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Sperm Single-Cell Sequencing Study Offers Insight Into Meiotic Variation

NEW YORK – A new method has enabled Harvard Medical School researchers to study tens of thousands of sperm genomes in parallel to examine variation in meiosis.

Previous studies have relied on genotyping data from families or direct visualization to investigate meiosis — a process needed for reproduction that is error-prone and can lead to aneuploidy. Harvard's Steven McCarroll and his colleagues have now created an approach they dubbed Sperm-seq to sequence thousands of sperm genomes quickly and at the same time. 

The researchers used their Sperm-seq approach to analyze more than 31,000 sperm cells from 20 donors. As they reported on Wednesday in Nature, they uncovered that crossover and other meiotic phenotypes vary from person to person as well as from cell to cell and chromosome to chromosome. Based on their findings, the researchers developed a model to describe the range of meiotic phenotypes observed.

"Our results can be incorporated with earlier observations into a unified model in which a core mechanism, the variable physical compaction of meiotic chromosomes, generates interindividual and cell-to-cell variation in diverse meiotic phenotypes," McCarroll and his colleagues noted in their paper.

As sperm genomes are tightly compacted, the researchers' Sperm-seq approach had to first make them accessible. They did this using reagents that mimic the enzymes eggs use when they decondense the sperm pronucleus. Following this nuclear decondensation, the researchers encapsulated the resulting sperm DNA florets into droplets with beads that added DNA barcodes to the sperm DNA. To do this, they adapted three technologies, Drop-seq, 10x Genomics Chromium Single Cell DNA, and 10x Genomics GemCode. At the same time, they developed and adapted computational tools for determining chromosomal phase and ploidy and uncovering crossover events.

They applied their approach to analyze 31,228 sperm cells from 20 sperm donors and were able to sequence a median 1 percent of the haploid genome of each cell. Within these sperm cells, there were 813,122 crossover events, and the recombination rate ranged between 22.2 and 28.1 crossover events per cell, which the researchers noted was in line with previous estimates. 

Additionally, individuals with high global crossover rates also had more crossovers on average on each chromosome.

These crossover events also tended to occur in similar spots, particularly in distal regions of chromosomes, across the different donors. Crossovers also occurred closer to centromeres, but that varied across people, with individuals with higher recombination rates having higher numbers of crossovers in their vicinity. This variance in crossover location and crossover spacing could reflect underlying biological factors that vary from person to person, the researchers noted.

They also uncovered aneuploidy events within their samples. Within the 31,228 sperm cells, from donors between the ages of 18 and 38, there were 787 whole-chromosome aneuploidies and 133 chromosome arm-level gains or losses. Overall, there were between 0.01 and 0.046 aneuploidy events per cell.

As the researchers noted, chromosomal segregation errors can occur during either meiosis I or meiosis II. Errors during meiosis I lead to chromosomes with different haplotypes at their centromeres, while errors during meiosis II lead to chromosomes with the same haplotype at their centromeres. In this cohort, sex chromosomes were 2.2 times as likely to be affected by errors during meiosis I than meiosis II, while autosomes were twice as likely to be affected by meiosis II errors than meiosis I errors.

These variations in meiotic phenotypes across chromosomes, cells, and people appear to be due to underlying heritable biological factors, the researchers wrote. In a model drawing on their findings and those of others, they suggested that the degree to which the sperm genome becomes compacted could influence where crossover events take place.

"Our model predicts that inherited genetic variation at these loci may bias the average degree of compaction of meiotic chromosomes; the fact that this same property varies among cells from the same donor shows that variance is well-tolerated and compatible with diverse-but-successful meiotic outcomes," they wrote.

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