No abstract

Mosaic loss of Chromosome Y (LOY) is a common acquired structural mutation in the leukocytes of aging men that is correlated with several age-related diseases including Alzheimer's disease (AD). The molecular basis of LOY in brain cells has not been systematically investigated. Here, we present a large-scale analysis of single-cell and single-nuclei RNA brain datasets, yielding 851,674 cells, to investigate the cell type–specific burden of LOY. LOY frequencies differed widely between donors and CNS cell types. Among five well-represented neural cell types, LOY was enriched in microglia and rare in neurons, astrocytes, and oligodendrocytes. In microglia, LOY was significantly enriched in AD subjects. Differential gene expression (DE) analysis in microglia found 172 autosomal genes, 3 X-linked genes, and 10 pseudoautosomal genes associated with LOY. To our knowledge, we provide the first evidence of LOY in the microglia, and highlight its potential roles in aging and the pathogenesis of neurodegenerative disorders such as AD.

Summary Despite the recent availability of complete genome sequences of tumors from thousands of patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic variants remains challenging, and only a handful of validated examples exist. By integrating whole-genome sequencing, genetic data, and allele-specific gene expression from TCGA, we identified 320 somatic non-coding mutations that affect gene expression in cis (FDR<0.25). These mutations cluster into 47 cis-regulatory elements that modulate expression of their subject genes through diverse molecular mechanisms. We further show that these mutations have hallmark features of non-coding drivers; namely, that they preferentially disrupt transcription factor binding motifs, are associated with a selective advantage, increased oncogene expression and decreased tumor suppressor expression.

39Despite the recent availability of complete genome sequences of tumors from thousands of 40 patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic 41 variants is notoriously challenging, and only a handful of validated examples exist. By integrating 42 whole-genome sequencing, gene expression, chromatin accessibility, and genetic data from 43 TCGA, we identified 301 non-coding somatic mutations that affect gene expression in cis. These 44 mutations cluster into 36 hotspot regions with diverse molecular mechanisms of gene expression 45 regulation. We further show that these mutations have hallmark features of noncoding drivers; 46