Functional genomics articles within Nature Communications

Microbial genomics is a widely under-utilized tool in mining in understanding water quality drivers. Here the authors show early acid generation and thiosulfate concentrations are driven by O2 dependent microbial sulfur oxidizing bacterial niches in a mine tailings impoundment

Cancer cells possess unique molecular features that can confer an increased dependence on specific genes. Here, the authors use CRISPR-Cas9 screens to identify selectively essential genes and therapeutic targets in chordoma.

It is debated whether the pervasive intergenic transcription from eukaryotic genomes has functional significance. Here, Xu et al. find that only 1–5% of yeast intergenic transcription is unattributable to chance promoter activity or neighboring gene expression.

During spermatogenic meiosis, chromatin changes due to transcription, homologous recombination, and chromosome synapsis must be coordinated. Here they show that A-MYC and BRDT regulate release of paused RNA PolII to induce a transcriptional burst during pachytene of prophase I.

Cyanobacteria mutants with improved tolerance to combined high light and high temperature (HLHT) are rarely reported. Here, the authors use a hypermutation system for adaptive laboratory evolution and identify a mutant with improved HLHT tolerance by enhancing expression of shikimate kinase.

Here the authors used an evidence-based strategy to prioritize causal pleiotropic variants of autoimmune diseases, and revealed  that rs4728142 modulates aberrant IRF5 alternative promoter usage by ZBTB3-mediated chromatin looping.

The current study identifies five genomic subclusters of brain regions for cortical thickness and surface area characterized by high levels of shared genetic signal. These subclusters map onto biological and functional parcellations of the cortex.

The 16p11.2 duplication confers risk for autism and schizophrenia, but the disease mechanisms are unknown. Here, the authors use proteomics to show dysregulation of synaptic and epilepsy-associated protein networks in the cortex of model mice, and demonstrate that correcting Prrt2 gene dosage rescues circuit hypersynchrony and behavioural phenotypes.

Few cancer drivers in non-coding regions have been identified so far. Here, the authors develop a transcription factor-aware burden test to predict non-coding variants and analyze the impact on transcription factor binding - especially ETS factors - as well as their impact on transcriptional activity.

The genetic basis of spider major ampullate (Ma) gland silk production remains unknown. Hu et al. unveil a molecular atlas of this gland for the golden orb-weaving spider combining genome assembly and multiomics, revealing the single-cell spatial architecture of silk production in the Ma gland.

Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.

Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.

Venom is a complex trait with unresolved underlying toxin expression dynamics. Here, the authors compare expression across sea anemone species, revealing variation in dominant toxin diploid copy number across populations which generates distinct haplotypes.

Puberty is an important developmental period marked by hormonal, metabolic and immunological changes. Here the authors report gene expression changes in immune cells associated with age and puberty, and that may be relevant for sex differences in susceptibility to asthma, in a longitudinal cohort of 251 children with asthma.

Traditional bulk sequencing data lack information about cell-type-specific gene expression. Here, the authors develop a Tissue-AdaPtive autoEncoder (TAPE), a deep learning method connecting bulk RNA-seq and single-cell RNA-seq, and apply it to analyze the cell type fractions and cell-type-specific gene expression in clinical data.

High genetic overlap across traits requires methods that can be used to disentangle shared and unique biological pathways. Here, the authors introduce TSEM, a multivariate method for examining tissue-specific gene expression, and apply it to identify genes associated with cognitive traits.

TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.

Progression of the canonical eukaryotic cell cycle is tightly regulated. While the cell cycle control of flagellated protozoa Trypanosoma brucei shares conserved features with other eukaryotes certain cell cycle checkpoints are absent. Here, Marques et al. provide a genome-scale RNAi screen followed by sorting of parasites according to their cell cycle stage to inform about cell cycle regulators of bloodstream T. brucei.

The genetic bases of yak adaptations to extreme conditions remains elusive. This study compares yak and cattle at a genomic and transcriptomic level, revealing a new type of endothelial cell and candidate genes related with elastic fiber formation in yak lungs that might contribute to high altitude adaptation.

Existing methods for generating sgRNA predictions do not account for the tracrRNA sequence. Here the authors report an on-target model, Rule Set 3, to generate optimal predictions for multiple tracrRNA variants, and validate this on a new dataset of sgRNAs showing improvement over prior prediction models.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Non-human primates are attractive laboratory animal models that can accurately reflect some developmental and pathological features of humans. Here the authors chart a reference cell map of cynomolgus monkeys using both scATAC-seq and scRNA-seq data across multiple organs, providing insights into the molecular dynamics and cellular heterogeneity of this organism.

A comprehensive data portal to explore plant regulomes is still unavailable. Here, the authors develop a web-based platform ChIP-Hub in the ENCODE standards and demonstrate its applications in the identification of hierarchical regulatory network, tissue-specific chromatin dynamics, putative enhancers and chromatin states.

Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.

Here the authors provide a multi-omic study of the nucleosome landscape in LNCaP cells and observe nine functional nucleosome states each with characteristic nucleosome footprints. Upon androgen stimulation, they observed changes in these nucleosome states accompanied by changes in binding and function of pioneer factors, including GATA2.

Tissue-based functional genomics resources including molecular quantitative trait loci datasets lack diversity in ancestry and tissue types and thus are inadequate for comprehensively investigating gene regulation. Global efforts to increase the tissue diversity will help achieve more equitable medical care.

