The evidence that most adult-onset common diseases have a polygenic genetic architecture
fully consistent with robust biological systems supported by multiple back-up mechanisms is …

The first phase of genome-wide association studies (GWAS) assessed the role of common
variation in human disease. Advances optimizing and economizing high-throughput …

The vast majority of missense variants observed in the human genome are of unknown
clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned on …

Abstract Background The UK 100,000 Genomes Project is in the process of investigating the
role of genome sequencing in patients with undiagnosed rare diseases after usual care and …

Detailed knowledge of how diversity in the sequence of the human genome affects
phenotypic diversity depends on a comprehensive and reliable characterization of both …

Background Splicing of genomic exons into mRNAs is a critical prerequisite for the accurate
synthesis of human proteins. Genetic variants impacting splicing underlie a substantial …

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date
(n= 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to …

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory
disease and cancer. Here, we assess the response of immune cells to lactate in the context …

Gene discovery for Mendelian conditions (MCs) offers a direct path to understanding
genome function. Approaches based on next-generation sequencing applied at scale have …

Interpreting the effects of genetic variants is key to understanding individual susceptibility to
disease and designing personalized therapeutic approaches. Modern experimental …