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Single cell methylation, RNA, and ATAC sequencing of ventral hippocampal brain tissue from inbred mouse strains

ABSTRACT: Despite advances in genetics over the last two decades, relating genetic variants to behavior remains a fundamental challenge. Particularly in mice, progress is frustrated by the low resolution of genetic mapping, and consequently by the thousands of candidate causal variants that must be screened. To assess the utility of DNA methylation marks in discovering causative variants we examined their relationship to genetic variation by generating genome-wide, base-pair resolution maps of multiple cell types from the hippocampus of eight fully sequenced inbred strains of Mus musculus. We find that the impact of sequence variation, as mediated by methylation changes, depends on local CpG sequence density. At CpG sequence densities of less than 40 CpG/Kb, cells compensate for loss of methylated sites by methylating additional sites to maintain methylation levels. At higher CpG sequence densities, the exact location of a methylated site becomes more important suggesting that variants affecting methylation sites in regions of high CpG density will have a greater effect on transcription. We test this hypothesis by assessing the effect of mutations on single cell transcript abundance for two inbred strains (C57BL/6J and DBA/2J). The effect of mutations that alter methylated CpG sites is restricted to regions of high sequence density, and from single cell ATAC-seq data, localizes predominantly to enhancers. With approximately tenfold fewer mutations in high than low sequence density CpG regions, candidate variants affecting transcript abundance, and hence downstream phenotypes, including behavior, can be prioritized based on CpG sequence density. Furthermore, our findings imply that DNA methylation influences the likelihood that mutations occur at specific sites in the genome, supporting the view that the distribution of mutations is not random.

ORGANISM(S): Mus musculus

PROVIDER: GSE245367 | GEO | 2023/12/04

REPOSITORIES: GEO

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Single cell methylation, RNA, and ATAC sequencing of ventral hippocampal brain tissue from inbred mouse strains

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