PLoS GeneticsPub Date : 2024-12-26eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011408
Anushya Petchiappan, Nadim Majdalani, Erin Wall, Susan Gottesman
{"title":"RcsF-independent mechanisms of signaling within the Rcs phosphorelay.","authors":"Anushya Petchiappan, Nadim Majdalani, Erin Wall, Susan Gottesman","doi":"10.1371/journal.pgen.1011408","DOIUrl":"10.1371/journal.pgen.1011408","url":null,"abstract":"<p><p>The Rcs (regulator of capsule synthesis) phosphorelay is a conserved cell envelope stress response mechanism in enterobacteria. It responds to perturbations at the cell surface and the peptidoglycan layer from a variety of sources, including antimicrobial peptides, beta-lactams, and changes in osmolarity. RcsF, an outer membrane lipoprotein, is the sensor for this pathway and activates the phosphorelay by interacting with an inner membrane protein IgaA. IgaA is essential; it negatively regulates the signaling by interacting with the phosphotransferase RcsD. We previously showed that RcsF-dependent signaling does not require the periplasmic domain of the histidine kinase RcsC and identified a dominant negative mutant of RcsD that can block signaling via increased interactions with IgaA. However, how the inducing signals are sensed and how signal is transduced to activate the transcription of the Rcs regulon remains unclear. In this study, we investigated how the Rcs cascade functions without its only known sensor, RcsF, and characterized the underlying mechanisms for three distinct RcsF-independent inducers. Previous reports showed that Rcs activity can be induced in the absence of RcsF by a loss of function mutation in the periplasmic oxidoreductase DsbA or by overexpression of the DnaK cochaperone DjlA. We identified an inner membrane protein, DrpB, as a multicopy RcsF-independent Rcs activator in E. coli. The loss of the periplasmic oxidoreductase DsbA and the overexpression of the DnaK cochaperone DjlA each trigger the Rcs cascade in the absence of RcsF by weakening IgaA-RcsD interactions in different ways. In contrast, the cell-division associated protein DrpB uniquely requires the RcsC periplasmic domain for activation; this domain is not needed for RcsF-dependent signaling. This suggests the possibility that the RcsC periplasmic domain acts as a sensor for some Rcs signals. Overall, the results add new understanding to how this complex phosphorelay can be activated by diverse mechanisms.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011408"},"PeriodicalIF":4.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-26eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011536
Thibault Latrille, Julien Joseph, Diego A Hartasánchez, Nicolas Salamin
{"title":"Estimating the proportion of beneficial mutations that are not adaptive in mammals.","authors":"Thibault Latrille, Julien Joseph, Diego A Hartasánchez, Nicolas Salamin","doi":"10.1371/journal.pgen.1011536","DOIUrl":"10.1371/journal.pgen.1011536","url":null,"abstract":"<p><p>Mutations can be beneficial by bringing innovation to their bearer, allowing them to adapt to environmental change. These mutations are typically unpredictable since they respond to an unforeseen change in the environment. However, mutations can also be beneficial because they are simply restoring a state of higher fitness that was lost due to genetic drift in a stable environment. In contrast to adaptive mutations, these beneficial non-adaptive mutations can be predicted if the underlying fitness landscape is stable and known. The contribution of such non-adaptive mutations to molecular evolution has been widely neglected mainly because their detection is very challenging. We have here reconstructed protein-coding gene fitness landscapes shared between mammals, using mutation-selection models and a multi-species alignments across 87 mammals. These fitness landscapes have allowed us to predict the fitness effect of polymorphisms found in 28 mammalian populations. Using methods that quantify selection at the population level, we have confirmed that beneficial non-adaptive mutations are indeed positively selected in extant populations. Our work confirms that deleterious substitutions are accumulating in mammals and are being reverted, generating a balance in which genomes are damaged and restored simultaneously at different loci. We observe that beneficial non-adaptive mutations represent between 15% and 45% of all beneficial mutations in 24 of 28 populations analyzed, suggesting that a substantial part of ongoing positive selection is not driven solely by adaptation to environmental change in mammals.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011536"},"PeriodicalIF":4.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-26eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011518
