| 1. |
- Basu, Swaraj, et al.
(författare)
-
A Catalogue of Putative cis-Regulatory Interactions Between Long Non-coding RNAs and Proximal Coding Genes Based on Correlative Analysis Across Diverse Human Tumors
- 2018
-
Ingår i: G3-Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 8:6, s. 2019-2025
-
Tidskriftsartikel (refereegranskat)abstract
- Antisense transcripts and other long non-coding RNAs are pervasive in mammalian cells, and some of these molecules have been proposed to regulate proximal protein-coding genes in cis. For example, non-coding transcription can contribute to inactivation of tumor suppressor genes in cancer, and antisense transcripts have been implicated in the epigenetic inactivation of imprinted genes. However, our knowledge is still limited and more such regulatory interactions likely await discovery. Here, we make use of available gene expression data from a large compendium of human tumors to generate hypotheses regarding non-coding-to-coding cis-regulatory relationships with emphasis on negative associations, as these are less likely to arise for reasons other than cis-regulation. We document a large number of possible regulatory interactions, including 193 coding/non-coding pairs that show expression patterns compatible with negative cis-regulation. Importantly, by this approach we capture several known cases, and many of the involved coding genes have known roles in cancer. Our study provides a large catalog of putative non-coding/coding cis-regulatory pairs that may serve as a basis for further experimental validation and characterization.
|
|
| 2. |
- Brandt, Monika, et al.
(författare)
-
Imputation-Based Fine-Mapping Suggests That Most QTL in an Outbred Chicken Advanced Intercross Body Weight Line Are Due to Multiple, Linked Loci
- 2017
-
Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 7:1, s. 119-128
-
Tidskriftsartikel (refereegranskat)abstract
- The Virginia chicken lines have been divergently selected for juvenile body weight for more than 50 generations. Today, the high- and low-weight lines show a >12-fold difference for the selected trait, 56-d body weight. These lines provide unique opportunities to study the genetic architecture of long-term, single-trait selection. Previously, several quantitative trait loci (QTL) contributing to weight differences between the lines were mapped in an F2-cross between them, and these were later replicated and fine-mapped in a nine-generation advanced intercross of them. Here, we explore the possibility to further increase the fine-mapping resolution of these QTL via a pedigree-based imputation strategy that aims to better capture the genetic diversity in the divergently selected, but outbred, founder lines. The founders of the intercross were high-density genotyped, and then pedigree-based imputation was used to assign genotypes throughout the pedigree. Imputation increased the marker density 20-fold in the selected QTL, providing 6911 markers for the subsequent analysis. Both single-marker association and multi-marker backward-elimination analyses were used to explore regions associated with 56-d body weight. The approach revealed several statistically and population structure independent associations and increased the mapping resolution. Further, most QTL were also found to contain multiple independent associations to markers that were not fixed in the founder populations, implying a complex underlying architecture due to the combined effects of multiple, linked loci perhaps located on independent haplotypes that still segregate in the selected lines.
|
|
| 3. |
- Juodakis, Julius, et al.
(författare)
-
Time-Variant Genetic Effects as a Cause for Preterm Birth: Insights from a Population of Maternal Cousins in Sweden.
- 2017
-
Ingår i: G3: Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 7:4, s. 1349-1356
-
Tidskriftsartikel (refereegranskat)abstract
- Preterm delivery (PTD) is the leading cause of neonatal mortality worldwide, yet its etiology remains largely unexplained. We propose that the genetic factors controlling this trait could act in a nonuniform manner during pregnancy, with each factor having a unique "window of sensitivity." We test this hypothesis by modeling the distribution of gestational ages (GAs) observed in maternal cousins from the Swedish Medical Birth Register (MBR) (n = 35,541 pairs). The models were built using a time-to-event framework, with simulated genetic factors that increase the hazard of birth either uniformly across the pregnancy (constant effect) or only in particular windows (varying effect). By including various combinations of these factors, we obtained four models that were then optimized and compared. Best fit to the clinical data was observed when most of the factors had time-variant effects, independently of the number of loci simulated. Finally, power simulations were performed to assess the ability to discover varying-effect loci by usual methods for genome-wide association testing. We believe that the tools and concepts presented here should prove useful for the design of future studies of PTD and provide new insights into the genetic architecture determining human GA.
|
|
| 4. |
- Lee, Mi Ok, et al.
