Genetic variation across and within individuals

Abstract

Germline variation and somatic mutation are intricately connected and together shape human traits and disease risks. Germline variants are present from conception, but they vary between individuals and accumulate over generations. By contrast, somatic mutations accumulate throughout life in a mosaic manner within an individual due to intrinsic and extrinsic sources of mutations and selection pressures acting on cells. Recent advancements, such as improved detection methods and increased resources for association studies, have drastically expanded our ability to investigate germline and somatic genetic variation and compare underlying mutational processes. A better understanding of the similarities and differences in the types, rates and patterns of germline and somatic variants, as well as their interplay, will help elucidate the mechanisms underlying their distinct yet interlinked roles in human health and biology.

Fig. 1 |. Comparison of variants across (germline) and within (somatic) individuals.

a, Origins of germline and somatic variants. Germline variants are inherited at conception from a parent and are transmissible to the offspring; somatic variants are only present in a single cell and its progeny, and they cannot be inherited (unless they occur in germ cells). b, The distribution of allelic fractions observed in sequencing data. The distributions that are close to 50% and 100% represent germline variants (present in all cells) that are heterozygous and homozygous, respectively, whereas the smaller distribution, close to 0%, represents putative somatic variants (present in some cells). c, Analogous aspects of studies on germline and somatic variants: rates of mutation acquisition across generations (germline) and individual age (somatic), ancestry (germline) and cell lineage (somatic) tracing, genetic association (germline) and mutational (somatic) signatures, and selection of specific variants in populations comprised of human individuals (germline) or cells (somatic)^,. AFR, African; EAS, East Asian; EUR, European; PC1, principal component 1; PC2, principal component 2; SAS, South Asian; SBS, single base substitution. Part c reprinted with permission from ref. , Wolters Kluwer.

Fig. 2 |. Patterns and rates of somatic variants.

a, Current estimates of single-nucleotide variant (SNV) somatic mutation rates are variable between stem cells of the seminiferous tubules; neurons^,; haematopoietic stem cells; stem cells of the bronchial, endometrial, colonic and small intestinal epithelium; and trophoblasts of the placenta. b, Profiles of three COSMIC reference mutational signatures showing the single base substitutions (SBS) and flanking 5′ and 3′ bases. Profiles differ by source of mutation: top (SBS5) is a flat, clock-like signature associated with age; middle (SBS7) is linked to ultraviolet light (UV) damage; and bottom (SBS88) is induced by colibactin produced by a genotoxic strain of Escherichia coli. Reference mutational signatures from refs. ,.

Fig. 3 |. Advancements in association analyses of germline variants.

a, Studying diverse populations helps identify additional variants that are not present in a single population. Counts of SNPs, insertions and deletions (indels), and copy number variations (CNVs) grouped by the geographical location of populations. b, Technical and methodological advancements have facilitated a shift from focusing solely on common coding variants to exploring rare coding, non-coding and structural variants. The protein-coding sequence is shown in red, and the regulatory features that determine where and when the protein coding sequence will be expressed are shown in yellow. c, New technologies capture various mechanistic levels that can differ by genotype or cell type. Left: structural variation can induce dramatic changes in chromatin organization and thus create specific signatures that are noticeable by visual inspection of Hi-C interaction maps. Right: cell type-specific assay for transposase-accessible chromatin with sequencing (ATAC-seq) peak due to differential chromatin accessibility between cell types X and Y. Mut, mutant; ORF, open reading frame; RBS, ribosomal binding site; TAD, topologically associated domain; TF, transcription factor; UTR, untranslated region; WT, wild type. Part a reprinted with permission from ref. , AAAS. Part c reprinted from ref. , Springer Nature Limited; adapted from ref. , Springer Nature Limited.

Fig. 4 |. Factors to consider in association analyses of somatic variants.

a, Causal inference. The effect (on human health) of somatic mutations can be confounded by environmental exposures and lifestyle, and can have potentially bi-directional causal relationships (that is, evidence supports clonal haematopoiesis as a causal risk factor of atherosclerosis, and atherosclerosis has also been shown to accelerate clonal haematopoiesis), necessitating careful consideration in analytical models. For example, tobacco smoking is associated with both increased somatic burden in normal bronchial cells and increased risk of lung cancer; therefore, it confounds the association between somatic mutation and lung cancer. Murine evidence shows both clonal haematopoiesis leading to atherosclerosis and atherosclerosis leading to clonal haematopoiesis^,. b, Tissue and cell specificity. Unlike germline variants, which are present in all cells, somatic mutations are present in a subset of cells within tissues. The typical pattern and clonal structure can be different between tissues and their architecture, with distribution of variant allele frequencies and histological sections shown for stomach (monoclonal tissue units), liver bile ducts (oligoclonal structure) and heart (polyclonal structure). Scale bars, 500 μm. c, Heterogeneous impact. The molecular and clinical consequences of somatic mutations can differ depending on the driver gene involved, suggesting that a nuanced, gene-specific approach is often more informative than broad categorizations. For example, TET2-mutant clonal haematopoiesis of indeterminate potential causes atherosclerosis in both animal experiments and human studies, whereas the role of DNMT3A-mutant clonal haematopoiesis of indeterminate potential in atherosclerosis is less clear. Part b reprinted from ref. , Springer Nature Limited.

Fig. 5 |. Interplay between germline and somatic variants.

a, Somatic variants can reverse the pathogenic effects of germline variants (known as somatic genetic rescue) by either reverting to the non-pathogenic sequence or compensating for the germline defect through changes elsewhere, thus leading to variable disease phenotypes and therapeutic resistance. b, Germline variants can predispose individuals to an increased rate of somatic mutations, as seen in clonal haematopoiesis^, (which can contribute to the development of haematological cancer and many other non-cancer diseases). c, Germline gene expression levels can modify somatic mutation-associated disease risks. For example, JAK2-mutant clonal haematopoiesis of indeterminate potential (CHIP) is associated with increased cardiovascular disease risk, and that risk is reduced among individuals with genetically predicted low expression of AIM2 (ref. 135). d, The risks of various cancers and other diseases can be increased by germline and/or somatic variants. For example, based on family studies, endometriosis has high heritability, and it is also associated with somatic variants in ARID1A, PIK3CA and KRAS^,.