Laura Garcia-Toscano, Heather N Currey, Joshua C Hincks, Jade G Stair, Nicolas J Lehrbach, Nicole F Liachko
{"title":"Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.","authors":"Laura Garcia-Toscano, Heather N Currey, Joshua C Hincks, Jade G Stair, Nicolas J Lehrbach, Nicole F Liachko","doi":"10.1371/journal.pgen.1011518","DOIUrl":"10.1371/journal.pgen.1011518","url":null,"abstract":"<p><p>Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011518"},"PeriodicalIF":4.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-23eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011351
Eric Cheng, Ran Lu, Abigail R Gerhold
{"title":"Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.","authors":"Eric Cheng, Ran Lu, Abigail R Gerhold","doi":"10.1371/journal.pgen.1011351","DOIUrl":"10.1371/journal.pgen.1011351","url":null,"abstract":"<p><p>Stem and progenitor cell mitosis is essential for tissue development and homeostasis. How these cells ensure proper chromosome segregation, and thereby maintain mitotic fidelity, in the complex physiological environment of a living animal is poorly understood. Here we use in situ live-cell imaging of C. elegans germline stem and progenitor cells (GSPCs) to ask how the signaling environment influences stem and progenitor cell mitosis in vivo. Through a candidate screen we identify a new role for the insulin/IGF receptor (IGFR), daf-2, during GSPC mitosis. Mitosis is delayed in daf-2/IGFR mutants, and these delays require canonical, DAF-2/IGFR to DAF-16/FoxO insulin signaling, here acting cell non-autonomously from the soma. Interestingly, mitotic delays in daf-2/IGFR mutants depend on the spindle assembly checkpoint but are not accompanied by a loss of mitotic fidelity. Correspondingly, we show that caloric restriction, which delays GSPC mitosis and compromises mitotic fidelity, does not act via the canonical insulin signaling pathway, and instead requires AMP-activated kinase (AMPK). Together this work demonstrates that GSPC mitosis is influenced by at least two genetically separable signaling pathways and highlights the importance of signaling networks for proper stem and progenitor cell mitosis in vivo.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011351"},"PeriodicalIF":4.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-23eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011401
Kira Orlovsky, Elena Appel, Shay Hantisteanu, Tsviya Olender, Joseph Lotem, Ditsa Levanon, Yoram Groner
{"title":"Runx3, Brn3a and Isl1 interplay orchestrates the transcriptional program in the early stages of proprioceptive neuron development.","authors":"Kira Orlovsky, Elena Appel, Shay Hantisteanu, Tsviya Olender, Joseph Lotem, Ditsa Levanon, Yoram Groner","doi":"10.1371/journal.pgen.1011401","DOIUrl":"10.1371/journal.pgen.1011401","url":null,"abstract":"<p><strong>Background: </strong>The development and diversification of sensory proprioceptive neurons, which reside in the dorsal root ganglia (DRG) and express the tropomyosin receptor kinase C (TrkC), depend on the transcription factor (TF) Runx3. Runx3-deficient mice develop severe limb ataxia due to TrkC neuron cell death. Two additional TFs Pou4f1 (also called Brn3a) and Isl1 also play an important role in sensory neuron development. Thus, we aimed to unravel the chromatin state of early-developing TrkC neurons and decipher the Runx3 high-confidence target genes (HCT) and the possible cooperation between Runx3, Brn3a and Isl1 in the regulation of these genes.</p><p><strong>Methods: </strong>Runx3 expression is driven by the gene proximal P2 promoter. Transcriptome analysis was conducted by RNA-seq on RNA isolated from heterozygous (P2+/-) vs. homozygous (P2-/-) TrkC neurons and differentially expressed genes (DEGs) were determined. Genome-wide occupancy of Runx3, Brn3a, Isl1 and histone H3 acetylated on lysine 27 (H3K27Ac) was determined using CUT&RUN. The landscape of Transposase-accessible chromatin was analyzed via ATAC-seq.</p><p><strong>Findings: </strong>The intersection of Runx3 genomic occupancy-associated genes and DEG data discovered 244 Runx3 HCT. Brn3a and Isl1 were found to bind to numerous genomic loci, some of which overlapped with Runx3. Most genomic regions bound by each of these three TFs or co-bound by them resided in distantly located enhancer regions rather than in gene promoters. In activated and suppressed neuronal Runx3 HCT, Runx3 cooperated mainly with Brn3a to regulate expression through distantly located enhancers. Interestingly, suppression of non-neuronal immune genes was mainly managed via Runx3 without Brn3a. The distribution of ATAC and H3K27Ac marked regions in Runx3 peaks containing at least one RUNX binding site (Runx3_RBS) revealed that while most promoter regions were marked by ATAC, a prominent fraction of intron/intergenic regions occupied by Runx3, Brn3a or Isl1 were unmarked by ATAC and/or H3K27Ac.</p><p><strong>Conclusions: </strong>These analyses shed new light on the interplay of Runx3, Brn3a, Isl1, and open chromatin regions in regulating the Runx3 HCT in the early developmental stages of TrkC neurons.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011401"},"PeriodicalIF":4.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-23eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011521
