High-throughput single cell genome sequencing reveals cell-autonomous equational segregation in meiosis I

We developed “sci-LIANTI”, a high-throughput, high-coverage single-cell DNA sequencing method that combines single-cell combinatorial indexing (“sci”) and linear amplification via transposon insertion (“LIANTI”). To characterize rare chromosome mis-segregation events in male meiosis and their relationship to the landscape of meiotic crossovers, we applied sci-LIANTI to profile the genomes of over 10,000 sperm precursors from infertile, interspecific as well as fertile, intraspecific F1 male mice. From 7,210 haploid and 355 2C M2 cells, we mapped 86,786 crossover events and identified genomic and epigenomic contexts that influence crossover hotness. Surprisingly, we observed equational chromosome segregation during meiosis I in both crosses. Moreover, segregation during meiosis I in individual cells can be highly biased towards either equational or reductional events in a cell-autonomous rather than a chromosome-autonomous manner. We anticipate that sci-LIANTI can be applied to fully characterize various recombination landscapes, as well as to other fields requiring high-throughput, high-coverage single-cell genome sequencing.