Single-cell methylation analysis of brain tissue prioritizes mutations that alter transcription

Jonathan Flint; Matthew G Heffel; Zeyuan Chen; Joel Mefford; Emilie Marcus; Patrick B Chen; Jason Ernst; Chongyuan Luo

doi:10.1016/j.xgen.2023.100454

Single-cell methylation analysis of brain tissue prioritizes mutations that alter transcription

Cell Genom. 2023 Dec 4;3(12):100454. doi: 10.1016/j.xgen.2023.100454. eCollection 2023 Dec 13.

Authors

Jonathan Flint¹, Matthew G Heffel², Zeyuan Chen³, Joel Mefford², Emilie Marcus⁴, Patrick B Chen⁵, Jason Ernst⁶, Chongyuan Luo²

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
² Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³ Department of Computer Science, Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁵ Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Department of Computer Science, Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Abstract

Relating genetic variants to behavior remains a fundamental challenge. To assess the utility of DNA methylation marks in discovering causative variants, we examined their relationship to genetic variation by generating single-nucleus methylomes from the hippocampus of eight inbred mouse strains. At CpG sequence densities under 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 will have a greater effect when occurring in higher CpG densities than in lower. We found this to be true for a variant's effect on transcript abundance, indicating that candidate variants can be prioritized based on CpG sequence density. 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.

Keywords: hippocampus; inbred mouse strains; methylation; variant function.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Associated data

figshare/10.6084/m9.figshare.23631984.v1

Abstract

Publication types

Associated data

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