| 1. |
- Dadras, Mahsa Shahidi, et al.
(författare)
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The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma
- 2021
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.
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| 2. |
- Bi, Huijuan, et al.
(författare)
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A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken
- 2023
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 19:4
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Tidskriftsartikel (refereegranskat)abstract
- The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.
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| 3. |
- Bianchi, Matteo, et al.
(författare)
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Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs
- 2020
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Ingår i: BMC Genomics. - : BMC. - 1471-2164. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed.Results: By employing genome-wide association followed by fine-mapping (top variant p-value=5.7x10(-6)), integrated with whole-genome resequencing and copy number variation analysis, we detected a similar to 8.9 kbp deletion strongly associated (p-value=0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail.Conclusions: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies.
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| 4. |
- Edvardsen, Rolf Brudvik, et al.
(författare)
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Heterochiasmy and the establishment of gsdf as a novel sex determining gene in Atlantic halibut
- 2022
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 18:2
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Tidskriftsartikel (refereegranskat)abstract
- Atlantic Halibut (Hippoglossus hippoglossus) has a X/Y genetic sex determination system, but the sex determining factor is not known. We produced a high-quality genome assembly from a male and identified parts of chromosome 13 as the Y chromosome due to sequence divergence between sexes and segregation of sex genotypes in pedigrees. Linkage analysis revealed that all chromosomes exhibit heterochiasmy, i.e. male-only and female-only meiotic recombination regions (MRR/FRR). We show that FRR/MRR intervals differ in nucleotide diversity and repeat class content and that this is true also for other Pleuronectidae species. We further show that remnants of a Gypsy-like transposable element insertion on chr13 promotes early male specific expression of gonadal somatic cell derived factor (gsdf). Less than 4.5 MYA, this male-determining element evolved on an autosomal FRR segment featuring pre-existing male meiotic recombination barriers, thereby creating a Y chromosome. Our findings indicate that heterochiasmy may facilitate the evolution of genetic sex determination systems relying on linkage of sexually antagonistic loci to a sex-determining factor. Author summaryEven closely related fish species can have different sex chromosomes, but this turn-over of sex determination systems is poorly understood. Here, we used large-scale genome sequencing to determine the DNA sequence of the Atlantic halibut chromosomes and compared sequencing data from males and females to identify the sex chromosomes. We show that males have much higher gene activity of the gene gonadal somatic cell derived factor (gsdf), which is located on the sex chromosomes and has a role in testicular development. The genome contains many mobile DNA sequences, transposable elements (TEs), one placed in front of gsdf, enhancing its activity. This made gsdf the sex determining factor, thereby creating a new Y-chromosome. We further describe how all Atlantic halibut chromosomes behave similar to sex chromosomes in that most regions only recombine in one sex. This phenomenon may contribute to the rapid turn-over of genetic sex determination systems in fish. Our results highlight the molecular events creating a new Y-chromosome and show that the new Atlantic halibut Y was formed less than 4.5 million years ago. Future studies in Atlantic halibut and closely related species can shed light on mechanisms contributing to sex chromosome evolution in fish.
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| 5. |
- Enbody, Erik D., et al.
(författare)
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A multispecies BCO2 beak color polymorphism in the Darwin's finch radiation
- 2021
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Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 31:24, s. 5597-5604.e7
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Tidskriftsartikel (refereegranskat)abstract
- Carotenoid-based polymorphisms are widespread in populations of birds, fish, and reptiles,(1) but generally little is known about the factors affecting their maintenance in populations.(2) We report a combined field and molecular-genetic investigation of a nestling beak color polymorphism in Darwin's finches. Beaks are pink or yellow, and yellow is recessive.(3) Here we show that the polymorphism arose in the Galapagos half a million years ago through a mutation associated with regulatory change in the BCO2 gene and is shared by 14 descendant species. The polymorphism is probably a balanced polymorphism, maintained by ecolog- ical selection associated with survival and diet. In cactus finches, the frequency of the yellow genotype is correlated with cactus fruit abundance and greater hatching success and may be altered by introgressive hybridization. Polymorphisms that are hidden as adults, as here, may be far more common than is currently recognized, and contribute to diversification in ways that are yet to be discovered.
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| 6. |
- Enbody, Erik D., et al.
