Recurrent somatic mutations reveal cancer drivers, but in whole genomes many non-coding hotspots are passengers generated by localized mutational processes. We developed MutFormer, a transformer/convo...

Mismatch repair deficiency (MMRd) is a central driver of cancer genome evolution, yet it is commonly reduced to a binary MSI-high versus microsatellite-stable call. Here we combine multiplex CRISPR/Ca...

We are offering a PhD fellowship in AI for Single-Cell Disease Genomics commencing 1 May 2026, or soon thereafter (flexible start date). The PhD project is part

We are looking for a highly motivated and dynamic postdoc for a 3-year position, to commence 15th April 2026, or soon thereafter (flexible start date). The PhD

The accurate duplication of the genome relies on the spatiotemporal control of DNA replication initiation, yet the determinants specifying mammalian origin locations remain elusive. By developing ORIF...

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepan...

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepan...

Background Nonsense-mediated mRNA decay (NMD) is a quality-control pathway that degrades mRNA bearing premature termination codons (PTCs) resulting from mutation or mis-splicing, and that additionally participates in gene regulation of unmutated transcripts. While NMD activity is known to differ between examples of PTCs, it is less well studied if human tissues differ in NMD activity, or if individuals differ. Results We analyzed exomes and matched transcriptomes from Human tumors and healthy tissues to quantify individual-level NMD efficiency, and assess its variability between tissues, tumors, and individuals. This was done by monitoring mRNA levels of endogenous NMD target transcripts, and additionally supported by allele-specific expression of germline PTCs. Nervous system and reproductive system tissues have lower NMD efficiency than other tissues, such as the digestive tract. Next, there is systematic inter-individual variability in NMD efficiency, and we identify two underlying mechanisms. First, somatic copy number alterations can robustly associate with NMD efficiency, prominently the commonly-occurring gain at chromosome 1q that encompasses two core NMD genes: SMG5 and SMG7 and additional functionally interacting genes such as PMF1 and GON4L. Second, deleterious germline variants in genes such as the KDM6B chromatin modifier can associate with higher or lower NMD efficiency in individuals. Variable NMD efficiency modulates positive selection upon somatic nonsense mutations in tumor suppressor genes, and is associated with cancer patient survival and immunotherapy responses. Conclusions NMD efficiency is variable across human tissues, and it is additionally variable across individuals and tumors thereof due to germline and somatic genetic alterations.

The nonsense-mediated mRNA decay (NMD) pathway degrades some but not all mRNAs bearing premature termination codons (PTCs). Decades of work have elucidated the molecular mechanisms of NMD. More recent...

A puzzling question in molecular biology has been why our bodies do not uniformly eliminate faulty genetic information—especially that which could lead to disease. A key mechanism responsible for this...

Citation metrics are widely used and misused. We have created a publicly available database of top-cited scientists that provides standardized information on citations, h-index, co-authorship adjusted...

Just as species adapt over generations, our body’s cells accumulate DNA changes throughout life. Most are harmless, yet a few “driver” mutations give a cell a competitive edge and can spark cancer. Ch...