Dynamic changes in human genomes
Postzygotic mutations accrue throughout a person’s lifetime, beginning in utero. Despite their pervasiveness, the impact of these mutations on health is not yet well understood outside of selected mutations implicated in cancer development. Rockweiler et al. analyzed postzygotic mutations in a variety of organ sites from 948 human donors in the Genotype-Tissue Expression (GTEx) project to create an atlas of these mutations across tissues, and then validated their findings using several published datasets. The authors also reconstructed the evolution of postzygotic mutations in different organs over the course of a life span and identified mutations with particularly deleterious impacts on human health. —YN
Structured Abstract
INTRODUCTION
Mutation lays the foundation for genetics, evolution, and our very existence and demise. Historically, genetics has focused on inherited variants and has only recently begun to examine the genetic changes that occur after fertilization, known as postzygotic mutations (PZMs). This bias is partially because of technological limitations and the simplifying assumption that all cells in a multicellular organism share the same genome.
RATIONALE
Most PZM research has been single-tissue studies. An exciting next generation of PZM studies now examine PZMs across multiple tissues within an individual. However, the relatively small number of individuals and tissue types examined thus far have limited the ability to ascribe sources of mutation variation among individuals or to provide detailed descriptions of embryonic mutations that occur after the first few cell divisions.
RESULTS
To expand the field’s knowledge of the origins and functional consequences of PZMs, we sought to answer four key questions: (i) Are PZMs detectable? (ii) Where do PZMs occur? (iii) When do PZMs occur? (iv) When do PZMs contribute to phenotypic variation?
We developed a suite of methods called Lachesis to detect single-nucleotide DNA PZMs from bulk RNA sequencing (RNA-seq) data. We applied these methods to the final major release of the NIH Genotype-Tissue Expression (GTEx) project—a catalog of 17,382 samples derived from 948 donors across 54 diverse tissues and cell types—to generate one of the largest and most diverse catalogs of PZMs in normal individuals.
PZMs were pervasive and highly variable among donors and tissues. Nearly half of the variation in mutation burden among tissue samples was explained by technical and biological effects, such as age and tissue type. We also found that 9% of this variation was attributed to donor-specific effects. This means that there may be systematic differences among individuals in the number of mutations that they carry due to genetic and/or environmental effects, even after controlling for age. The types of mutations, i.e., mutation spectra, were also variable across tissues, which suggests that mutational mechanisms may be different across tissues.
To estimate when PZMs occur during development, we first identified putative prenatal PZMs in the catalog and then mapped them to a developmental tree. Mutation burden and spectra varied throughout prenatal development, with early embryogenesis being the most mutagenic.
Finally, to investigate the functional consequences of PZMs, we compared the predicted deleteriousness and selection strength on PZMs across space and time. We found that the predicted functional impact of PZMs varies during prenatal development and across tissues, and we identified a class of low-frequency prenatal mutations apparently more deleterious than all other forms of human genetic variation considered. The deleteriousness of germline mutations decreased through the lifecycle: testicular germ cells carried more deleterious mutations than ejaculated sperm and sperm resulting in viable offspring.
CONCLUSION
In this work, we present methods for detecting PZMs and a comprehensive and diverse atlas of PZMs in normal development and aging. Akin to how expansive surveys of normal germline variation are immensely beneficial for human and medical genetics, this catalog contributes to our understanding of normal postzygotic variation so that abnormal variation can be identified and interpreted. Uncovering the effects of these PZMs on human health and disease is an exciting and valuable endeavor.
