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Biology subjects

Breton, G.

Publications and source records attributed to Breton, G..

8 recordsLinked to original sources

Ancient tree-topologies and gene-flow processes among human lineages in Africa

The deep history of human evolution in Africa remains intensely debated, with increasingly complex models being proposed. To investigate this, we sequenced and analysed 73 novel high-quality whole genomes from 14 Central and Southern African populations with diverse cultural practices. Using extensive simulations and machine-learning Approximate Bayesian Computation (ABC), we jointly reconstructed their demographic history of divergences and migrations. We find extensive genome-wide diversity within and among populations, including substantial local genetic differentiation not fully explained by geography or cultural practices. These patterns highlight the importance of explicitly considering local genomic diversity when reconstructing human evolutionary history. We find that tree-like population histories with long periods of drift separated by short pulses of unidirectional gene-flow better explain the data than continuous gene-flow. Without invoking archaic admixture, our models accurately fit observed genomic variation and identify multiple episodes of gene-flow coinciding with major ecological and cultural changes in Sub-Saharan Africa.

genetics↗

Experimental evaluation of a direct fitness effect of the de novo evolved mouse gene Pldi

De novo evolved genes emerge from random non-coding sequences and have, therefore, no homologs from which a function could be inferred. While expression analysis and knockout experiments can provide insights into the function, they do not directly test whether the gene is beneficial for its carrier. Here, we have used a seminatural environment experiment to test the fitness of the previously identified de novo evolved mouse gene Pldi, which is thought to be involved in sperm differentiation. We used a knockout mouse strain for this gene and competed it against its parental wildtype strain for several generations of free reproduction. We found that the knockout (ko) allele frequency decreased consistently across three replicates of the experiment. Using an approximate Bayesian computation framework that simulated the data under a demographic scenario mimicking the experiments demography, we could estimate a fitness coefficient ranging between 0.15 to 0.67 for the wildtype allele compared to the ko allele in males. We conclude that a gene that has evolved de novo from a random intergenic sequence can have a measurable fitness benefit.

evolutionary biology↗

Distinct gene expression by expanded clones of quiescent memory CD4+ T cells harboring intact latent HIV-1 proviruses

Antiretroviral therapy controls but does not cure HIV-1 infection due to a reservoir of rare CD4+ T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here we report a novel strategy to enrich clones of latent cells carrying intact, replication- competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single cell transcriptomic analysis of 1,050 CD4+ T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis revealed that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, Granzymes A and K, cystatin F, LYAR and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4+ T cell population opening new possibilities for eradication. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/482683v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@19e89d2org.highwire.dtl.DTLVardef@16a5685org.highwire.dtl.DTLVardef@563a97org.highwire.dtl.DTLVardef@120a224_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

hNOP2/NSUN1 Regulates Ribosome Biogenesis through Stabilization of snoRNP Complexes and Cytosine-5 Methylation of 28S rRNA.

5-Methylcytosine (m5C) is a base modification broadly found on various RNAs in the human transcriptome. In eukaryotes, m5C is catalyzed by enzymes of the NSUN family composed of seven human members (NSUN1-7). NOP2/NSUN1 has been primarily characterized in budding yeast as an essential ribosome biogenesis factor required for the deposition of m5C on the 25S ribosomal RNA (rRNA). Although human NOP2/NSUN1 has been known to be an oncogene overexpressed in several types of cancer, its functions and substrates remain poorly characterized. Here we used a miCLIP-seq approach to identify human NOP2/NSUN1 RNA substrates. Our analysis revealed that NOP2/NSUN1 catalyzes the deposition of m5C at position 4447 on the 28S rRNA. We also find that NOP2/NSUN1 binds to the 5ETS region of the pre-rRNA transcript and regulates pre-rRNA processing through non-catalytic complex formation with box C/D snoRNAs. We provide evidence that NOP2/NSUN1 facilitates the recruitment of U3 and U8 snoRNAs to pre-90S ribosomal particles and their stable assembly into snoRNP complexes. Remarkably, expression of both WT and catalytically inactive NOP2/NSUN1 in knockdown background rescues the rRNA processing defects and the stable assembly of box C/D snoRNP complexes, suggesting that NOP2/NSUN1-mediated deposition of m5C on rRNA is not required for ribosome synthesis.

