Volume 53 Issue 4, April 2021

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for more than 5,000 genes, including 2,850 novel null, 2,987 novel conditional-ready and 4,433 novel reporter alleles.

We present the Polygenic Score (PGS) Catalog (https://www.PGSCatalog.org), an open resource of published scores (including variants, alleles and weights) and consistently curated metadata required for reproducibility and independent applications. The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with a platform for PGS dissemination, research and translation.

The structure of chromatin is associated with its function, but precisely how is unclear. New data show that the higher-order architecture of the genome is similar among cell types with widely variant fates and gene expression patterns, thus challenging the view that chromatin domains determine function in the genome.

Polycomb-group proteins assemble into two primary complexes—Polycomb repressive complex (PRC) 1 and 2—that safeguard cell fate by repressing gene transcription. Two new studies explore the PRC1 landscape during the transition from gametes to embryos in mice, thus providing insight into the intergenerational transmission of epigenetic information and gene regulation dynamics as embryos prepare for gastrulation.

Stretches of non-coding DNA that have remained identical across millions of years of evolution are typically assumed to have functional regulatory roles that would be compromised by any amount of nucleotide substitution. A new study finds that these ultraconserved regions are more robust to mutagenesis than their level of conservation would suggest.

Case–case genome-wide association studies (GWAS) within a single genotyped cohort have proven useful in identifying genetic variants explaining different health outcomes, yet they are limited by data availability. A new study by Peyrot and Price proposes a clever statistical method to overcome this problem by inferring case–case GWAS results from a pair of standard case–control GWAS summary statistics that need not be from the same cohort.

Immune responses require a delicate balance: a weak response can cause immunodeficiency, whereas an excessive response can lead to hyperinflammatory disease and hematological malignancy. Because spleen tyrosine kinase has roles in multiple signaling pathways, its gain-of-function alterations in humans cause hypogammaglobulinemia as well as autoinflammation and predisposition to B cell lymphoma.

Genome-wide CRISPR screens for proviral host factors of SARS-CoV-2 and HCoV-229E human coronaviruses show that the lysosomal protein TMEM106B is required for SARS-CoV-2 infection.

Identification of the genetic differences between two different disorders has been hampered by a need for individual-level data from cases of both disorders. CC-GWAS enables the comparison of allele frequencies among cases of two disorders using case–control GWAS summary statistics.

Single-cell ATAC-seq analysis of human pancreatic islet cells identifies different cell clusters and transcription factors that underlie lineage- and state-specific regulation and helps prioritize type 2 diabetes risk variants.

Human–chimpanzee tetraploid fusions serve as a model to study gene expression differences between these species, allowing for separation of cis- from trans-regulatory effects and analysis of unique craniofacial morphologies.

Single-cell analysis of Drosophila development with Hi-M suggests that physical proximity between regulatory regions does not necessarily instruct transcriptional states. Multi-way analyses identify the existence of regulatory hubs that emerge before topologically associating domains.

Chromatin conformation is largely independent of dorsoventral gene expression during early embryonic development in Drosophila. Despite tissue-specific differences in chromatin state and gene expression, three-dimensional chromatin organization is maintained across tissues.

Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

CRISPR–Cas9 tiled screens of the β-globin gene cluster identify an NF-Y bound activator element at the γ-globin promoter. Binding competition by the transcriptional repressor BCL11A leads to NF-Y eviction and a switch from fetal to adult globin gene expression.

Mutagenesis of 23 ultraconserved enhancers and examination of their activities in transgenic mouse reporter assays show that overall their regulatory properties are robust to mutation. Manipulation of endogenous loci in mice corroborates reporter assay data.

A pediatric cancer dependency map generated with genome-scale CRISPR–Cas9 loss-of-function screens in 82 pediatric cancer cell lines highlights genetic dependencies across a range of tumor types.

In early mouse embryos, PRC1-mediated H2AK119ub1 deposition precedes H3K27me3. Deficiency in variant PRC1 reduces H2AK119ub1 and leads to gene-selective loss of H3K27me3 in oocytes, which is inherited by embryos.

H2AK119ub1 and H3K27me3 have different genome-wide dynamics in mouse preimplantation embryos. Loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation.

A chromosome-scale genome assembly of rye inbred line ‘Lo7’ provides insights into its incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution and the yield benefits of rye–wheat introgressions.

A high-quality genome assembly of Weining rye sheds new light on gene duplications and their effects on starch biosynthesis genes, gene expression features underlying early heading trait and putative domestication-associated chromosomal regions.