(författare)
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Community-wide genome sequencing reveals 30 years of Darwin's finch evolution
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 381:6665, s. 1427-
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Tidskriftsartikel (refereegranskat)abstract
- A fundamental goal in evolutionary biology is to understand the genetic architecture of adaptive traits. Using whole-genome data of 3955 of Darwin's finches on the Galapagos Island of Daphne Major, we identified six loci of large effect that explain 45% of the variation in the highly heritable beak size of Geospiza fortis, a key ecological trait. The major locus is a supergene comprising four genes. Abrupt changes in allele frequencies at the loci accompanied a strong change in beak size caused by natural selection during a drought. A gradual change in Geospiza scandens occurred across 30 years as a result of introgressive hybridization with G. fortis. This study shows how a few loci with large effect on a fitness-related trait contribute to the genetic potential for rapid adaptive radiation.
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| 7. |
- Guo, Ying, et al.
(författare)
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Whole-genome selective sweep analyses identifies the region and candidate gene associated with white earlobe color in Mediterranean chickens
- 2024
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Ingår i: Poultry Science. - : Elsevier. - 0032-5791 .- 1525-3171. ; 103:1
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Tidskriftsartikel (refereegranskat)abstract
- We compared the genomes of multiple domestic chicken breeds with red and white earlobes to identify the differentiated regions between groups of breeds differing in earlobe color. This was done using a selective sweep mapping approach based on whole-genome sequence data. The most significant selective sweep was identified on chromosome 11, where the white earlobe chicken breeds originated from Mediterranean share a common haplotype, and where multiple candidate genes are located. The most plausible functional candidate gene is the Melanocor-tin 1 Receptor (MC1R), a receptor known to regulate pigmentation in the skin and hair, and it is also the gene with the strongest positional support from the haplotype-based analyses. It, however, still needs to be explored experimentally to identify effects also on chicken earlobe color variation. Our study is the first exploration of the genetic basis of white earlobe color in Mediterranean chickens using a selective sweep mapping method based on whole-genome sequencing data and shows its value for identifying likely func-tional genes mediating the pigmentation in earlobe. It also indicates a potential novel role of MC1R in birds and exemplifies how selection on fancy traits has influenced the genome during formation of the modern chicken breeds.
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| 8. |
- Hill, Jason, et al.
(författare)
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Spatiotemporal variations in retrovirus-host interactions among Darwin’s finches
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Endogenous retroviruses (ERVs) are inherited remnants of retroviruses that colonized host germline over millions of years, providing a sampling of retroviral diversity across time. Here, we utilize the strength of Darwin’s finches, a system synonymous with evolutionary studies, for investigating ERV history, revealing recent retrovirus-host interactions in natural populations. By mapping ERV variation across all species of Darwin’s finches and comparing with outgroup species, we highlight geographical and historical patterns of retrovirus-host occurrence, utilizing the system for evaluating the extent and timing of retroviral activity in hosts undergoing adaptive radiation and colonization of new environments. We find shared ERVs among all samples indicating retrovirus-host associations pre-dating host speciation, as well as considerable ERV variation across populations of the entire Darwin’s finches’ radiation. Unexpected ERV variation in finch species on different islands suggests historical changes in gene flow and selection. Non-random distribution of ERVs along and between chromosomes, and across finch species, suggests association between ERV accumulation and the rapid speciation of Darwin’s finches.
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| 9. |
- Hård, Joanna, et al.
(författare)
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Long-read whole-genome analysis of human single cells
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into the genomic architecture of individual cells. Clonally expanded CD8+ T-cells from a human donor were subjected to droplet-based multiple displacement amplification (dMDA) to generate long molecules with reduced bias. PacBio sequencing generated up to 40% genome coverage per single-cell, enabling detection of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, also in regions inaccessible by short reads. 28 somatic SNVs were detected, including one case of mitochondrial heteroplasmy. 5473 high-confidence SVs/cell were discovered, a sixteen-fold increase compared to Illumina-based results from clonally related cells. Single-cell de novo assembly generated a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, our work shows the promise of long-read sequencing toward characterization of the full spectrum of genetic variation in single cells.
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| 10. |
- Kjaerner-Semb, Erik, et al.
