- Author Correction: Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. [Published Erratum]
- NGenNat Genet 2018 Nov 12
- In the version of the article published, the author list is not accurate. Igor Cima and Min-Han Tan should have been authors, appearing after Mark Wong in the author list, while Paul Jongjoon Choi sh...
In the version of the article published, the author list is not accurate. Igor Cima and Min-Han Tan should have been authors, appearing after Mark Wong in the author list, while Paul Jongjoon Choi should not have been listed as an author. Igor Cima and Min-Han Tan both have the affiliation Institute of Bioengineering and Nanotechnology, Singapore, Singapore, and their contributions should have been noted in the Author Contributions section as "I.C. preprocessed Primary Cell Atlas data with inputs from M.-H.T." The following description of the contribution of Paul Jongjoon Choi should not have appeared: "P.J.C. supported the smFISH experiments." In the 'RCA: global panel' section of the Online Methods, the following sentence should have appeared as the second sentence, "An expression atlas of human primary cells (the Primary Cell Atlas) was preprocessed similarly to in ref. 55," with new reference 55 (Cima, I. et al. Tumor-derived circulating endothelial cell clusters in colorectal cancer. Science Transl. Med. 8, 345ra89, 2016).
- Subtype-specific regulatory network rewiring in acute myeloid leukemia. [Journal Article]
- NGenNat Genet 2018 Nov 12
- Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant r...
Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.
- Cilia-driven cerebrospinal fluid flow directs expression of urotensin neuropeptides to straighten the vertebrate body axis. [Journal Article]
- NGenNat Genet 2018 Nov 12
- Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders ...
Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders such as idiopathic scoliosis, characterized by three-dimensional curvatures of the spine1. Although abnormal cerebrospinal fluid (CSF) flow has been implicated in the development of idiopathic scoliosis2, the molecular mechanisms operating downstream of CSF flow remain obscure. Here we show that, in zebrafish embryos, cilia-driven CSF flow transports adrenergic signals that induce urotensin neuropeptides in CSF-contacting neurons along the spinal cord. Urotensins activate their receptor on slow-twitch muscle fibers of the dorsal somite; the contraction of these fibers likely results in straightening of the body axis. Consistent with this, mutation of the urotensin receptor resulted in severe scoliosis in adult zebrafish, closely mimicking the human disorder. These findings suggest that disruption of urotensin signaling by impaired CSF flow could be a critical etiological factor underlying the pathology of idiopathic scoliosis.
- Genebank genomics highlights the diversity of a global barley collection. [Journal Article]
- NGenNat Genet 2018 Nov 12
- Genebanks hold comprehensive collections of cultivars, landraces and crop wild relatives of all major food crops, but their detailed characterization has so far been limited to sparse core sets. The ...
Genebanks hold comprehensive collections of cultivars, landraces and crop wild relatives of all major food crops, but their detailed characterization has so far been limited to sparse core sets. The analysis of genome-wide genotyping-by-sequencing data for almost all barley accessions of the German ex situ genebank provides insights into the global population structure of domesticated barley and points out redundancies and coverage gaps in one of the world's major genebanks. Our large sample size and dense marker data afford great power for genome-wide association scans. We detect known and novel loci underlying morphological traits differentiating barley genepools, find evidence for convergent selection for barbless awns in barley and rice and show that a major-effect resistance locus conferring resistance to bymovirus infection has been favored by traditional farmers. This study outlines future directions for genomics-assisted genebank management and the utilization of germplasm collections for linking natural variation to human selection during crop evolution.
- Heterochromatin-Enriched Assemblies Reveal the Sequence and Organization of the Drosophila melanogaster Y Chromosome. [Journal Article]
- GGenetics 2018 Nov 12
- Heterochromatic regions of the genome are repeat-rich and poor in protein coding genes, and are therefore underrepresented in even the best genome assemblies. One of the most difficult regions of the...
Heterochromatic regions of the genome are repeat-rich and poor in protein coding genes, and are therefore underrepresented in even the best genome assemblies. One of the most difficult regions of the genome to assemble are sex-limited chromosomes. The Drosophila melanogaster Y chromosome is entirely heterochromatic, yet has wide-ranging effects on male fertility, fitness, and genome-wide gene expression. The genetic basis of this phenotypic variation is difficult to study, in part because we do not know the detailed organization of the Y chromosome. To study Y chromosome organization in D. melanogaster, we develop an assembly strategy involving the in silico enrichment of heterochromatic long single-molecule reads and use these reads to create targeted de novo assemblies of heterochromatic sequences. We assigned contigs to the Y chromosome using Illumina reads to identify male-specific sequences. Our pipeline extends the D. melanogaster reference genome by 11.9 Mb, closes 43.8% of the gaps, and improves overall contiguity. The addition of 10.6 MB of Y-linked sequence permitted us to study the organization of repeats and genes along the Y chromosome. We detected a high rate of duplication to the pericentric regions of the Y chromosome from other regions in the genome. Most of these duplicated genes exist in multiple copies. We detail the evolutionary history of one sex-linked gene family-crystal-Stellate While the Y chromosome does not undergo crossing over, we observed high gene conversion rates within and between members of the crystal-Stellate gene family, Su(Ste), and PCKR, compared to genome-wide estimates. Our results suggest that gene conversion and gene duplication play an important role in the evolution of Y-linked genes.
