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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.
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.
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.
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.
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.
Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples.
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.
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.
The language used in genetic and medical research to describe populations has a fraught history, and current practices must be sensitively considered when reporting on genetic cohorts and analyses.
How somatic and germline mutations interact in cancer remains largely unexplored. A study of 17,152 patients with cancer suggests that the relative contribution of pathogenic germline mutations is governed by lineage and penetrance.
A concerning trend in genetics is the common use of the term ‘trans-ethnic’ to describe analyses that combine or compare several ancestrally diverse populations. In this commentary, we discuss how this term is inaccurate and alienating. We propose that geneticists avoid using the term trans-ethnic entirely and that researchers across disciplines reach a new consensus about the best terms to use to describe the populations we study.
A study of 17,152 patients with cancer identified pathogenic germline variants in cancer predisposition genes. Although tumors showed biallelic inactivation for high-penetrance genes, this was not the case in most patients with pathogenic variants in low-penetrance genes, suggesting alternative routes to tumorigenesis.
Genome-wide association analysis of irritable bowel syndrome identifies genetic susceptibility loci and highlights shared pathways with mood and anxiety disorders.
A new study shows that re-expressing PKD genes early in the course of the disease can fully reverse polycystic kidney disease in mice. These results reveal an unexpected ability of the kidney to regenerate following genetic rescue of polycystin function.
The genomes of cells across human tissues are riddled by changes to their DNA1–3. Many of these mutations do not alter the properties of a cell, and are neutral passengers. However, a small proportion can change a cell’s fitness, and increase or decrease the progeny that originate from the mutated cell4. How many of these alterations under positive selection (drivers) exist in total is unknown. Whether the current list of drivers is almost complete, or whether large proportions of positively selected drivers in the human genome remain undetected is yet to be determined.
