Genetics — Weekly Evidence Brief

Recent advancements in whole-genome sequencing (WGS) are significantly improving our understanding of complex human phenotypes. WGS now captures approximately 88% of pedigree-based heritability, with rare non-coding variants contributing a substantial 79% to rare-variant heritability, revealing a deeper genetic architecture than previously known 1. Concurrently, refined statistical modeling in sQTL discovery, such as the MAJIQTL pipeline, is better connecting disease-causing variants to their functional insights, notably implicating a specific variant in Alzheimer's disease 2. Furthermore, the identification of 'cellular constraint' regions—conserved domains of facultative heterochromatin—promises to enhance causal variant identification and clinical diagnostic predictions across diverse cell types and diseases 3.

In precision oncology, comprehensive genomic profiling is proving indispensable for tailoring treatments. Techniques like whole-exome, whole-genome, and RNA sequencing characterize tumor biology, pinpointing actionable mutations, fusions, and key biomarkers like tumor mutational burden, which guide targeted therapies 4. Beyond protein-coding genes, noncoding alterations, including promoter/enhancer mutations and long noncoding RNAs, are emerging as critical biomarkers and therapeutic targets in cancers like breast cancer, paving the way for personalized medicine 5. The analysis of super-enhancer landscapes also provides novel epigenetic perspectives to dissect cancer heterogeneity, aiding in subtype discovery and the identification of therapeutic opportunities for SE-driven malignancies 6.

Understanding neurological and psychiatric disorders is being transformed by genomics. A significant extent of shared genetic risk factors (pleiotropy) has been identified across various neurological and psychiatric conditions, fundamentally challenging traditional disease classifications and informing future precision medicine strategies 7. Single-nucleus multi-omics approaches are uncovering shared and distinct regulatory changes and molecular pathways driving diseases like Pick's and Alzheimer's, revealing potential therapeutic targets 8. For vascular dementia, APOE is identified as a strong associated protein, and specific drug candidates such as benserazide and puromycin have been highlighted as potential therapeutic interventions, providing a framework for targeted drug development 9. Additionally, improved computational frameworks for single-cell RNA sequencing data, such as LSMetacell, are enhancing co-expression network analysis in Alzheimer's disease, revealing cell-type-specific modules crucial for disease understanding 10.

Novel genetic mechanisms are also being elucidated, offering deeper insights into disease pathology. Alternative start codon selection, for instance, has been found to shape mitochondrial function and contribute to rare human diseases by generating 'isoform-selective alleles' that can bypass pathogenic nonsense or frameshift mutations 11. Furthermore, allele-specific immune gene quantification in single-cell RNA sequencing data provides a critical tool for advancing personalized medicine in areas like tumor immunology and autoimmune diseases by detailing expression patterns and immunogenomic diversity 12. The fundamental process of mammalian mitochondrial DNA inheritance is also better understood, with experimental evidence showing that the mtDNA bottleneck size directly modulates the efficacy of purifying selection, impacting the origin and propagation of disease-causing mtDNA mutations 13.