- Identification and validation of QTL and their associated genes for pre-emergent metribuzin tolerance in hexaploid wheat (Triticum aestivum L.). [Journal Article]
- BGBMC Genet 2018 Nov 12; 19(1):102
- CONCLUSIONS: Metribuzin causes photo-inhibition by interrupting electron flow in PSII. Consequently, chlorophyll traits enabled the measure of high proportion of genetic variability in the mapping population. The validated molecular markers associated with metribuzin tolerance mediating QTL may be used in marker-assisted breeding to select metribuzin tolerant lines. Alternatively, validated favourable alleles could be introgressed into elite wheat cultivars to enhance metribuzin tolerance and improve grain yield in dryland farming for sustainable wheat production.
- SNP markers associated with body size and pelt length in American mink (Neovison vison). [Journal Article]
- BGBMC Genet 2018 Nov 12; 19(1):103
- CONCLUSIONS: Combining association results with existing functional information of genes and mammalian phenotype databases, we proposed WWC3, MAP2K4, SLC7A1 and USP22 as candidate genes for body weight and pelt length in mink.
- Current and future perspectives of liquid biopsies in genomics-driven oncology. [Review]
- NRNat Rev Genet 2018 Nov 08
- Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sa...
Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized.
- Epithelial Shaping by Diverse Apical Extracellular Matrices Requires the Nidogen Domain Protein DEX-1 in Caenorhabditis elegans. [Journal Article]
- GGenetics 2018 Nov 08
- The body's external surfaces and the insides of biological tubes, like the vascular system, are lined by a lipid, glycoprotein-, and glycosaminoglycan-rich apical extracellular matrix (aECM). aECMs a...
The body's external surfaces and the insides of biological tubes, like the vascular system, are lined by a lipid, glycoprotein-, and glycosaminoglycan-rich apical extracellular matrix (aECM). aECMs are the body's first line of defense against infectious agents and promote tissue integrity and morphogenesis, but are poorly described relative to basement membranes and stromal ECMs. While some aECM components, such as zona pellucida domain (ZP) proteins, have been identified, little is known regarding the overall composition of the aECM or the mechanisms by which different aECM components work together to shape epithelial tissues. In Caenorhabditis elegans, external epithelia develop in the context of an ill-defined ZP-containing aECM that precedes secretion of the collagenous cuticle. C. elegans has 43 genes that encode at least 65 unique ZP proteins, and we show that some of these comprise distinct pre-cuticle aECMs in the embryo. Previously, the nidogen- and EGF-domain protein DEX-1 was shown to anchor dendrites to the C. elegans nose tip in concert with the ZP protein DYF-7. Here, we identified a new, strong loss-of-function allele of dex-1, cs201dex-1 mutants die as L1 larvae and have a variety of tissue distortion phenotypes, including excretory defects, pharyngeal ingression, alae defects, and a short and fat body shape, that strongly resemble those of genes encoding ZP proteins. DEX-1 localizes to ZP-containing aECMs in the tissues that show defects in dex-1 mutants. Our studies suggest that DEX-1 is a component of multiple distinct embryonic aECMs that shape developing epithelia, and a potential partner of multiple ZP proteins.
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- Epidermal Remodeling in Caenorhabditis elegans Dauers Requires the Nidogen Domain Protein DEX-1. [Journal Article]
- GGenetics 2018 Nov 08
- Phenotypic plasticity is a critical component of an organism's ability to thrive in a changing environment. The free-living nematode, Caenorhabditis elegans, adapts to unfavorable environmental condi...
Phenotypic plasticity is a critical component of an organism's ability to thrive in a changing environment. The free-living nematode, Caenorhabditis elegans, adapts to unfavorable environmental conditions by pausing reproductive development and entering a stress-resistant larval stage known as dauer. The transition into dauer is marked by vast morphological changes - including remodeling of epidermis, neurons and muscle. Though many of these dauer-specific traits have been described, the molecular basis of dauer-specific remodeling is still poorly understood. Here we show that the nidogen-domain containing protein DEX-1 facilitates stage-specific tissue remodeling during dauer morphogenesis. DEX-1 was previously shown to regulate sensory dendrite formation during embryogenesis. We find that DEX-1 is also required for proper remodeling of the stem cell-like epidermal seam cells. dex-1 mutant dauers lack distinct lateral cuticular alae during dauer and have increased sensitivity to sodium dodecyl sulfate (SDS). Furthermore, we find that DEX-1 is required for proper dauer mobility. We show that DEX-1 is secreted from the seam cells during dauer, but acts locally in a cell autonomous manner. We find that dex-1 expression during dauer is regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 acts with a family of zona pellucida domain-encoding genes to regulate dauer-specific epidermal remodeling. Taken together, our data indicate that DEX-1 is an extracellular matrix component that plays a central role in C. elegans epidermal remodeling during dauer.