(författare)
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Comparison of anadromous and landlocked Atlantic salmon genomes reveals signatures of parallel and relaxed selection across the Northern Hemisphere
- 2021
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Ingår i: Evolutionary Applications. - : John Wiley & Sons. - 1752-4571. ; 14:2, s. 446-461
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Tidskriftsartikel (refereegranskat)abstract
- Most Atlantic salmon (Salmo salarL.) populations follow an anadromous life cycle, spending early life in freshwater, migrating to the sea for feeding, and returning to rivers to spawn. At the end of the last ice age similar to 10,000 years ago, several populations of Atlantic salmon became landlocked. Comparing their genomes to their anadromous counterparts can help identify genetic variation related to either freshwater residency or anadromy. The objective of this study was to identify consistently divergent loci between anadromous and landlocked Atlantic salmon strains throughout their geographical distribution, with the long-term aim of identifying traits relevant for salmon aquaculture, including fresh and seawater growth, omega-3 metabolism, smoltification, and disease resistance. We used a Pool-seq approach (n = 10-40 individuals per population) to sequence the genomes of twelve anadromous and six landlocked Atlantic salmon populations covering a large part of the Northern Hemisphere and conducted a genomewide association study to identify genomic regions having been under different selection pressure in landlocked and anadromous strains. A total of 28 genomic regions were identified and includedcadm1on Chr 13 andppargc1aon Chr 18. Seven of the regions additionally displayed consistently reduced heterozygosity in fish obtained from landlocked populations, including the genes gpr132, cdca4, and sertad2 on Chr 15. We also found 16 regions, includingigf1on Chr 17, which consistently display reduced heterozygosity in the anadromous populations compared to the freshwater populations, indicating relaxed selection on traits associated with anadromy in landlocked salmon. In conclusion, we have identified 37 regions which may harbor genetic variation relevant for improving fish welfare and quality in the salmon farming industry and for understanding life-history traits in fish.
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| 11. |
- Ou, Jen-Hsiang, et al.
(författare)
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Complex genetic architecture of the chicken Growth1 QTL region
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene, polygenic traits are influenced by multiple genetic loci, each exerting a modest effect on the trait. This cumulative impact of numerous genes, interactions among them, environmental factors, and epigenetic modifications results in a multifaceted architecture of genetic contributions to complex traits.Given the well-characterized genome, diverse traits, and range of genetic resources, chicken (Gallus gallus) was employed as a model organism to dissect the intricate genetic makeup of a previously identified major Quantitative Trait Loci (QTL) for body weight on chromosome 1.A multigenerational advanced intercross line (AIL) of 3215 chickens whose genomes had been sequenced to an average of 0.4x was analyzed using genome-wide association study (GWAS) and variance-heterogeneity GWAS (vGWAS) to identify markers associated with 8-week body weight. Additionally, epistatic interactions were studied using the natural and orthogonal interaction (NOIA) model.Six genetic modules, two from GWAS and four from vGWAS, were strongly associated with the studied trait. We found evidence of both additive- and non-additive interactions between these modules and constructed a putative local epistasis network for the region. Our screens for functional alleles revealed a missense variant in the gene ribonuclease H2 subunit B (RNASEH2B), which has previously been associated with growth-related traits in chickens and Darwin’s finches. In addition, one of the most strongly associated SNPs identified is located in a non-coding region upstream of the long non-coding RNA, ENSGALG00000053256, previously suggested as a candidate gene for regulating chicken body weight. By studying large numbers of individuals from a family material using approaches to capture both additive and non-additive effects, this study advances our understanding of genetic complexities in a highly polygenic trait and has practical implications for poultry breeding and agriculture.
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| 12. |
- Ou, Jen-Hsiang
(författare)
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Exploring the Genetic Landscape of Chicken Populations : Admixture, Growth QTLs, and Long-Term Selection Dynamics
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis analyzes the genetic structure of chicken populations across different breeding histories and environments. Genomic methodologies were used to uncover complex traits and domestication history over time. The work consists of three studies contributing to a broader understanding of chicken genetic diversity and the impact of selective breeding practices.The first study delves into the global chicken population, using genome-wide analysis to uncover the intricate fine structure and historical admixture events that have shaped these populations. The research has unveiled significant connections between populations and pivotal breeding events, highlighting the complex relationships within chicken populations. This study offers intriguing insights into the genetic continuity and admixture patterns across diverse chicken breeds, from junglefowl to commercial lines.The second study focuses on the genetic complexity within a specific quantitative trait locus (QTL) region known as Growth1, which is influential in chicken growth. This study, conducted using an advanced intercross line from the Virginia body weight line, identifies significant additive, haplotype, and epistasis effects within the Growth1 QTL region. The findings challenge simplistic genetic models by demonstrating the involvement of multiple loci in regulating body weight and contribute to understanding complex trait architecture.The third study extends the investigation to the long-term effects of selection on chicken lines, providing a deeper understanding of the genetic mechanisms underlying selection responses. By mapping multiple additive QTLs associated with body weight compared with the GWA study results, several novel regions were determined and are still contributing to the selection response even after 40 generations of intense selection.These different views provide practical insights into chickens' intricate genetic makeup. By analyzing their domestication history, genetic variation effects, and the population's response to selective breeding, we better understand one of the most important economic organisms for humans — the chicken. This understanding can potentially inform and improve selective breeding practices, leading to more efficient and sustainable poultry production.
