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Biology subjects

Vöhringer, H. S.

Publications and source records attributed to Vöhringer, H. S..

2 recordsLinked to original sources

Semi-supervised Omics Factor Analysis (SOFA) disentangles known sources of variation from latent factors in multi-omics data

A fundamental design pattern in biomolecular studies is to assay the same set of samples (organisms, tissue biopsies, or individual cells) by multiple different omics assays. Group Factor Analysis (GFA) and its adaptation to high-dimensional settings, Multi-Omics Factor Analysis (MOFA), are widely used as a first-line approach to analyse such data and are effective in detecting patterns of correlation, organize them into so-called latent factors, and identify common and assay-specific factors. However, in many applications a subset of the found factors just rediscovers already known covariates (e.g., disease subtypes, environmental covariates) while others may represent genuine novelty. Here, we present Semi-supervised Omics Factor Analysis (SOFA), a method that incorporates known covariates into the model upfront and focuses the factor discovery on novel sources of variation. We show SOFAs effectiveness for discovering novel patterns by applying it to cancer, brain development and heart failure multi-omic data sets.

bioinformatics↗

Life without mismatch repair

Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutS), but not MLH1 or PMS2 (MutL), caused 5-methylcytosine-dependent hypermutation, indicating that MutS is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation. HighlightsO_LIMMR repairs 1-10 lesions/day in every normal cell and thousands more in tumor cells C_LIO_LIMMR patterns and rates are shaped by genotype, tissue type and malignant transformation C_LIO_LIMSH2 and MSH6 are pivotal for repairing spontaneous deamination of methylated cytosine C_LIO_LIReplication indels and substitutions vary by leading versus lagging strand and genotype C_LI

genomics↗