Magdalena Bohutínská, Eliška Petříková, Tom R Booker, Cristina Vives Cobo, Jakub Vlček, Gabriela Šrámková, Alžběta Poupětová, Jakub Hojka, Karol Marhold, Levi Yant, Filip Kolář, Roswitha Schmickl
{"title":"Polyploids broadly generate novel haplotypes from trans-specific variation in Arabidopsis arenosa and Arabidopsis lyrata.","authors":"Magdalena Bohutínská, Eliška Petříková, Tom R Booker, Cristina Vives Cobo, Jakub Vlček, Gabriela Šrámková, Alžběta Poupětová, Jakub Hojka, Karol Marhold, Levi Yant, Filip Kolář, Roswitha Schmickl","doi":"10.1371/journal.pgen.1011521","DOIUrl":"10.1371/journal.pgen.1011521","url":null,"abstract":"<p><p>Polyploidy, the result of whole genome duplication (WGD), is widespread across the tree of life and is often associated with speciation and adaptability. It is thought that adaptation in autopolyploids (within-species polyploids) may be facilitated by increased access to genetic variation. This variation may be sourced from gene flow with sister diploids and new access to other tetraploid lineages, as well as from increased mutational targets provided by doubled DNA content. Here, we deconstruct in detail the origins of haplotypes displaying the strongest selection signals in established, successful autopolyploids, Arabidopsis lyrata and Arabidopsis arenosa. We see strong signatures of selection in 17 genes implied in meiosis, cell cycle, and transcription across all four autotetraploid lineages present in our expanded sampling of 983 sequenced genomes. Most prominent in our results is the finding that the tetraploid-characteristic haplotypes with the most robust signals of selection were completely absent in all diploid sisters. In contrast, the fine-scaled variant 'mosaics' in the tetraploids originated from highly diverse evolutionary sources. These include widespread novel reassortments of trans-specific polymorphism from diploids, new mutations, and tetraploid-specific inter-species hybridization-a pattern that is in line with the broad-scale acquisition and reshuffling of potentially adaptive variation in tetraploids.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011521"},"PeriodicalIF":4.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-17eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011512
Jamie McGowan, Thomas A Richards, Neil Hall, David Swarbreck
{"title":"Multiple independent genetic code reassignments of the UAG stop codon in phyllopharyngean ciliates.","authors":"Jamie McGowan, Thomas A Richards, Neil Hall, David Swarbreck","doi":"10.1371/journal.pgen.1011512","DOIUrl":"10.1371/journal.pgen.1011512","url":null,"abstract":"<p><p>The translation of nucleotide sequences into amino acid sequences, governed by the genetic code, is one of the most conserved features of molecular biology. The standard genetic code, which uses 61 sense codons to encode one of the 20 standard amino acids and 3 stop codons (UAA, UAG, and UGA) to terminate translation, is used by most extant organisms. The protistan phylum Ciliophora (the 'ciliates') are the most prominent exception to this norm, exhibiting the grfeatest diversity of nuclear genetic code variants and evidence of repeated changes in the code. In this study, we report the discovery of multiple independent genetic code changes within the Phyllopharyngea class of ciliates. By mining publicly available ciliate genome datasets, we discovered that three ciliate species from the TARA Oceans eukaryotic metagenome dataset use the UAG codon to putatively encode leucine. We identified novel suppressor tRNA genes in two of these genomes which are predicted to decode the reassigned UAG codon to leucine. Phylogenomics analysis revealed that these three uncultivated taxa form a monophyletic lineage within the Phyllopharyngea class. Expanding our analysis by reassembling published phyllopharyngean genome datasets led to the discovery that the UAG codon had also been reassigned to putatively code for glutamine in Hartmannula sinica and Trochilia petrani. Phylogenomics analysis suggests that this occurred via two independent genetic code change events. These data demonstrate that the reassigned UAG codons have widespread usage as sense codons within the phyllopharyngean ciliates. Furthermore, we show that the function of UAA is firmly fixed as the preferred stop codon. These findings shed light on the evolvability of the genetic code in understudied microbial eukaryotes.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011512"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-16eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011517