(författare)
-
Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice
- 2022
-
Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 12:2
-
Tidskriftsartikel (refereegranskat)abstract
- The high mobility group AT-hook 2 (HMGA2) protein works as an architectural regulator by binding AT-rich DNA sequences to induce conformational changes affecting transcription. Genomic deletions disrupting HMGA2 coding sequences and flanking noncoding sequences cause dwarfism in mice and rabbits. Here, CRISPR/Cas9 was used in mice to generate an Hmga2 null allele that specifically disrupts only the coding sequence. The loss of one or both alleles of Hmga2 resulted in reduced body size of 20% and 60%, respectively, compared to wild-type littermates as well as an allometric reduction in skull length in Hmga2(-/-) mice. Both male and female Hmga2(-/-) mice are infertile, whereas Hmga2(+/-) mice are fertile. Examination of reproductive tissues of Hmga2(-/-) males revealed a significantly reduced size of testis, epididymis, and seminal vesicle compared to controls, and 70% of knock-out males showed externalized penis, but no cryptorchidism was observed. Sperm analyses revealed severe oligospermia in mutant males and slightly decreased sperm viability, increased DNA damage but normal sperm chromatin compaction. Testis histology surprisingly revealed a normal seminiferous epithelium, despite the significant reduction in testis size. In addition, Hmga2(-/-) mice showed a significantly reduced exploratory behavior. In summary, the phenotypic effects in mouse using targeted mutagenesis confirmed that Hmga2 is affecting prenatal and postnatal growth regulation, male reproductive tissue development, and presents the first indication that Hmga2 function is required for normal mouse behavior. No specific effect, despite an allometric reduction, on craniofacial development was noted in contrast to previous reports of an altered craniofacial development in mice and rabbits carrying deletions of both coding and noncoding sequences at the 5 ' part of Hmga2.
|
|
| 5. |
- Lubuta, Patrice, et al.
(författare)
-
Investigating the Influence of Glycerol on the Utilization of Glucose in Yarrowia lipolytica Using RNA-Seq-Based Transcriptomics
- 2019
-
Ingår i: G3: Genes, Genomes, Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 9:12, s. 4059-4071
-
Tidskriftsartikel (refereegranskat)abstract
- Glycerol is considered as a promising substrate for biotechnological applications and the non-conventional yeast Yarrowia lipolytica has been used extensively for the valorization of this compound. Contrary to S. cerevisiae, Y. lipolytica seems to prefer glycerol over glucose and it has been reported previously that the presence of glycerol can suppress the consumption of glucose in co-substrate fermentations. Based on these observations, we hypothesized glycerol repression-like effects in Y. lipolytica, which are converse to well described carbon repression mechanisms ensuring the prioritized use of glucose (e.g., in S. cerevisiae). We therefore aimed to investigate this effect on the level of transcription. Strains varying in the degree of glucose suppression were chosen and characterized in high-resolution growth screenings, resulting in the detection of different growth phenotypes under glycerol-glucose mixed conditions. Two strains, IBT and W29, were selected and cultivated in chemostats using glucose, glycerol and glucose/glycerol as carbon sources, followed by an RNA-Seq-based transcriptome analysis. We could show that several transporters were significantly higher expressed in W29, which is potentially related to the observed physiological differences. However, most of the expression variation between the strains were regardless of the carbon source applied, and cross-comparisons revealed that the strain-specific carbon source responses underwent in the opposite direction. A deeper analysis of the substrate specific carbon source response led to the identification of several differentially expressed genes with orthologous functions related to signal transduction and transcriptional regulation. This study provides an initial investigation on potentially novel carbon source regulation mechanisms in yeasts. Copyright © 2019 Lubuta et al.
|
|
| 6. |
- Moumad, Khalid, et al.
