Genome mining yields putative disease-associated ROMK variants with distinct defects
by Nga H. Nguyen, Srikant Sarangi, Erin M. McChesney, Shaohu Sheng, Jacob D. Durrant, Aidan W. Porter, Thomas R. Kleyman, Zachary W. Pitluk, Jeffrey L. Brodsky
Bartter syndrome is a group of rare genetic disorders that compromise kidney function by impairing electrolyte reabsorption. Left untreated, the resulting hyponatremia, hypokalemia, and dehydration can be fatal, and there is currently no cure. Bartter syndrome type II specifically arises from mutations inKCNJ1, which encodes the renal outer medullary potassium channel, ROMK. Over 40 Bartter syndrome-associated mutations inKCNJ1 have been identified, yet their molec...
Source: PLoS Genetics - November 13, 2023 Category: Genetics & Stem Cells Authors: Nga H. Nguyen Source Type: research
Exportin-mediated nucleocytoplasmic transport maintains Pch2 homeostasis during meiosis
by Esther Herruzo, Estefan ía Sánchez-Díaz, Sara González-Arranz, Beatriz Santos, Jesús A. Carballo, Pedro A. San-Segundo
The meiotic recombination checkpoint reinforces the order of events during meiotic prophase I, ensuring the accurate distribution of chromosomes to the gametes. The AAA+ ATPase Pch2 remodels the Hop1 axial protein enabling adequate levels of Hop1-T318 phosphorylation to support the ensuing checkpoint response. While these events are localized at chromosome axes, the checkpoint activating function of Pch2 relies on its cytoplasmic population. In contrast, forced nuclear accumulation of Pch2 leads t...
Source: PLoS Genetics - November 10, 2023 Category: Genetics & Stem Cells Authors: Esther Herruzo Source Type: research
< i > RET < /i > enhancer haplotype-dependent remodeling of the human fetal gut development program
by Sumantra Chatterjee, Lauren E. Fries, Or Yaacov, Nan Hu, Hanna E. Berk-Rauch, Aravinda Chakravarti
Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants inRET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that theseRET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression ofRET, members of theRET-EDNRB ...
Source: PLoS Genetics - November 10, 2023 Category: Genetics & Stem Cells Authors: Sumantra Chatterjee Source Type: research
Coordination of Pickpocket ion channel delivery and dendrite growth in Drosophila sensory neurons
by Josephine W. Mitchell, Ipek Midillioglu, Ethan Schauer, Bei Wang, Chun Han, Jill Wildonger
Sensory neurons enable an organism to perceive external stimuli, which is essential for survival. The sensory capacity of a neuron depends on the elaboration of its dendritic arbor and the localization of sensory ion channels to the dendritic membrane. However, it is not well understood when and how ion channels localize to growing sensory dendrites and whether their delivery is coordinated with growth of the dendritic arbor. We investigated the localization of the DEG/ENaC/ASIC ion channel Pickpocket (Ppk) in the peripheral sens...
Source: PLoS Genetics - November 9, 2023 Category: Genetics & Stem Cells Authors: Josephine W. Mitchell Source Type: research
Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis
by Sun-Hee Hwang, Kevin Andrew White, Bandarigoda Nipunika Somatilaka, Baolin Wang, Saikat Mukhopadhyay
A fundamental problem in tissue morphogenesis is identifying how subcellular signaling regulates mesoscale organization of tissues. The primary cilium is a paradigmatic organelle for compartmentalized subcellular signaling. How signaling emanating from cilia orchestrates tissue organization —especially, the role of cilia-generated effectors in mediating diverse morpho-phenotypic outcomes—is not well understood. In the hedgehog pathway, bifunctional GLI transcription factors generate both GLI-activators (GLI-A) and G...
Source: PLoS Genetics - November 9, 2023 Category: Genetics & Stem Cells Authors: Sun-Hee Hwang Source Type: research
Spt5 C-terminal repeat domain phosphorylation and length negatively regulate heterochromatin through distinct mechanisms
by Sarah MacKinnon, Viviane Pag é, Jennifer J. Chen, Ali Shariat-Panahi, Ryan D. Martin, Terence E. Hébert, Jason C. Tanny
Heterochromatin is a condensed chromatin structure that represses transcription of repetitive DNA elements and developmental genes, and is required for genome stability. Paradoxically, transcription of heterochromatic sequences is required for establishment of heterochromatin in diverse eukaryotic species. As such, components of the transcriptional machinery can play important roles in establishing heterochromatin. How these factors coordinate with heterochromatin proteins at nascent heterochromatic...
Source: PLoS Genetics - November 8, 2023 Category: Genetics & Stem Cells Authors: Sarah MacKinnon Source Type: research
Dominant negative variants in < i > KIF5B < /i > cause osteogenesis imperfecta via down regulation of mTOR signaling
ConclusionWe report dominant negative variants in theKIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets forKIF5B in skeletal development. (Source: PLoS Genetics)
Source: PLoS Genetics - November 7, 2023 Category: Genetics & Stem Cells Authors: Ronit Marom Source Type: research
Lineage-specific genes are clustered with HET-domain genes and respond to environmental and genetic manipulations regulating reproduction in < i > Neurospora < /i >
by Zheng Wang, Yen-Wen Wang, Takao Kasuga, Francesc Lopez-Giraldez, Yang Zhang, Zhang Zhang, Yaning Wang, Caihong Dong, Anita Sil, Frances Trail, Oded Yarden, Jeffrey P. Townsend
Lineage-specific genes (LSGs) have long been postulated to play roles in the establishment of genetic barriers to intercrossing and speciation. In the genome ofNeurospora crassa, most of the 670Neurospora LSGs that are aggregated adjacent to the telomeres are clustered with 61% of the HET-domain genes, some of which regulate self-recognition and define vegetative incompatibility groups. In contrast, the LSG-encoding proteins possess few to no dom...
