MosaicBase: A Knowledgebase of Postzygotic Mosaic Variants in Noncancer Disease-related and Healthy Human Individuals

Abstract

Mosaic variants resulting from postzygotic mutations are prevalent in the human genome and play important roles in human diseases. However, except for cancer-related variants, there is no collection of postzygotic mosaic variants in noncancer disease-related and healthy individuals. Here, we present MosaicBase, a comprehensive database that includes 6698 mosaic variants related to 266 noncancer diseases and 27,991 mosaic variants identified in 422 healthy individuals. Genomic and phenotypic information of each variant was manually extracted and curated from 383 publications. MosaicBase supports the query of variants with Online Mendelian Inheritance in Man (OMIM) entries, genomic coordinates, gene symbols, or Entrez IDs. We also provide an integrated genome browser for users to easily access mosaic variants and their related annotations for any genomic region. By analyzing the variants collected in MosaicBase, we find that mosaic variants that directly contribute to disease phenotype show features distinct from those of variants in individuals with mild or no phenotypes, in terms of their genomic distribution, mutation signatures, and fraction of mutant cells. MosaicBase will not only assist clinicians in genetic counseling and diagnosis but also provide a useful resource to understand the genomic baseline of postzygotic mutations in the general human population. MosaicBase is publicly available at http://mosaicbase.com/ or http://49.4.21.8:8000.

Keywords: MosaicBase; Mosaicism; Mutation; Noncancer; Postzygotic.

Figure 1

Overview of the data collection, storage, and visualization of MosaicBase

Figure 2

Screenshots of MosaicBase A. The main page provides the search modes and multiple links to different utilities of the database. B. Disease ontology-based advanced search page and an example of a result table. C. The variant pages from the basic search results; these pages provide information about each variant and its corresponding gene, individual and publication annotation, the individuals carrying the same variant, as well as the publications describing the variant. D. Integrated genome browser to visualize mosaic variants with genetic and epigenetic annotations. E. Summary statistics of the publications, mutational spectrum, and individuals collected in MosaicBase. F. Detailed tutorials for the introduction, data presentation, and usage of MosaicBase.

Figure 3

Statistics about the publication, individual, and variant data collected in MosaicBase A. Number of relevant publications from 1989 to June 2018 collected from PubMed. Data before 1997 were condensed. Query terms and inclusion/exclusion criteria for literature acquisition are described in File S1. B. Summary of different categories of mosaic carriers. Left: Number of patients (grouped by gender) and healthy individuals. Right: Number of parents and grandparents (grouped by gender). C. Genomic distribution of mosaic variants. Chromosomal bands are illustrated in the outer circle with centromeres in red. Histograms show the count of mosaic variants for 1-Mb interval in each inner circle. Genomic coordinates and color codes of the categories are shown in the center.

Figure 4

Genomic features of mosaic variants collected in MosaicBase A. PCC of the density of mosaic variants and genomic features. Genomic density within each 1-Mb interval was linearly correlated with GC content, DHS regions, replication timing, and histone modification profiles measured in the GM12878 cell line. B. Tri-nucleotide genomic context of mosaic variants. C. Estimated contribution of mutation signatures for mosaic variants. 60 single-base substitution signatures and artefact signatures from COSMIC were considered, and a linear regression model was used to estimate the proportion of signatures. D. Mutant allele fraction of 491 mosaic variants in 358 individuals from parents/grandparents group (left) and 34,689 variants in all the 2182 individuals (including 1402 noncancer patients, 358 parents/grandparents of the patients, and 422 healthy individuals) collected in MosaicBase (right). Significantly higher mosaic allele fractions were observed in individuals with disease phenotypes (P = 5.9 × 10⁻⁵ and P < 2.2 × 10⁻¹⁶; two-tailed Mann–Whitney U test). In panels A–C, 5,711,196 common germline variants with population allele frequency ≥ 0.1 in dbSNP (version 137) were shown for comparison. H2AZ, histone 2A.Z variant; DHS, DNase I hypersensitive; PCC, Pearson correlation coefficient.