Human mitochondria experience substantial stress and malfunction in neurological diseases. Here, the authors reveal DELE1 as a multimodal sensor of protein import and processing defects, rationalizing mitochondrial stress integration.

Responses to diet composition may be linked to susceptibility to metabolic diseases such as type 2 diabetes. Here the authors report that Drosophila melanogaster displays genetic variation in survival on different diets and describe the importance for JNK-pathway and a conserved orphan nuclear hormone receptor tailless in regulating sugar tolerance.

How gene regulatory elements regulate gene expression during cellular differentiation remains largely unknown. Here the authors use perturbation-based massively parallel reporter assays at early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide different transcriptional patterns.

Epistasis can lead to different phenotypic consequences from the same mutation. Here the authors carry out a genome-wide analysis of conditionally essential genes in yeast, finding that gene essentiality changes tend to occur concordantly among components of the same protein complex or metabolic pathway.

Numerous rationally-designed and directed-evolution variants of SpCas9 have been reported to expand the utility of CRISPR technology. Here the authors make comparisons of numerous Cas9 variants, nominate options for base editing screens with denser coverage with A>G and C>T base editing screens and identify loss-of-function mutations in BRCA1 and Venetoclax-resistant mutations in BCL2.

Bacteria use specific silencing proteins to prevent spurious transcription of horizontally acquired DNA. Here, Forrest et al. describe differences in silencing strategies between E. coli and Bacillus subtilis, driven by the respective specificities of the silencing protein and the RNA polymerase in each organism.

The successful use of CRISPR-based mutagenesis in non-conventional microorganisms requires high activity sgRNAs. Here, the authors present DeepGuide, a neural network-based architecture, that learns from genome-wide CRISPR activity profiles to accurately design Cas9 and Cas12a sgRNAs with high activity in the oleaginous yeast Yarrowia lipolytica.

Context specificity confounds genetic analysis and prevents reproducible genome engineering. Here, the authors report a pan-CRISPR analysis of specificity in mammalian cells and identify ultra-compact sgRNA subsets for genome-scale screens.

N6-methyladenosine (m⁶A) plays important role in lineage specifications of embryonic stem cells, but its role at specific sites has not been assessed. Here the authors develop an adenine editor-based strategy, and systematically identify functional m⁶A sites that control lineage decisions in human embryonic stem cells.

What prevents a generalist predator from evolving and outperforming specialist predators? By combing analyses of natural variation with experimental evolution, Stewart et al. suggest that predator variation persists because most mutations have prey-specific effects, which results in relaxed selection

Forward genetic approaches such as CRISPR screens are powerful ways to identify essential genes and those that influence host-pathogen interactions. Here the authors design a bioinformatics portal for sgRNA design and a recombination-mediated cassette system for delivery into mosquito cell lines.

Perturbations of the cardiopharyngeal mesoderm can lead to congenital defects in individuals with 22q11.2 deletion syndrome. Here the authors use single cell RNA-sequencing to identify a multilineage primed population within the mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells.

The analysis of essential genes in pathogens can be used to discover potential antimicrobial targets. Here, the authors use a machine learning model and chemogenomic analyses to generate genome-wide gene essentiality predictions for the fungal pathogen Candida albicans, define the function of three uncharacterized essential genes, and identify the target of a new antifungal compound.

Off-target effects often confound the interpretation of CRISPR screens. Here, the authors introduce a computational method that corrects for off-targets in gRNA depletion assays, circumventing the need to completely discard unspecific guides.

The exact protein features that control passage through the eukaryotic secretory system remain largely unknown. Here the authors report SECRiFY which they use to evaluate the secretory potential of polypeptides on a proteome-wide scale in yeast, revealing a role for flexibility and intrinsic disorder.

Human polymorphisms in nicotinic acetylcholine receptor genes have been linked to both smoking and lung diseases like Chronic Obstructive Pulmonary Disease (COPD) or lung cancer. Here the authors identify a direct role for a human coding polymorphism in COPD-like lesions independent of smoke or nicotine exposure.

Transparent data sharing is central to scientific progress, but limited for human sequencing data because of patient privacy concerns. Here, the authors propose an approach that removes certain types of genetic information in sequencing data, without affecting count-based downstream analyses.

Cell-based transcriptional reporters are an invaluable part of highthroughput screening, but many such reporters have weak or transient responses. Here, the authors describe a digitizer circuit for amplifying reporter activity, increasing sensitivity, and retaining memory of pathway activation.

While inductive signals controlling germline specification are well characterized, the intrinsic factors that allow epiblast cells to respond to such signals remain largely unknown. Here the authors use in vitro differentiated primordial germ cells to show that partial retention of histone H3K4 monomethylation within relevant enhancers is important for germline competence and specification.

Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries.

Evolutionary arms races can drive adaptations in hosts and parasites as well as among competing parasites. A combination of multi-omics and functional tests identifies a set of genes that allow a parasitic wasp to minimize intraspecific competition by inducing hosts to escape before more wasps can parasitize them.

Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.

Identifying causal variants at GWAS loci is important to understand disease mechanisms. Here the authors use massively parallel reporter assays to identify type 2 diabetes-associated variants that alter cis-regulatory activity, narrowing in on the causal variants and genetic mechanisms behind the disease.