Live snapshots of bivalent hyperstretching (orange arrows) and premature bivalent separation (red and purple arrows), phenomena more common in older oocytes. [RIKEN]
Live snapshots of bivalent hyperstretching (orange arrows) and premature bivalent separation (red and purple arrows), phenomena more common in older oocytes. [RIKEN]

Older oocytes, it is known, are more liable to the sorts of chromosome segregation errors that lead to miscarriages, or genetic diseases such as Down syndrome. And while such errors have been attributed to reduced chromosome cohesion, direct evidence has been lacking. Now, however, direct evidence has been obtained by researchers at the RIKEN Center for Developmental Biology in Japan.

These scientists, led by Tomoya Kitajima, Ph.D., report that paired copies of matching chromosomes often separate from each other at the wrong time. Premature separation, the scientists add, leads to early division of chromosomes and their incorrect segregation into mature egg cells.

Going even further, and looking into the causes of premature separation, the scientists identified phenomena they call reduced bivalent adhesion and hyperstretching.

The details appeared July 1 in Nature Communications, in an article entitled, “Bivalent separation into univalents precedes age-related meiosis I errors in oocytes.” Essentially, in older cells, bivalents sometimes separate early, and consequently sister chromatids divide in the first state of meiosis, rather than in the second stage.

Most cells have two copies of each chromosome—one from each parent. Immature egg cells begin this way, but are transformed through a process called meiosis into mature egg cells that only have one copy of each chromosome. At the beginning of meiosis each chromosome copies itself and joins with its matching pair to form a group of four chromosomes that swap genetic material.

These groups of four chromosomes—the bivalents—then split apart into single pairs, and the cell divides. One part continues as the egg cell and the other part degrades. In the second stage of meiosis, the single pairs of chromosomes—two sister chromatids joined in the middle—separate and the egg cell divides again in the same way, leaving a single mature egg cell with one copy of each chromosome.

In older egg cells, however, chromosome segregation errors are more common. To determine the most common type of age-related segregation errors, the researchers first used a novel high-resolution imaging technique to visualize chromosomes in live mouse egg cells throughout the whole first stage of meiosis.

“[We provide the first live analysis of single chromosomes undergoing segregation errors during [meiosis I] in the oocytes of naturally aged mice,” wrote the authors of the Nature Communications article. “Chromosome tracking reveals that 80% of the errors are preceded by bivalent separation into univalents.”

In other words, the dominant type of error was predivision of sister chromatids, and not movement of intact chromosome pairs to only one of the new cells.

The tracking data also allowed researchers to go back in time and look at what was happening to chromosomes that eventually segregated incorrectly. They found that a large majority of them had been part of bivalents whose connection between paired chromosome copies had become hyperstretched and then snapped earlier in meiosis, leaving single pairs.

“The set of the univalents is biased toward balanced and unbalanced predivision of sister chromatids during [meiosis I],” the authors continued. “Moreover, we find univalents predisposed to predivision in human oocytes.” That is, age-related segregation errors could be tracked back to increased number of prematurely separated chromosome pairs.

“We were surprised and pleased that the vast majority of errors are preceded by a single common event—bivalent separation,” said Dr. Kitajima. “Now we can focus our efforts on developing an artificial tie to suppress premature separation and on understanding the molecular mechanism underlying the age-related reduction in bivalent cohesion that appears to precede it.”

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