Biology subjects

Goldmann, J. M.

Publications and source records attributed to Goldmann, J. M..

3 recordsLinked to original sources

bioRxiv2020

Stochasticity explains differences in the number of de novo mutations between families

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a significant family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring. In addition, by modeling DNM data from 1714 multi-offspring families we estimated that the family specific contribution explains approximately 5.2% of the variation in DNM number. Furthermore, we found no significant difference between the observed number of DNMs and those based on a stochastic Poisson process. We conclude that a family-specific contribution to DNMs is small and that stochasticity explains a large proportion of variation in DNM counts.

genomics↗

bioRxiv2020

Population sequencing data reveal a compendium of mutational processes in human germline

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

genetics↗

bioRxiv2017

Germline De Novo Mutation Clusters Arise During Oocyte Aging In Genomic Regions With Increased Double-Strand Break Incidence

Clustering of mutations has been found both in somatic mutations from cancer genomes and in germline de novo mutations (DNMs). We identified 1,755 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios and investigated the underlying mutational mechanisms. We found that the number of clusters on the maternalallele was positively correlated with maternal age and that these consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in regions with an overall increased maternal mutation rate. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G mutations. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions and de novo deletions events. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.

genomics↗