How DNA crossovers can drive both healthy and abnormal sperm formation

In the famous words of movie character Forrest Gump, "Life is like a box of chocolates; you never know what you're gonna get."

The same principle applies to human genetics. When the body forms sperm or egg cells in a special type of cell division called meiosis, our DNA mixes and matches in seemingly infinite and unpredictable combinations.

Later, when just two of the great variety of sperm and egg cells meet, they produce children who are different from their parents.

Meiosis would go terribly wrong without crossovers: the swapping of DNA segments between closely aligned pairs of chromosomes, one inherited from each parent.

Faulty crossover formation can leave cells with too many or too few chromosomes, known as aneuploidy. Since aneuploidy in turn can lead to infertility, miscarriages and conditions such as Down syndrome, learning how crossovers are regulated is key to understanding human reproduction and improving reproductive health.

A study published in Nature by geneticists in the Blavatnik Institute at Harvard Medical School and at the Broad Institute of MIT and Harvard provides new insights into this fundamental process.

The researchers simultaneously analyzed crossovers and aneuploidy on all chromosomes in more than 30,000 human sperm cells using a new genome-wide sequencing tool. Using this approach, they measured a five-fold range of aneuploidy rates from person to person in the most comprehensive estimate to date and propose that a single biological process helps regulate the number, location and spacing of crossovers.

The findings help answer a longstanding question about why and how crossover rates vary across sperm cells and across people.

The work was conducted in the lab of Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS and an institute member in the Stanley Center for Psychiatric Research at Broad.

"The genome of each individual sperm tells a detailed story about human inheritance: what went well, what went wrong, what went differently than in other sperm," said McCarroll. "Collectively, tens of thousands of such stories teach us a lot about the meiotic processes and their vulnerabilities."

The sperm factor

Though infertility can result from either partner, treatments have tended to focus on the egg side. This is in part because eggs are known to have much higher rates of aneuploidy than sperm and because little can be measured about sperm beyond counts and motility.

Still, the contribution of sperm genetics to infertility and miscarriages has been relatively understudied, said study first author Avery Davis Bell, a former PhD student in the McCarroll lab, who is now a postdoctoral fellow at the Georgia Institute of Technology. "We wanted to get a baseline for 'the male factor' in human infertility and reproductive health, namely, how often aneuploidy occurs in sperm."

Bell and colleagues needed to study tens of thousands of sperm genome-wide to generate robust statistics, but no technology existed that could easily do so. So she took a technology developed by McCarroll and Broad associate member Evan Macosko called Drop-Seq, which analyzes DNA from large numbers of individual cells using tiny droplets, and further developed it to study sperm cells. The team dubbed the new approach Sperm-seq.

The researchers obtained samples from 20 donors, analyzing a total of 31,228 sperm cells. Sperm-seq allowed the team to detect every crossover in every sperm cell—more than 813,000 in all.

They found that the number of aneuploid sperm ranged from 1 percent to 5 percent from person to person, with an average of 2.5 percent. This estimate aligns with previous studies that used microscopy to visually examine subsets of chromosomes.

Expanding knowledge about how people have different sperm aneuploidy rates could further assist sperm banks and fertility clinics as they try to maximize sperm viability and improve prospective parents' fertility, said Bell.

Analyses revealed individual sperm with many other kinds of genetic anomalies beyond simple aneuploidies.

The researchers further discovered that the number, location and spacing of crossovers vary together, across sperm cells and across people. In cells with a lot of crossovers, the team found, the crossovers tend to be closer together and located proportionally more in the central regions of chromosomes than at the ends.

"Seeing the same patterns in people and in cells is really interesting because it suggests an underlying regulation," said Bell.

The team suspects that these variations are driven by the degree to which chromosomes get compacted during meiosis. Previous research in the field showed that compaction is linked with crossover rates.

Sperm-seq also revealed that aneuploidy happens at different frequencies at different stages of meiosis from chromosome to chromosome and from person to person.

The McCarroll lab has made Sperm-seq protocols freely available to advance genetics research.

Support for this study was provided by the National Institutes of Health, the Broad Institute NextGen program, and an HMS Program in Genetics and Genomics NIH Ruth L. Kirschstein training grant.

Adapted from a story published by Harvard Medical School.