Source: PLoS Genetics - November 7, 2023 Category: Genetics & Stem Cells Authors: Zheng Wang Source Type: research
BRASS: Permutation methods for binary traits in genetic association studies with structured samples
by Joelle Mbatchou, Mark Abney, Mary Sara McPeek
In genetic association analysis of complex traits, permutation testing can be a valuable tool for assessing significance when the distribution of the test statistic is unknown or not well-approximated. This commonly arises, e.g, in tests of gene-set, pathway or genome-wide significance, or when the statistic is formed by machine learning or data adaptive methods. Existing applications include eQTL mapping, association testing with rare variants, inclusion of admixed individuals in genetic association analysis, and epistasis detection among many others. For genetic associati...
Source: PLoS Genetics - November 7, 2023 Category: Genetics & Stem Cells Authors: Joelle Mbatchou Source Type: research
Methods for mediation analysis with high-dimensional DNA methylation data: Possible choices and comparisons
by Dylan Clark-Boucher, Xiang Zhou, Jiacong Du, Yongmei Liu, Belinda L. Needham, Jennifer A. Smith, Bhramar Mukherjee
Epigenetic researchers often evaluate DNA methylation as a potential mediator of the effect of social/environmental exposures on a health outcome. Modern statistical methods for jointly evaluating many mediators have not been widely adopted. We compare seven methods for high-dimensional mediation analysis with continuous outcomes through both diverse simulations and analysis of DNAm data from a large multi-ethnic cohort in the United States, while providing an R package for their seamless implementation an...
Source: PLoS Genetics - November 7, 2023 Category: Genetics & Stem Cells Authors: Dylan Clark-Boucher Source Type: research
Domain-adaptive neural networks improve supervised machine learning based on simulated population genetic data
by Ziyi Mo, Adam Siepel
Investigators have recently introduced powerful methods for population genetic inference that rely on supervised machine learning from simulated data. Despite their performance advantages, these methods can fail when the simulated training data does not adequately resemble data from the real world. Here, we show that this “simulation mis-specification” problem can be framed as a “domain adaptation” problem, where a model learned from one data distribution is applied to a dataset drawn from a different distribution. By applying an established domain-adaptation technique based on a gradient r...
Source: PLoS Genetics - November 7, 2023 Category: Genetics & Stem Cells Authors: Ziyi Mo Source Type: research
PGP-14 establishes a polar lipid permeability barrier within the < i > C < /i > . < i > elegans < /i > pharyngeal cuticle
by Muntasir Kamal, Levon Tokmakjian, Jessica Knox, Duhyun Han, Houtan Moshiri, Lilia Magomedova, Ken CQ Nguyen, Hong Zheng, Andrew R. Burns, Brittany Cooke, Jessica Lacoste, May Yeo, David H. Hall, Carolyn L. Cummins, Peter J. Roy
The cuticles of ecdysozoan animals are barriers to material loss and xenobiotic insult. Key to this barrier is lipid content, the establishment of which is poorly understood. Here, we show that the p-glycoprotein PGP-14 functions coincidently with the sphingomyelin synthase SMS-5 to establish a polar lipid barrier within the pharyngeal cuticle of the nematodeC.elegans. We show that PGP-14 and SM...
Source: PLoS Genetics - November 6, 2023 Category: Genetics & Stem Cells Authors: Muntasir Kamal Source Type: research
Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina
In this study, we tested whether factors in volved in dedifferentiation ofDrosophila CNS are implicated in the regenerative response in the zebrafish retina. We found thathairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors.prospero homeobox 1a (prox1a) is expressed in differentiated PRs and may promote PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1a is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1a also induces a downregulation of Her6. Together, we ide...
Source: PLoS Genetics - November 6, 2023 Category: Genetics & Stem Cells Authors: Kellie Veen Source Type: research
Genome instability footprint under rapamycin and hydroxyurea treatments
by Jing Li, Simon Stenberg, Jia-Xing Yue, Ekaterina Mikhalev, Dawn Thompson, Jonas Warringer, Gianni Liti
The mutational processes dictating the accumulation of mutations in genomes are shaped by genetic background, environment and their interactions. Accurate quantification of mutation rates and spectra under drugs has important implications in disease treatment. Here, we used whole-genome sequencing and time-resolved growth phenotyping of yeast mutation accumulation lines to give a detailed view of the mutagenic effects of rapamycin and hydroxyurea on the genome and cell growth. Mutation rates depended on the genetic ba...
Source: PLoS Genetics - November 6, 2023 Category: Genetics & Stem Cells Authors: Jing Li Source Type: research
Central metabolism is a key player in < i > E < /i > . < i > coli < /i > biofilm stimulation by sub-MIC antibiotics
by Luke N. Yaeger, Shawn French, Eric D. Brown, Jean Philippe C ôté, Lori L. Burrows
Exposure ofEscherichia coli to sub-inhibitory antibiotics stimulates biofilm formation through poorly characterized mechanisms. Using a high-throughput Congo Red binding assay to report on biofilm matrix production, we screened ~4000E.coli K12 deletion mutants for deficiencies in this biofilm stimulation response. We screened using three different antibiotics to identify core components of the biofilm stimulation response. Mutants lackingacnA,nuoE, orlpdA failed to respond to sub-MIC cefixime and novobiocin, implicating central metaboli...
Source: PLoS Genetics - November 2, 2023 Category: Genetics & Stem Cells Authors: Luke N. Yaeger Source Type: research