(författare)
-
Genetic Polymorphisms in Host Innate Immune Sensor Genes and the Risk of Nasopharyngeal Carcinoma in North Africa
- 2013
-
Ingår i: G3: Genes, Genomes, Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 3:6, s. 971-977
-
Tidskriftsartikel (refereegranskat)abstract
- Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world. It is an Epstein-Barr virus-associated malignancy with an unusual racial and geographical distribution. The host innate immune sensor genes play an important role in infection recognition and immune response against viruses. Therefore, we examined the association between polymorphisms in genes within a group of pattern recognition receptors (including families of Toll-like receptors, C-type lectin receptors, and retinoic acid-inducible gene I-like receptors) and NPC susceptibility. Twenty-six single-nucleotide polymorphisms (SNPs) in five pattern-recognition genes were genotyped in 492 North African NPC cases and 373 frequency-matched controls. TLR3_rs3775291 was the most significantly associated SNP (odds ratio [OR] 1.49; 95% confidence interval [95% CI] 1.11-2.00; P = 0.008; dominant model). The analysis showed also that CD209_rs7248637 (OR 0.69; 95% CI 0.52-0.93; P = 0.02; dominant model) and DDX58_rs56309110 (OR 0.70; 95% CI 0.51-0.98; P = 0.04) were associated with the risk of NPC. An 18% increased risk per allele was observed for the five most significantly associated SNPs, TLR3_rs3775291, CD209_rs7248637, DDX58_rs56309110, CD209_rs4804800, and MBL2_rs10824792, (p(trend) = 8.2 x 10(-4)). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NPC. These preliminary findings require replication in larger studies.
|
|
| 7. |
- Persson, Karl, 1988, et al.
(författare)
-
Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis.
- 2022
-
Ingår i: G3 (Bethesda, Md.). - : Oxford University Press (OUP). - 2160-1836. ; 12:11
-
Tidskriftsartikel (refereegranskat)abstract
- Adaptive evolution of clonally dividing cells and microbes is the ultimate cause of cancer and infectious diseases. The possibility of constraining the adaptation of cell populations, by inhibiting proteins enhancing the evolvability, has therefore attracted interest. However, our current understanding of how genes influence adaptation kinetics is limited, partly because accurately measuring adaptation for many cell populations is challenging. We used a high-throughput adaptive laboratory evolution platform to track the adaptation of >18,000 cell populations corresponding to single-gene deletion strains in the haploid yeast deletion collection. We report that the preadaptation fitness of gene knockouts near-perfectly (R2= 0.91) predicts their adaptation to arsenic, leaving at the most a marginal role for dedicated evolvability gene functions. We tracked the adaptation of another >23,000 gene knockout populations to a diverse range of selection pressures and generalized the almost perfect (R2=0.72-0.98) capacity of preadaptation fitness to predict adaptation. We also reconstructed mutations in FPS1, ASK10, and ARR3, which together account for almost all arsenic adaptation in wild-type cells, in gene deletions covering a broad fitness range and show that the predictability of arsenic adaptation can be understood as a by global epistasis, where excluding arsenic is more beneficial to arsenic unfit cells. The paucity of genes with a meaningful evolvability effect on adaptation diminishes the prospects of developing adjuvant drugs aiming to slow antimicrobial and chemotherapy resistance.
|
|
| 8. |
- van Mourik, Paula M, et al.
(författare)
-
Upregulation of dNTP Levels After Telomerase Inactivation Influences Telomerase-Independent Telomere Maintenance Pathway Choice in Saccharomyces cerevisiae
- 2018
-
Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 8:8, s. 2551-2558
-
Tidskriftsartikel (refereegranskat)abstract
- In 10–15% of cancers, telomere length is maintained by a telomerase-independent, recombination-mediated pathway called alternative lengthening of telomeres (ALT). ALT mechanisms were first seen, and have been best studied, in telomerase-null Saccharomyces cerevisiae cells called “survivors”. There are two main types of survivors. Type I survivors amplify Y′ subtelomeric elements while type II survivors, similar to the majority of human ALT cells, amplify the terminal telomeric repeats. Both types of survivors require Rad52, a key homologous recombination protein, and Pol32, a non-essential subunit of DNA polymerase δ. A number of additional proteins have been reported to be important for either type I or type II survivor formation, but it is still unclear how these two pathways maintain telomeres. In this study, we performed a genome-wide screen to identify novel genes that are important for the formation of type II ALT-like survivors. We identified 23 genes that disrupt type II survivor formation when deleted. 17 of these genes had not been previously reported to do so. Several of these genes (DUN1, CCR4, and MOT2) are known to be involved in the regulation of dNTP levels. We find that dNTP levels are elevated early after telomerase inactivation and that this increase favors the formation of type II survivors.
|
|
