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.
Two studies from geneticists in the Blavatnik Institute at Harvard Medical School provide new insights into this fundamental process.
The first study, published online June 3 in Nature, simultaneously analyzes crossovers and aneuploidy on all chromosomes in more than 30,000 human sperm cells using a new genome-wide sequencing tool.
The researchers 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 director of genomic neurobiology in the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.
"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 second study, which looked at meiosis in developing worm egg cells, helps explain why crossovers occur more often in some locations along chromosomes than in others. The team found that crossovers are likelier to go wrong at the centers or extreme ends of chromosomes, suggesting that egg cells minimize crossovers in those areas while allowing them in more reliable locations.
"It's terrific to see how findings in male and female meiosis and in different species can complement and inform each other," said Colaiácovo.
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 Avery Davis Bell, a former PhD student in biological and biomedical sciences in the McCarroll lab.
"We wanted to get a baseline for 'the male factor' in human infertility and reproductive health, namely, how often aneuploidy occurs in sperm," said Bell, first author of the Nature study and now a postdoctoral fellow at the Georgia Institute of Technology.
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 at HMS, she took a technology that 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.