Volume 53 Issue 12, December 2021

Although clear genetic connections to ALS were first established three decades ago, there has been negligible progress in the development of disease-modifying treatments for this disease. Despite tremendous unmet need, industry has often been largely baffled by a disease seemingly designed to thwart current effective drug development approaches. In the largest genetic study of ALS to date, van Rheenen and colleagues use sophisticated analyses to gain novel insights into its pathogenesis.

Oncogene amplification is a major driver of tumorigenesis; yet, the mechanisms generating amplification are only partially understood. New research reports on the identification of a new focal amplification pattern termed ‘seismic amplification’ that is hypothesized to originate from recombination between extrachromosomal DNA circles.

The human endometrium exhibits complex signaling cascades mediated by spatial–temporal cellular interactions. Understanding the normal endometrial microenvironment is the first step towards understanding diseases of endometrial dysfunction.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

Re-expression of Pkd genes in cystic kidneys results in rapid reversal of autosomal dominant polycystic kidney disease phenotypes in mice, revealing an unexpected capacity for renal plasticity under the control of Pkd gene function.

A CRISPR paralog targeting library profiling 815 paralog families across 11 cell lines identifies DUSP4 and DUSP6 as paralog pairs whose combined inactivation confers sensitivity to cells resistant to MAPK inhibitors or cells harboring NRAS or BRAF mutations.

Seismic amplifications arise from several cycles of circular recombination of circular extrachromosomal DNA formed as a result of chromothripsis. The process provides a mechanism for oncogene amplification in a number of different human tumor types.

Polycomb proteins can regulate epigenetic transcriptional memory during cell differentiation. This memory operates in cis and is linked to the strength of activating inputs.

Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

A genome-wide association study of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders highlights links with over 370 disease endpoints and other traits.