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| 13. |
- Pavelin, Jon, et al.
(författare)
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The nedd-8 activating enzyme gene underlies genetic resistance to infectious pancreatic necrosis virus in Atlantic salmon
- 2021
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Ingår i: Genomics. - : Elsevier. - 0888-7543 .- 1089-8646. ; 113:6, s. 3842-3850
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Tidskriftsartikel (refereegranskat)abstract
- Genetic resistance to infectious pancreatic necrosis virus (IPNV) in Atlantic salmon is a rare example of a trait where a single locus (QTL) explains almost all of the genetic variation. Genetic marker tests based on this QTL on salmon chromosome 26 have been widely applied in selective breeding to markedly reduce the incidence of the disease. In the current study, whole genome sequencing and functional annotation approaches were applied to characterise genes and variants in the QTL region. This was complemented by an analysis of differential expression between salmon fry of homozygous resistant and homozygous susceptible genotypes challenged with IPNV. These analyses pointed to the NEDD-8 activating enzyme 1 (nae1) gene as a putative functional candidate underlying the QTL effect. The role of nae1 in IPN resistance was further assessed via CRISPR-Cas9 knockout of the nae1 gene and chemical inhibition of the nae1 protein activity in Atlantic salmon cell lines, both of which resulted in highly significant reduction in productive IPNV replication. In contrast, CRISPR-Cas9 knockout of a candidate gene previously purported to be a cellular receptor for the virus (cdh1) did not have a major impact on productive IPNV replication. These results suggest that nae1 is the causative gene underlying the major QTL affecting resistance to IPNV in salmon, provide further evidence for the critical role of neddylation in hostpathogen interactions, and highlight the value in combining high-throughput genomics approaches with targeted genome editing to understand the genetic basis of disease resistance.
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| 14. |
- Rafati, Nima, et al.
(författare)
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Reconstruction of the birth of a male sex chromosome present in Atlantic herring
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy Of Sciences. - 0027-8424 .- 1091-6490. ; 117:39, s. 24359-24368
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.
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| 15. |
- Rubin, Carl-Johan, et al.
(författare)
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Rapid adaptive radiation of Darwin's finches depends on ancestral genetic modules
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:27
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Tidskriftsartikel (refereegranskat)abstract
- Recent adaptive radiations are models for investigating mechanisms contributing to the evolution of biodiversity. An unresolved question is the relative importance of new mutations, ancestral variants, and introgressive hybridization for phenotypic evolution and speciation. Here, we address this issue using Darwin's finches and investigate the genomic architecture underlying their phenotypic diversity. Admixture mapping for beak and body size in the small, medium, and large ground finches revealed 28 loci showing strong genetic differentiation. These loci represent ancestral haplotype blocks with origins predating speciation events during the Darwin's finch radiation. Genes expressed in the developing beak are overrepresented in these genomic regions. Ancestral haplotypes constitute genetic modules for selection and act as key determinants of the unusual phenotypic diversity of Darwin's finches. Such ancestral haplotype blocks can be critical for how species adapt to environmental variability and change.
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| 16. |
- Sato, Daiki X., et al.
