Mechanism may fuel Downs babies in older moms
Dartmouth research on cell division has found a protein path that may explain molecular mistakes causing some women in their late 30's and older to have babies with Down syndrome.
In Down syndrome, a fetus inherits three copies of chromosome 21 (also known as Trisomy 21). Chromosome segregation errors in immature egg cells (or oocytes) are the leading cause of birth defects and pregnancy loss. By the time a woman reaches her late thirties, her probability for chromosome errors exceeds 30 percent. Although the phenomenon — the maternal age effect — is well known, researchers are only beginning to understand the molecular mechanisms responsible.
During her late thirties, the chance a woman will conceive a Down syndrome fetus increases dramatically from mistakes in meiosis — the cell division steps that create gametes or sex cells (sperm and eggs). These meiotic mistakes can lead to gametes with the wrong number of chromosomes, and can lead to Down syndrome.
The study appears in the journal PLOS Genetics.
Accurate chromosome segregation during meiosis depends on protein linking. Linking, or cohesion, holds together sister chromatids — identical copies of a replicated chromosome.
Recent evidence from Dartmouth and other labs indicate that meiotic cohesion weakens over time — the maternal age effect.
A widely held view is that under normal conditions, meiotic cohesion only happens once as an oocyte undergoes DNA replication.
This means that in order for there to be error-free segregation in human oocytes, meiotic cohesion established in fetal development must remain unchanged until menopause. A gradual decline in cohesion links over time is thought to contribute to the maternal age effect. However, researchers at Dartmouth and elsewhere questioned that idea. They doubted that the original cohesive linkages remain intact for even five years, much less 25 years.
The research raised an alternative possibility — that maintenance of chromatid cohesion is an active process. That such maintenance uses a specialized "rejuvenation" program to establish new cohesive links during the time oocytes remain "arrested," until they are ovulated.
In 2003, Bickel established that the fruit fly Drosophila can be used to study why more mistakes occur during cell division as eggs become older.
In this latest research, she and her co-authors tested the idea that oocytes possess an active cohesion rejuvenation program by reducing cohesion proteins in oocytes after DNA replication but before oocyte maturation and ovulation.
Their results show that when cohesion proteins are reduced in this period, cohesion is lost prematurely and chromosomes missegregate during the meiotic divisions.
Their work provides the first demonstration that under normal physiologic circumstances, new cohesive linkages occur in oocytes after DNA replication.
These replacement linkages are essential for oocytes to maintain meiotic cohesion for long periods of time.
"Whether rejuvenation of meiotic cohesion occurs in mammals remains to be demonstrated, but it is hard to understand why fruit flies would possess a mechanism to actively keep cohesion intact during a short time frame (six days) if no similar program exists during the much longer time frame that mammalian oocytes must maintain cohesion (months to years)," says Sharon Bickel, Associate Professor, and study's senior author.
Under normal conditions, rejuvenating cohesion in fruit fly oocytes ensures that the number of cohesive links are sufficient to accurately promote chromosome segregation. But when experimental techniques force these cells to undergo "aging," cohesion is lost prematurely and chromosomes missegregate. Therefore, under "aging" conditions, the normal rejuvenation pathway in fruit fly oocytes is incapable of sustaining cohesion.
Bickel: "This raises that intriguing possibility that if a similar meiotic cohesion rejuvenation pathway also operates in human oocytes, its effectiveness may decline with age.
"Cohesion defects may become pronounced in older women not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages at the same rate at which they are lost.
"Further investigation of this possibility may change the way we think about the maternal age effect."
Meiosis is a specialized type of cell division that gives rise to sperm and eggs. In a woman's thirties, errors in meiotic chromosome segregation rise exponentially, significantly increasing the probability that she will conceive a fetus with Down Syndrome (Trisomy 21). Accurate chromosome segregation during meiosis depends on protein linkages (cohesion) that hold sister chromatids together. The widely held view is that under normal conditions, cohesion can only be established during DNA replication, and the original cohesive linkages formed in fetal oocytes are gradually lost as a woman ages. However, it seems unlikely that the same cohesion proteins could survive for even five years, much less 25 years. Here we show that Drosophila oocytes possess an active rejuvenation program that is required to load newly synthesized cohesion proteins and to establish new cohesive linkages after meiotic DNA replication. When we reduce the proteins responsible for rejuvenation after meiotic S phase, cohesion is lost and meiotic chromosomes missegregate. If such a rejuvenation pathway also exists in human oocytes and becomes less efficient with age, oocytes of older women may no longer be able to replace cohesive linkages at the same rate that they are lost.
Return to top of page