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New single-cell sperm sequencing method uncovers insights into meiotic variation

A new method has allowed researchers at Harvard Medical School to examine variation in meiosis by studying tens of thousands of individual sperm genomes in parallel.

Previously, studies relied on genotyping data from families or visualisations to investigate meiosis. Meiosis is an error-prone process that can lead to aneuploidy, so the team led by Steven McCarroll created an approach they called “Sperm-seq” to sequence thousands of sperm genomes rapidly at the same time.

They used their sperm-seq approach to analyse over 31,000 sperm cells from 20 donors aged between 18 and 38, and uncovered that crossover and other meiotic phenotypes vary from person to person as well as cell to cell and chromosome to chromosome. The study, that was published in Nature yesterday, helped researchers develop a model to describe the range of meiotic phenotypes observed.

McCarroll and his colleagues added in the paper that their “results can be incorporated with earlier observations into a unified model”. The sperm-seq approach first had to make the sperm genomes accessible, as they are tightly compacted. To do this, they used reagents that mimic the enzymes that eggs use to decondense the sperm pronucleus. They then encapsulated the resulting sperm DNA florets into droplets with beads that added DNA barcodes to the sperm DNA, they simultaneously developed and adapted computational tools for determining the chromosomal phase, ploidy, and uncovering crossover events.

This approach was used to analyse the 31,228 sperm cells and sequenced around 1% of the haploid genome of each cell. The researchers found 813,122 crossover events, and the recombination rate ranged between 22.2 and 28.1 crossover events per cell, which is in line with previous estimates.

The researchers also noted that the crossover events tended to occur in similar locations, particularly in the distal regions of chromosomes across the donors. They also noted that crossovers happened nearer to centromeres, but this differed between donors.

Aneuploidy events were also uncovered within the samples. Of the 31,2228 sperm cells, there were 787 whole-chromosome aneuploidies and 133 chromosome arm-level gains or losses. Chromosomal segregation can happen during meiosis I or II, and in this cohort, sex chromosomes were 2.2x more likely to be affected by errors during meiosis I than II, while autosomes were twice as likely to be affected by meiosis II errors than meiosis I.

The researchers noted that variations between meiotic phenotypes appeared to be due to underlying heritable biological factors and suggested that the degree to which the sperm genome becomes compacted could influence where crossover events take place.

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