Abstract

Placentas can exhibit chromosomal aberrations that are absent from the fetus. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. We investigated the phylogeny of human placental cells as reconstructed from somatic mutations. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.