Random allelic expression in the adult human body.

Genes are typically assumed to express both parental alleles similarly, yet cell lines show random allelic expression (RAE) for many autosomal genes that could shape genetic effects. Thus, understanding RAE in human tissues could improve our understanding of phenotypic variation. Here, we develop a methodology to perform genome-wide profiling of RAE and biallelic expression in GTEx datasets for 832 people and 54 tissues. We report 2,762 autosomal genes with some RAE properties similar to randomly inactivated X-linked genes. We found that RAE is associated with rapidly evolving regions in the human genome, adaptive signaling processes, and genes linked to age-related diseases such as neurodegeneration and cancer. We define putative mechanistic subtypes of RAE distinguished by gene overlaps on sense and antisense DNA strands, aggregation in clusters near telomeres, and increased regulatory complexity and inputs compared with biallelic genes. We provide foundations to study RAE in human phenotypes, evolution, and disease.

Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches.

BACKGROUND: When interpreting sequencing data from multiple spatial or longitudinal biopsies, detecting sample mix-ups is essential, yet more difficult than in studies of germline variation. In most genomic studies of tumors, genetic variation is detected through pairwise comparisons of the tumor and a matched normal tissue from the sample donor. In many cases, only somatic variants are reported, which hinders the use of existing tools that detect sample swaps solely based on genotypes of inherited variants. To address this problem, we have developed Somalier, a tool that operates directly on alignments and does not require jointly called germline variants. Instead, Somalier extracts a small sketch of informative genetic variation for each sample. Sketches from hundreds of germline or somatic samples can then be compared in under a second, making Somalier a useful tool for measuring relatedness in large cohorts. Somalier produces both text output and an interactive visual report that facilitates the detection and correction of sample swaps using multiple relatedness metrics. RESULTS: We introduce the tool and demonstrate its utility on a cohort of five glioma samples each with a normal, tumor, and cell-free DNA sample. Applying Somalier to high-coverage sequence data from the 1000 Genomes Project also identifies several related samples. We also demonstrate that it can distinguish pairs of whole-genome and RNA-seq samples from the same individuals in the Genotype-Tissue Expression (GTEx) project. CONCLUSIONS: Somalier is a tool that can rapidly evaluate relatedness from sequencing data. It can be applied to diverse sequencing data types and genome builds and is available under an MIT license at github.com/brentp/somalier .

Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.