Biology subjects

Holt, S.

Publications and source records attributed to Holt, S..

3 recordsLinked to original sources

bioRxiv2024

CCG interruptions are unstable and hypermethylated in DM1 patients

Myotonic dystrophy type 1 (DM1) exhibits highly heterogeneous clinical manifestations caused by an unstable CTG repeat expansion reaching up to 4,000 CTG. The dynamics of CTG repeats and clinical variability depends on the CTG repeat number, CNG repeat interruptions, DNA methylation, somatic mosaicism, but also gene modifiers. Around 10% of the DM1 population carries triplet repeat interruptions (CCG, CGG, CTC, CAG), which differ in number and nature between DM1 families. CCG interruptions have been associated with stabilization of the CTG repeat expansions and a milder phenotype in the DM1 population. However, the dynamics and precise role of interruptions in CTG repeat instability remain relatively underexplored due to the complexities of analyzing them. In this study, we showed that the number of CCG interruptions within the expansion varies within tissues and between generations using single-molecule real-time long-read sequencing. Although the interrupted expanded alleles showed global stabilization, the CCG interruptions themselves displayed variability across generations and within somatic tissues. Importantly, our findings reveal, for the first time, CCG hypermethylation within the CTG expansion, which is linked to downstream hypermethylation of the repeat. These results support the hypothesis that methylation of CCG interruptions within the expanded DMPK alleles may contribute to the stabilization of trinucleotide repeats.

molecular biology↗

bioRxiv2022

Did circular DNA shape the evolution of mammalian genomes?

Extrachromosomal circular DNA of chromosomal origin (eccDNA) can rapidly shape the evolution and adaptation of mitotically dividing cells such as tumor cells. However, whether eccDNA has a permanent impact on genome evolution through the germline is largely unexplored. Here, we propose that a large fraction of the syntenic changes that are found between mammalian species are caused by germline transposition of eccDNA. We have previously shown the existence of eccDNA in mammalian meiotic cells. By reanalysis of available synteny maps, we now find that up to 6% of mammalian genomes might have rearranged via a circular DNA intermediate. Hence, eccDNA in the germline is expected to have large effects on evolution of gene order. HighlightsO_LIExtrachromosomal circular DNA (eccDNA) is present in mammalian germline cells showing that eccDNAs are not excluded, repressed or eliminated during meiosis C_LIO_LILarge eccDNA reinsertions into the genome can change gene synteny in a recognizable pattern based on its circular junction and integration breakpoint. C_LIO_LIBy reanalyzing synteny maps form 8 mammalian species, we show that 6% of genome of the ungulates cow and sheep can be explained by eccDNA insertions. C_LIO_LIWe propose that reinsertion of large eccDNA that are fixed in germline cells may have contributed to speciation barriers and evolution of new species C_LI

genetics↗

bioRxiv2019

The COMPARE Data Hubs

Data sharing enables research communities to exchange findings and build upon the knowledge that arises from their discoveries. Areas of public and animal health as well as food safety would benefit from rapid data sharing when it comes to emergencies. However, ethical, regulatory, and institutional challenges, as well as lack of suitable platforms which provide an infrastructure for data sharing in structured formats often lead to data not being shared, or at most shared in form of supplementary materials in journal publications. Here, we describe an informatics platform that includes workflows for structured data storage, managing and pre-publication sharing of pathogen sequencing data and its analysis interpretations with relevant stakeholders.

bioinformatics↗