Rockweiler, N. B. | bioRxiv Science

bioRxiv2021

The origins and functional effects of postzygotic mutations throughout the human lifespan

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remains unclear. To study the origins and functional consequences of PZMs, we generated a multi-tissue atlas of PZMs from 948 donors using the final major release of the Genotype-Tissue Expression (GTEx) project. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, while 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we find that their type and predicted functional impact varies during prenatal development, across tissues, and the germ cell lifecycle. Remarkably, a class of prenatal mutations was predicted to be more deleterious than any other category of genetic variation investigated and under positive selection as strong as somatic mutations in cancers. In total, the data indicate that PZMs can contribute to phenotypic variation throughout the human lifespan, and, to better understand the relationship between genotype and phenotype, we must broaden the long-held assumption of one genome per individual to multiple, dynamic genomes per individual. One-Sentence SummaryThe predicted rates, functional effects and selection pressure of postzygotic mutations vary through the human lifecycle.

genomics↗

bioRxiv2018

Somatically Mutated Genes Under Positive and Negative Selection Found by Transcriptome Sequence Analysis Include Oncogene and Tumor Suppressor Candidates

IntroductionOncogenic somatic mutations confer proliferative advantage and undergo positive clonal selection. We developed software and applied new analytical approaches to identify: (1) somatic mutations in diverse tissues, (2) somatically mutated genes under positive and negative selection, (3) post-transcriptional modifications in the mitochondrial transcriptome, and (4) inherited germline alleles predisposing people to higher somatic mutation burden or higher levels of post-transcriptional modification.\n\nMethodsTranscriptome sequence data (Genotype Tissue Expression project) for 7051 tissue samples from 549 postmortem donors and representing 44 tissue types were used. Germline mutations were inferred from whole-exome DNA sequencing and SNP arrays. DNA somatic mutations were inferred from variant allele frequencies (VAF) in RNA-seq data. Post-transcriptional modifications were inferred from Polymorphism Information Content (PIC) at the p9 sites of mitochondrial tRNA sequences. Positive and negative clonal selection was evaluated using a nonsynonomous/synonomous mutation rate (dN/dS) model. Genome-wide association studies (GWAS) were assessed with mitochondrial PIC for post-transcriptional modification level, or using the total number of somatic mutations observed per donor for somatic mutation burden.\n\nResultsOur dN/dS model identified 78 genes under negative selection for somatic mutations (dN/dS < 1, padj < 0.05) and 14 under positive selection (dN/dS > 1, padj <0.05). Our GWAS identified 2 sites associated with post-transcriptional modification (1 approaching significance with p=5.99x10-8, 1 with p<5x10-8) and [~]20 sites associated with somatic mutation burden (p<5x10- 8).\n\nConclusionsTo our knowledge these are the first genome-wide association studies on normal somatic mutation burden. These studies were an attempt to increase understanding of the somatic mutation process. Our work identified somatic mutations at the global organismal level that may promote cell proliferation in a tissue-specific manner. By identifying tissue-specific mutations in actively expressed genes that appear before cancer phenotype is detected, this work also identifies gene candidates that might initiate tumorigenesis.

genomics↗