The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage

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Abstract
Few data exist on somatic mutation in the epithelial cell lineages that play a central role in human biology and disease. To delineate the “landscape” of somatic mutation in a human epithelial cell lineage, we determined the frequency and molecular nature of somatic mutations occurring in vivo in the X-linked HPRT gene of kidney tubular epithelial cells. Kidney epithelial mutants were frequent (range 0.5 to 4.2 × 10−4) and contained a high proportion of unreported HPRT base substitutions, −1-bp deletions and multiple mutations. This spectrum of somatic mutation differed from HPRT mutations identified in human peripheral blood T lymphocytes and from germ-line HPRT mutations identified in Lesch–Nyhan syndrome or hyperuricemia patients. Our results indicate that DNA damage and mutagenesis may have unusual or mechanistically interesting features in kidney tubular epithelium, and that somatic mutation may play a more important role in human kidney disease than has been previously appreciated.