(författare)
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Brain Transcriptomics of Wild and Domestic Rabbits Suggests That Changes in Dopamine Signaling and Ciliary Function Contributed to Evolution of Tameness
- 2020
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Ingår i: Genome Biology and Evolution. - : OXFORD UNIV PRESS. - 1759-6653. ; 12:10, s. 1918-1928
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Tidskriftsartikel (refereegranskat)abstract
- Domestication has resulted in immense phenotypic changes in animals despite their relatively short evolutionary history. The European rabbit is one of the most recently domesticated animals, but exhibits distinct morphological, physiological, and behavioral differences from their wild conspecifics. A previous study revealed that sequence variants with striking allele frequency differences between wild and domestic rabbits were enriched in conserved noncoding regions, in the vicinity of genes involved in nervous system development. This suggests that a large proportion of the genetic changes targeted by selection during domestication might affect gene regulation. Here, we generated RNA-sequencing data for four brain regions (amygdala, hypothalamus, hippocampus, and parietal/temporal cortex) sampled at birth and revealed hundreds of differentially expressed genes (DEGs) between wild and domestic rabbits. DEGs in amygdala were significantly enriched for genes associated with dopaminergic function and all 12 DEGs in this category showed higher expression in domestic rabbits. DEGs in hippocampus were enriched for genes associated with ciliary function, all 21 genes in this category showed lower expression in domestic rabbits. These results indicate an important role of dopamine signaling and ciliary function in the evolution of tameness during rabbit domestication. Our study shows that gene expression in specific pathways has been profoundly altered during domestication, but that the majority of genes showing differential expression in this study have not been the direct targets of selection.
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| 17. |
- Westergren Jakobsson, Amanda, et al.
(författare)
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The Human Adenovirus 2 Transcriptome : An Amazing Complexity of Alternatively Spliced mRNAs
- 2021
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Ingår i: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 95:4
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Tidskriftsartikel (refereegranskat)abstract
- We have used the Nanopore long-read sequencing platform to demonstrate how amazingly complex the human adenovirus type 2 (Ad2) transcriptome is with a flexible splicing machinery producing a range of novel mRNAs both from the early and late transcription units. In total we report more than 900 alternatively spliced mRNAs produced from the Ad2 transcriptome whereof more than 850 are novel mRNAs. A surprising finding was that more than 50% of all E1A transcripts extended upstream of the previously defined transcriptional start site. The novel start sites mapped close to the inverted terminal repeat (ITR) and within the E1A enhancer region. We speculate that novel promoters or enhancer driven transcription, so-called eRNA transcription, is responsible for producing these novel mRNAs. Their existence was verified by a peptide in the Ad2 proteome that was unique for the E1A ITR mRNA. Although we show a high complexity of alternative splicing from most early and late regions, the E3 region was by far the most complex when expressed at late times of infection. More than 400 alternatively spliced mRNAs were observed in this region alone. These mRNAs included extended L4 mRNAs containing E3 and L5 sequences and readthrough mRNAs combining E3 and L5 sequences. Our findings demonstrate that the virus has a remarkable capacity to produce novel exon combinations, which will offer the virus an evolutionary advantage to change the gene expression repertoire and protein production in an evolving environment.IMPORTANCE Work in the adenovirus system led to the groundbreaking discovery of RNA splicing and alternative RNA splicing in 1977. These mechanisms are essential in mammalian evolution by increasing the coding capacity of a genome. Here, we have used a long-read sequencing technology to characterize the complexity of human adenovirus pre-mRNA splicing in detail. It is mindboggling that the viral genome, which only houses around 36,000 bp, not being much larger than a single cellular gene, generates more than 900 alternatively spliced mRNAs. Recently, adenoviruses have been used as the backbone in several promising SARS-CoV-2 vaccines. Further improvement of adenovirus-based vaccines demands that the virus can be tamed into an innocent carrier of foreign genes. This requires a full understanding of the components that govern adenovirus replication and gene expression.
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| 18. |
- Wojewodzic, Marcin W., et al.
(författare)
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Ultralow amounts of DNA from long-term archived serum samples produce high-quality methylomes
- 2021
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term stored serum is considered challenging for epigenomic analyses: as there are no cells, circulating DNA is scarce, and amplification removes epigenetic signals. Additionally, pre-analytical treatments and storage might introduce biases and fragmentation to the DNA. In particular, starting with low-input DNA can result in low-diversity libraries. However, successful whole-genome bisulphite sequencing (WGBS) of such serum samples has the potential to open biobanks for epigenetic analyses and deliver novel prediagnostic biomarkers. Here, we perform WGBS using the Accel-NGS library preparation kit on ultralow amounts of DNA from long-term archived samples with diverse pretreatments from the Janus Serum Bank.Results: Ninety-four of the 96 samples produced satisfactory methylation calls; an average of 578 M reads per sample generated a mean coverage of 17× and mean duplication level of 35%. Failed samples were related to poor bisulphite conversion rather than to sequencing or library preparation. We demonstrate the feasibility of WGBS on ultralow DNA yields from serum samples stored up to 48 years.Conclusions: Our results show the potential of large serum biobank collections for future epigenomic studies and biomarker discovery.
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