Somatic mutation analysis during aging

Introduction: Our lab studies somatic mutation in the human brain. Somatic mutation is the process by which mutations occur in cells of the developing or postnatal body. Somatic mutations that occur in a proliferative cells are inherited by all cells derived from that mutated founder. We refer to these variants as clonal somatic mutations. Somatic mutations occurring in post-mitotic cells are restricted to the cell in which they occurred. We refer to these variants as non-clonal somatic mutations. In the human brain, most clonal somatic mutations reflect embryonic development, making them useful for lineage tracing studies. Non-clonal somatic mutations in the brain accumulate during life in differentiated cells like neurons and oligodendrocytes. Studying the molecular features of these variants, for example the type of base change comprising a substitution, or the nucleotide context in which a mutation occurs, nominates mechanisms responsible for generating a given mutation.

Study Design: We have performed single-cell whole-genome sequencing (scWGS) on several postmortem human donors from across human lifespan to profile changes in the burden, molecular signature, and distribution of somatic mutations during life. Many of the donors we studied in our lab were also part of the cohort of the dataset we currently request from NIAGADS, published in Cell by Ganz et al. We aim to integrate the data from Ganz et al. with our own to increase the statistical power of our study.

Analysis Plan: Data will be mapped to the human genome using the BWA algorithm, and mutations will be identified using SCAN2 pipeline and other pipelines as needed to broaden our study. Mutation burden, distribution, and signatures will be compared across cell types, during aging, and across collection sites (Boston Children's Hospital for these data, UMass Chan Medical School for our data). The only phenotypic data we would share would be age, sex, cause of death, and QC data (RIN, etc.)

Planned Collaboration: We may share these data with Dr. Zhiping Weng, also at UMass Chan Medical School. We often collaborate with her computational biology group to analyze genomic data.

DNA damage has long been thought to contribute to human aging. Our lab uses cutting-edge techniques to study specific types of DNA damage, called somatic mutations, in the human brain at high resolution. We will add the data in this collection to our own to increase the power of our study to learn new things about human brain aging, possibly leading to new anti-aging interventions.