molecular biology↗

Persistent Cellular Immunity to SARS-CoV-2 Infection

SARS-CoV-2 is responsible for an ongoing pandemic that affected millions of individuals around the globe. To gain further understanding of the immune response in recovered individuals we measured T cell responses in paired samples obtained an average of 1.3 and 6.1 months after infection from 41 individuals. The data indicate that recovered individuals show persistent polyfunctional SARS-CoV-2 antigen specific memory that could contribute to rapid recall responses. In addition, recovered individuals show enduring immune alterations in relative numbers of CD4+ and CD8+ T cells, expression of activation/exhaustion markers, and cell division. SummaryWe show that SARS-CoV-2 infection elicits broadly reactive and highly functional memory T cell responses that persist 6 months after infection. In addition, recovered individuals show enduring immune alterations in CD4+ and CD8+ T cells compartments.

immunology↗

Mycobacterium tuberculosis hijacks an evolutionary recent IFN-IL-6-CEBP axis linked to monocyte development and disease severity in humans

Monocyte counts are increased during human tuberculosis (TB) but it has not been determined whether Mycobacterium tuberculosis (Mtb) directly regulates myeloid commitment. We demonstrated that exposure to Mtb directs primary human CD34+ cells to differentiate into monocytes/macrophages. In vitro myeloid conversion did not require type I or type II IFN signaling. In contrast, Mtb enhanced IL-6 responses by CD34+ cell cultures and IL-6R neutralization inhibited myeloid differentiation and decreased mycobacterial growth in vitro. Integrated systems biology analysis of transcriptomic, proteomic and genomic data of large data sets of healthy controls and TB patients established the existence of a myeloid IL-6/IL6R/CEBP gene module associated with disease severity. Furthermore, genetic and functional analysis revealed the IL6/IL6R/CEBP gene module has undergone recent evolutionary selection, including Neanderthal introgression and human pathogen adaptation, connected to systemic monocyte counts. These results suggest Mtb co-opts an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.

immunology↗

Functional dissection of the ARGONAUTE7 promoter

ARGONAUTES are the central effector proteins of RNA silencing which bind target transcripts in a small RNA-guided manner. Arabidopsis thaliana has ten ARGONAUTE (AGO) genes, with specialized roles in RNA-directed DNA methylation, post-transcriptional gene silencing, and antiviral defense. To better understand specialization among AGO genes at the level of transcriptional regulation we tested a library of 1497 transcription factors for binding to the promoters of AGO1, AGO10, and AGO7 using yeast 1-hybrid assays. A ranked list of candidate DNA-binding TFs revealed binding of the AGO7 promoter by a number of proteins in two families: the miR156-regulated SPL family and the miR319-regulated TCP family, both of which have roles in developmental timing and leaf morphology. Possible functions for SPL and TCP binding are unclear: we showed that these binding sites are not required for the polar expression pattern of AGO7, nor for the function of AGO7 in leaf shape. Normal AGO7 transcription levels and function appear to depend instead on an adjacent 124-bp region. Progress in understanding the structure of this promoter may aid efforts to understand how the conserved AGO7-triggered TAS3 pathway functions in timing and polarity.

plant biology↗

Hnf4a mediates microbial control of intestinal gene expression and inflammation

Microbiota influence diverse aspects of intestinal epithelial physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of host gene expression are poorly understood. Using an unbiased screening strategy, we found that the zebrafish Hepatic nuclear factor 4 alpha (Hnf4a) transcription factor specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis disclosed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells revealed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of Hnf4a and Hnf4g occupancy. Interspecies meta-analysis suggests Hnf4a may mediate microbial contributions to inflammatory bowel disease pathogenesis. These results indicate Hnf4a plays a critical conserved role in maintaining intestinal homeostasis in response to microbiota and inflammation.

genomics↗