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The authors present a CRISPR-library-based approach for highly efficient and precise genome-wide variant engineering. They examine the functional consequences of premature termination codons within all annotated essential genes in yeast.
Single-cell RNA sequencing (scRNA-seq) of ~25,000 peripheral blood mononuclear cells from 45 donors identifies new celltype-specific cis-eQTLs and genetic variants that significantly alter co-expression relationships (‘co-expression QTLs’).
The fetal globin gene repressors BCL11A and ZBTB7A directly bind γ-globin gene promoter regions. Repressor binding is disrupted by naturally occurring point mutations located upstream of the transcriptional start site that are associated with hereditary persistence of fetal hemoglobin.
Meta-analysis of exome sequencing data identifies new recurrently mutated driver genes for prostate cancer. Comparison of primary and metastatic tumors further identifies genomic markers for advanced prostate cancer that may inform risk stratification.
The authors study the cis-regulatory evolution of the Shh locus in vertebrates. Using genomic editing and chromatin profiling, they conclude that paired fins emerged through the co-option of developmental programs for the median fins of gnathostomes.
Analysis of whole-genome sequencing data from 1,291 parent–offspring trios identifies patterns of clustered de novo mutations. Clusters increase in number with maternal age and are associated with DNA double-strand-break processes.
This study presents a map of sequence constraint in humans based on 11,257 whole-genome sequences and 16,384 heptamers. The map identifies regulatory elements among the most constrained regions of the genome and will aid interpretation of noncoding variants.
Biallelic loss-of-function mutations in TGFB1 are reported in three individuals with severe infantile inflammatory bowel disease and neurodevelopmental delay. These findings highlight a critical role for TGF-β1 in human intestinal homeostasis and central nervous system development.
Meta-analysis of data from 58,265 cattle shows that the genetic architecture underlying stature is similar to that in humans, where many genomic regions individually explain only a small amount of phenotypic variance.
Identification of AvrStb6, the fungal avirulence effector that triggers Stb6-mediated resistance in wheat, here demonstrates that neither host resistance nor fungicide treatment suppresses fungal sexual reproduction, thus unveiling implications of fungal sex in plant disease control.
The authors report map-based cloning of the wheat Stb6 gene, which encodes a conserved wall-associated receptor kinase (WAK)-like protein. Stb6 confers gene-for-gene disease resistance to fungal pathogen Zymoseptoria tritici by recognition of a matching pathogen effector.
Whole-exome sequencing identifies mutations in CLCN2 in individuals with familial hyperaldosteronism type II or early-onset primary aldosteronism. These gain-of-function mutations cause chloride channel opening and glomerulosa cell depolarization, showing a role for anion channels in aldosterone production.
A gain-of-function mutation in the CLCN2 chloride channel gene (encoding ClC-2) causes primary aldosteronism. The mutation abolishes voltage-dependent gating of ClC-2, highlighting a role for chloride conduction in regulating aldosterone biosynthesis.
Exome-wide analyses identify low-frequency coding variants associated with esophageal squamous cell carcinoma. One of the risk variants, in CYP26B1, is associated with enhanced enzymatic activity and lower levels of all-trans retinoic acid in serum.
A conserved microRNA targets LTR retrotransposons in Arabidopsis pollen, stimulating epigenetically activated siRNAs in a dose-dependent manner through RNA Pol IV. These miR845b-dependent easiRNAs mediate the interploidy hybridization barrier that leads to seed abortion.
Depletion of easiRNAs (epigenetically activated small interfering RNAs) relieves the triploid block reproduction barrier mediated by increased paternal ploidy in Arabidposis. Loss of RNA Pol IV blocks easiRNA formation and rescues triploid seeds.
MC4R colocalizes with ADCY3 at primary cilia in hypothalamic neurons, and MC4R mutations associated with human obesity impair this localization. Inhibition of adenylyl cyclase signaling at primary cilia of neurons leads to increased body weight in mice.
Genetic analysis of children with severe obesity identifies mutations in the ADCY3 gene (encoding adenylate cyclase 3). These variants are rare in public databases and affect the functional activity of the protein, indicating that ADCY3 is a potential pharmacological target for obesity treatment.