A Cornell-led study is challenging a decades-old explanation for how chromosomes exchange genetic material within the biological process that forms eggs and sperm in mammals.
Published in the journal Molecular Biology and Evolution, the study found that chromosome length alone cannot explain why males and females differ in how chromosomes exchange DNA during the formation of eggs and sperm. Instead, the researchers found that sex-specific mechanisms help determine how often and where these DNA exchanges, called crossovers, occur.
The study was led by Tegan Horan, a research associate in the lab of Paula Cohen, and a recipient of a prestigious NIH K99 career transition award. Cohen is a professor of genetics in the College of Veterinary Medicine and also the founding director of the Cornell Reproductive Sciences Center (CoRe), which brings together researchers across Cornell to study fertility, pregnancy, reproductive aging and early development.
During meiosis, the specialized cell division that produces eggs and sperm, chromosomes exchange segments of DNA through crossover events to create genetic diversity, while ensuring chromosomes separate correctly into eggs and sperm. Scientists have long believed that longer chromosome structures produce more crossovers.
PWD Mouse
“For years, chromosome length seemed to explain the differences we saw between males and females,” Horan said. “But this one mouse strain kept breaking the rules. These males were somehow packing more crossovers onto shorter chromosomes, even with the normal mechanisms that limit crossover formation. That stuck with me, and it became clear that chromosome length couldn’t be the whole story. Something else was shaping the process.”
To test that idea, Horan and colleagues analyzed five genetically diverse mouse strains and tracked multiple stages of the recombination process. The team measured chromosome structure, DNA repair activity and crossover formation in both males and females.
Their findings challenged a long-standing model of how crossovers are regulated. One mouse strain, known as PWD, defied decades of scientific assumptions. Male mice generated more crossovers than females even though their chromosome structures were shorter.
Instead, the researchers discovered that males and females differ in how efficiently they convert early DNA repair events into mature crossovers. The study also identified sex-specific differences in the molecular pathways that regulate crossover formation and placement along chromosomes.
Errors in crossover formation or regulation can lead to aneuploidy, a condition in which cells have the wrong number of chromosomes. Aneuploidy is a leading cause of infertility, miscarriage and genetic disorders, Cohen said.
Their analysis revealed another unexpected finding. Although a relatively rare class of crossovers accounts for only a small fraction of all crossover events, it helps ensure every chromosome pair receives at least one crossover-a critical safeguard against chromosome segregation errors and aneuploidy.
“These processes are remarkably similar across mammalian species, but what is surprising is the significant increase in error rates observed in humans,” Cohen said. “Studies estimate that 30% to 70% of human eggs are likely to have the wrong number of chromosomes due to errors in crossover formation or regulation.
“Many of those eggs will never be fertilized, but some could result in miscarriages and chromosomal conditions such as Down syndrome,” she continued “So, it’s essential that we understand how things work in species such as mice, before we can start to understand why things can go so wrong in human females.”
Horan said the study also illustrates that reproductive biology is more complex than scientists once believed.
“One of the biggest lessons from this work is that there isn’t a single universal blueprint for meiosis,” Horan said. “The same molecular machinery is at work, but it can be used differently depending on sex and genetic background.
“That’s an important reminder that understanding reproductive biology means asking not just how the process works, but why it works differently under different biological conditions.”
Henry C. Smith is the communications specialist for Biological Systems at Cornell Research and Innovation.
