases. The efficiency and success of these approaches depend on knowledge of DNA variation and linkage disequilibrium. This thesis describes the comparative sequencing of regions across the candidate genes HTR2C, MA OA MAOB, IDE, KIF11 and HHEX to illustrate the importance of understanding the fine scale nucleotide and LD distribution for improvements in association study design with Obsesty, Depression and Alzheimer's disease. In HTR2C, recombination between the commonly used nsSNP marker, Cys23Ser, and the promoter was observed (Paper I). Furthermore, nucleotide and haplotype analysis showed that gene conversion in the promoter contributed to the complexity of LD. If the functional promoter polymorphisms act in the susceptibility to serotonergic-related phenotypes, this work suggests that the unknown structure of LD across HTR2C could have been an issue in previous association studies using Cys23Ser. Support for HTR2C promoter polymorphisms in obesity was provided by the associations of promoter haplotype, TA 13GCG ( P>0.0001) with BMI 30 > kgm-2 and promoter SNP, -995G>A, (P = 0.01) with serum-leptin/%body fat (Paper I). Suggestive, but not significant, effects were observed by the HTR2C promoter haplotype GGCC in depression (Paper IV). Sequence variation was scarce in the AL40 regions studied. This contributes to the hypothesis that these genes are under selective pressure and that much of the variants in public databases for MAOA/B could be population specific (Paper II). Lack of MAO variation was reflected in the poor validation rate of SNPs and LD complex structure in a Swedish twin sample group. While MAOB SNPs were found to correlate with depressive state in elderly Swedish Twins, no association was observed with polymorphisms in this gene and trbcactivity (Paper II). Conversely, low trbc-activity was found to associate with MAOA SNPs and haplotypes. A potentially additive effect on the risk for depression per MAO haplotype was observed. In a larger sample no significant associations were found with any of the MAO SNPs are haplotypes (Paper IV). However, a trend towards departures from HWE between the genes may suggest that this region warrents further sequencing to identify potential regulatory mechanisms of MAO expression. A wealth of polymorphisms was found in re-sequencing IDE, KIF11, HHEX and conserved regions within a haplotype block associated with Alzheimer's Disease. However, no significant associations between IDE and KIF11 SNPs, and Alzheimer's disease were observed. These works demonstrate the advantages of re-sequencing in providing a better understanding of the various genetic factors influencing studies of polymorphisms with complex diseases. With advances in technology and throughput, sequencing will become instrumental in the location of disease genes and the identification of causative polymorphisms.
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| 9. |
- Ovchinnikov, Vladimir, et al.
(författare)
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Caecilian Genomes Reveal the Molecular Basis of Adaptation and Convergent Evolution of Limblessness in Snakes and Caecilians
- 2023
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 40:5
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Tidskriftsartikel (refereegranskat)abstract
- We present genome sequences for the caecilians Geotrypetes seraphini (3.8 Gb) and Microcaecilia unicolor (4.7 Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons being the most abundant. We identify 1,150 orthogroups that are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception, and immunity amongst others. We discover that caecilian genomes are missing the zone of polarizing activity regulatorysequence (ZRS) enhancer of Sonic Hedgehog which is also mutated in snakes. In vivo deletions have shown ZRS is required for limb development in mice, thus, revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.
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| 10. |
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