In 2004, researchers at Mount Sinai School of Medicine in New York produced a line of mice with an intriguing mutation. The mice make a defective form of a protein called SMC1beta that binds to chromosomes during the crossing-over stage. Pat Hunt and Terry Hassold, on the lookout for anything that might be involved in damage to chromosomes in the eggs of older women, recognized a hot prospect.

SMC1beta is part of a complex, or cluster, of four proteins called cohesins. The complex holds the two strands of each chromosome together while they break and recombine with the strands of their partner chromosome. Hunt and Hassold envision the cohesin complex wrapping around the strands like a rubber band. It has to stay there until meiosis I ends, which in human females might be decades later. Could problems with SMC1beta lead to errors in crossing over—and to chromosome damage?

When their former post-doc Craig Hodges examined oocytes from mice that had the defective form of SMC1beta, he found major problems with the crossovers.

“It looks like they’re making the right number [of crossovers], but when we go to look at them to see if they’re functional, whoa! We don’t see them in the same places, and if we look over time, we see fewer and fewer and they get closer and closer to the ends [of the chromosomes] until they’re just gone,” says Hunt.

By the time the mice with mutant SMC1beta were six months old, 80 percent of the chromosomes in their developing eggs were no longer attached to their partners. The meiotic choreography had completely fallen apart.

Hunt thinks the defective SMC1beta allows the cohesin complex to slide to the ends of the chromosomes and fall off, like a loose rubber band, so the DNA strands drift apart. With those strands not hanging together, the partnered chromosomes are unable to stay lined up properly.

Hunt thinks something similar could happen as women age, even if they start with normal SMC1beta. Perhaps the cohesins that hold the chromosome strands together degrade over time. After all, they were first laid down when the woman was herself an embryo.

“If that was 40 years ago, are you working with 40-year-old proteins?” asks Hunt. Most proteins in the body get replaced over much shorter time frames. She and Hassold are now trying to determine whether SMC1beta gets damaged over time and whether failure to repair or replace it contributes to the high rate of chromosome abnormalities in older eggs.

“There are a lot of candidates you can think of for making the maternal age effect, but this is a no-brainer,” says Hassold. “It has the features you would predict a maternal age-dependent factor would have. It’s probably not the only one”—but it’s a good place to start.