Brief Communications

An approach combining infection of primary human epithelial cells with a barcoded lentiviral-based library followed by engraftment into mice yields biologically relevant models of bladder and prostate cancer harboring complex genetic perturbations.

A test of four genomic sequence-to-expression deep learning models (Enformer, Basenji2, ExPecto, Xpresso) finds that they often fail to predict the correct direction of effect of cis-regulatory genetic variation on gene expression.

The chemotherapeutic agent CX-5461 is shown to be a potent mutagen in hTERT-RPE1, HAP1 and human induced pluripotent stem cells. The compound generates distinct mutational patterns of single- and double-base substitutions, as well as of small insertions and deletions, that were detectable following a single exposure.

GLIMPSE2 is an improved method using sparse models for accurate, efficient and cost-effective genotype imputation in low-coverage whole-genome sequencing data.

Adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests for quantitative traits, particularly when using sparse mixed models or simple linear models as an alternative to dense mixed-model approaches.

Reanalysis of the immunotherapy-treated MSK-IMPACT cohort finds that chromosomal arm-level aneuploidy scores are an independent predictor of survival for patients with low tumor mutational burden.

SAIGE-GENE+ performs set-based rare variant association tests with improved type 1 error control and computational efficiency by collapsing ultra-rare variants and conducting multiple tests corresponding to different minor allele frequency cutoffs and annotations.

Multi-ancestry genome-wide analyses identify variants near UGT2A1 and UGT2A2 associated with COVID-19-related loss of smell or taste. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants.

Multi-ancestry fine-mapping of the OAS1/2/3 region shows that a splice site variant in OAS1 is likely responsible for the association of this locus with the risk of severe COVID-19.

Postzygotic inactivating mutations in RHOA cause a mosaic neuroectodermal syndrome characterized by linear hypopigmentation, leukoencephalopathy and craniofacial anomalies, highlighting the role of RHOA in human development and disease.

The long noncoding RNA SCHLAP1 has been reported to act by depleting the SWI/SNF complex from genomic sites, but new data show that SWI/SNF remains localized to chromatin in the presence of SCHLAP1, suggesting that SCHLAP1 may act independently of SWI/SNF.

In vivo analysis of pairwise combinations of tumor suppressor losses using a barcode-based assay in mice identifies unpredicted genetic interactions and shows that the effects of tumor suppressor alterations can be context-dependent.

The clinical phenotype associated with BRD4 haploinsufficiency overlaps with Cornelia de Lange syndrome, which is often caused by mutations in NIPBL. The authors show that BRD4 and NIPBL physically interact and co-bind at super-enhancers.

Individuals from a Greenlandic Inuit population with homozygous loss-of-function variants in ADCY3 (adenylate cyclase 3) have increased risk for obesity and type 2 diabetes. Carriers of rare ADCY3 variants in trans-ancestry populations also show increased association with type 2 diabetes.

Linda Richards, Paul Lockhart, Christel Depienne and colleagues identify heterozygous DCC mutations in four families and five sporadic individuals with agenesis of the corpus callosum (ACC). They report that DCC mutations result in variable dominant phenotypes with incomplete penetrance, including mirror movements and ACC associated with a favorable developmental prognosis.

Timothy Chan and colleagues find that somatic mutations in SERPINB3 or SERPINB4 are associated with longer survival in patients with melanoma who received anti-CTLA4 immunotherapy. These findings may have implications for precision medicine efforts in cancer.

Johannes Beckers, Martin Hrabě de Angelis and colleagues use in vitro fertilization to demonstrate epigenetic germline inheritance of acquired metabolic disorders in mice. They show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes.

David Solit and colleagues report that inactivating CDH1 mutations are found in 84% of plasmacytoid bladder cancer samples tested and are not found in other bladder cancer subtypes. CRISPR/Cas9-mediated knockout of CDH1 in cell lines leads to enhanced cellular migration.

Rogier Versteeg and colleagues analyze the whole-genome sequences of 108 neuroblastoma samples and detect structural rearrangements of TERT in 23% of high-stage cases. TERT rearrangements are associated with increased TERT expression, increased telomere length and very poor prognosis.

Yardena Samuels and colleagues report the analysis of 501 melanoma exomes and the identification of RASA2 as a tumor-suppressor gene mutated in 5% of melanomas. RASA2 mutations led to increased RAS activation, and RASA2 loss was associated with shorter patient survival times.