Biology subjects

Breuss, M. W.

Publications and source records attributed to Breuss, M. W..

3 recordsLinked to original sources

bioRxiv2020

DeepMosaic: Control-independent mosaic single nucleotide variant detection using deep convolutional neural networks

Introductory paragraphMosaic variants (MVs) reflect mutagenic processes during embryonic development1 and environmental exposure2, accumulate with aging, and underlie diseases such as cancer and autism3. The detection of MVs has been computationally challenging due to sparse representation in non-clonally expanded tissues. While heuristic filters and tools trained on clonally expanded MVs with high allelic fractions are proposed, they show relatively lower sensitivity and more false discoveries4-9. Here we present DeepMosaic, combining an image-based visualization module for single nucleotide MVs, and a convolutional neural networks-based classification module for control-independent MV detection. DeepMosaic achieved higher accuracy compared with existing methods on biological and simulated sequencing data, with a 96.34% (158/164) experimental validation rate. Of 932 mosaic variants detected by DeepMosaic in 16 whole genome sequenced samples, 21.89-58.58% (204/932-546/932) MVs were overlooked by other methods. Thus, DeepMosaic represents a highly accurate MV classifier that can be implemented as an alternative or complement to existing methods.

genomics↗

bioRxiv2020

Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

Every newborn harbors scores of new single nucleotide variants (SNVs) that may impact health and disease1-4; the majority of these are contributed by the paternal germ cells5. In some cases, these mutations are identifiable in a subset of the parents cells--a phenomenon called mosaicism, which is capable of producing disease recurrence6-8. Here, we provide a comprehensive analysis of male gonadal mosaic mutations, employing 300x whole genome sequencing (WGS) of blood and sperm in 17 healthy individuals, including assessment across multiple samples and age groups. Approximately 1 in 15 healthy males is predicted to harbor a transmissible, likely pathogenic exonic variant that is mosaic in his sperm. In general, only a third of sperm mosaic mutations were detectable in blood cells, all were remarkably stable over the course of months to years, and 23% were present in 5% or more of sperm cells. There was no evidence of age-dependent clonal expansion or collapse, as seen in hematopoiesis. Thus, despite the observed increase of mutations in offspring of men with advanced paternal age, detectable sperm mosaicism remains stable, represents a life-long transmission risk to offspring, and suggests a testis stem cell niche that prevents widespread clonality.

genomics↗

bioRxiv2020

Somatic mosaicism in the mature brain reveals clonal cellular distributions during cortical development

The structure of the human neocortex underlies species-specific features and is a reflection of intricate developmental programs. Here we analyzed neocortical cellular lineages through a comprehensive assessment of brain somatic mosaicism--which acts as a neutral recorder of lineage history. We employed deep whole genome and variant sequencing in a single postmortem neurotypical human brain across 25 anatomic regions and three distinct modalities: bulk geographies, sorted cell types, and single nuclei. We identified 259 mosaic variants, revealing remarkable differences in localization, clonal abundance, cell type specificity, and clade distribution. We identified a set of hierarchical cellular diffusion barriers, whereby the left-right axis separation of the neocortex occurs prior to anterior-posterior and dorsal-ventral axis separation. We also found that stochastic distribution is a driver of clonal dispersion, and that rules regarding cellular lineages and anatomical boundaries are often ignored. Our data provides a comprehensive analysis of brain somatic mosaicism across the human cerebral cortex, deconvolving clonal distributions and migration patterns in the human embryo. One Sentence SummaryComprehensive evaluation of brain somatic mosaicism in the adult human identifies rules governing cellular distribution during embryogenesis.

genomics↗