Justine Guguin, Ting-Yu Chen, Silvestre Cuinat, Alicia Besson, Eloïse Bertiaux, Lucile Boutaud, Nolan Ardito, Miren Imaz Murguiondo, Sara Cabet, Virginie Hamel, Sophie Thomas, Bertrand Pain, Patrick Edery, Audrey Putoux, Tang K Tang, Sylvie Mazoyer, Marion Delous
{"title":"A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids.","authors":"Justine Guguin, Ting-Yu Chen, Silvestre Cuinat, Alicia Besson, Eloïse Bertiaux, Lucile Boutaud, Nolan Ardito, Miren Imaz Murguiondo, Sara Cabet, Virginie Hamel, Sophie Thomas, Bertrand Pain, Patrick Edery, Audrey Putoux, Tang K Tang, Sylvie Mazoyer, Marion Delous","doi":"10.1371/journal.pgen.1011517","DOIUrl":"10.1371/journal.pgen.1011517","url":null,"abstract":"<p><p>Taybi-Linder syndrome (TALS) is a rare autosomal recessive disorder characterized by severe microcephaly with abnormal gyral pattern, severe growth retardation and bone abnormalities. It is caused by pathogenic variants in the RNU4ATAC gene. Its transcript, the small nuclear RNA U4atac, is involved in the excision of ~850 minor introns. Here, we report a patient presenting with TALS features but no pathogenic variants were found in RNU4ATAC, instead the homozygous RTTN c.2953A>G variant was detected by whole-exome sequencing. After deciphering the impact of the variant on the RTTN protein function at centrosome in engineered RTTN-depleted RPE1 cells and patient fibroblasts, we analysed neural stem cells (NSC) derived from CRISPR/Cas9-edited induced pluripotent stem cells and revealed major cell cycle and mitotic abnormalities, leading to aneuploidy, cell cycle arrest and cell death. In cortical organoids, we discovered an additional function of RTTN in the self-organisation of NSC into neural rosettes, by observing delayed apico-basal polarization of NSC. Altogether, these defects contributed to a marked delay of rosette formation in RTTN-mutated organoids, thus impeding their overall growth and shedding light on mechanisms leading to microcephaly.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011517"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-16eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011514
Qinghe Li, Yuhong Liu, Yuanyuan Wang, Qi Zhang, Na Zhang, Danli Song, Fei Wang, Qianmei Gao, Yuxin Chen, Gaomeng Zhang, Jie Wen, Guiping Zhao, Li Chen, Yu Gao
{"title":"Spop deficiency impairs adipogenesis and promotes thermogenic capacity in mice.","authors":"Qinghe Li, Yuhong Liu, Yuanyuan Wang, Qi Zhang, Na Zhang, Danli Song, Fei Wang, Qianmei Gao, Yuxin Chen, Gaomeng Zhang, Jie Wen, Guiping Zhao, Li Chen, Yu Gao","doi":"10.1371/journal.pgen.1011514","DOIUrl":"10.1371/journal.pgen.1011514","url":null,"abstract":"<p><p>As the adaptor protein that determines substrate specificity of the Cul3-SPOP-Rbx1 E3 ligase complex, SPOP is involved in numerous biological processes. However, its physiological connections with adipogenesis and thermogenesis remain poorly understood. In the current study, we report that the conditional knockout of Spop in mice results in substantial changes in protein expression, including the upregulation of a critical factor associated with thermogenesis, UCP1. Loss of SPOP also led to defects in body weight gain. In addition, conditional knockout mice exhibited resistance to high-fat-diet-induced obesity. Proteomics analysis found that proteins upregulated in the knockout mice are primarily enriched for functions in glycolysis/gluconeogenesis, oxidative phosphorylation, and thermogenesis. Furthermore, Spop knockout mice were more resilient during cold tolerance assay compared with the wild-type controls. Finally, the knockout of SPOP efficiently impaired adipogenesis in primary preadipocytes and the expression of associated genes. Collectively, these findings demonstrate the critical roles of SPOP in regulating adipogenesis and thermogenic capacity in mice.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011514"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-12-16eCollection Date: 2024-12-01DOI: 10.1371/journal.pgen.1011242
Kelsey E Grinde, Brian L Browning, Alexander P Reiner, Timothy A Thornton, Sharon R Browning
{"title":"Adjusting for principal components can induce collider bias in genome-wide association studies.","authors":"Kelsey E Grinde, Brian L Browning, Alexander P Reiner, Timothy A Thornton, Sharon R Browning","doi":"10.1371/journal.pgen.1011242","DOIUrl":"10.1371/journal.pgen.1011242","url":null,"abstract":"<p><p>Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 12","pages":"e1011242"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}