Research Square · Oct 19, 2026
The Missing Somatic Genome: Mosaic Variation in Repetitive and Structurally Complex DNA Across Mammalian Tissues
By Biswas B
Somatic mosaicism is increasingly recognised as a fundamental property of mammalian tissues, yet its genomic architecture has been reconstructed predominantly from regions that can be represented accurately by reference genomes and interrogated reliably by short-read sequencing. This creates a potentially important ascertainment problem. Centromeric and pericentromeric satellites, acrocentric short arms and ribosomal DNA arrays, tandem repeats, segmental duplications, mobile elements, telomeric and subtelomeric regions, and other structurally complex loci have historically been incompletely assembled, ambiguously mapped, or excluded from conventional somatic-variant analyses. Telomere-to-telomere assemblies, pangenomes, long-read sequencing, single-molecule methods and increasingly powerful single-cell approaches are now making substantial parts of this previously inaccessible sequence experimentally tractable. This Review proposes the “Missing Somatic Genome Hypothesis”: repetitive and structurally complex genomic compartments contain a quantitatively and functionally important burden of postzygotic variation that has been systematically underestimated. Evidence from tandem-repeat instability, mobile-element mobilisation, centromeric diversity, segmental duplications, ribosomal DNA biology and tissue-specific structural mosaicism supports the biological plausibility of this framework, although direct body-wide measurements remain limited. The Review distinguishes established evidence from inference and defines experimental strategies capable of determining whether incorporation of the previously inaccessible genome materially changes current understanding of mammalian somatic mutation, tissue evolution, ageing and disease.