KNOXVILLE -- Scientists at the University of Tennessee, Knoxville, and Lawrence Berkeley National Laboratory (LBNL) have published new findings about a cause of a condition at the root of genetic disorders such as Down Syndrome, pregnancy loss and infertility.
Called aneuploidy, the condition is an abnormal number of chromosomes, and the research team found that if a mother's egg cell has a mutation in just one copy of a gene, called Bub1, then she is less likely to have offspring that survive to birth.
The findings appear in the online early edition of the Proceedings of the National Academy of Sciences for the week of July 13.
Sundar Venkatachalam, an assistant professor of biochemistry and cellular and molecular biology at UT Knoxville, originally was studying the gene for a possible connection to colon cancer, when he found his lab mice showed strange fertility characteristics.
"Where you would normally expect a female to have eight to 10 pups, there were only one or two pups that survived to term in the litters of females that had one copy of Bub1," said Venkatachalam. "So this was unusual when we were looking for cancer effects, especially in this group of females."
Ordinarily, both copies of a gene in a chromosome must carry the same mutation in order for an organism to be adversely effected, but the drastic effects of a single mutation were unexpected.
Venkatachalam, working with pathologist Robert Donnell at the UT College of Veterinary Medicine and LBNL researcher Francesco Marchetti, also found that the harmful effects of this mutation increased with a mother's age. As the female mice got older, there was eventually a complete loss of their ability to support a full-term pregnancy that lined up with an increase in aneuploidy. The same is true in humans: the chance of having an aneuploid pregnancy increases with the age of the mother.
For the past several years, scientists have used mice to study the genetic causes of aneuploidy. They've zeroed in on mutations in a handful of genes as the culprits, including Bub1.
The gene plays a role in a checkpoint that ensures that chromosomes are properly divided during meiosis, the cell division process that enables a stem cell to become an egg. This checkpoint hiccups when Bub1 is mutated, sometimes producing an egg with an extra chromosome or an egg with a missing chromosome.
The team linked the issue to females by mating both a male with one bad copy of the gene with a normal female and a female with a bad copy of the gene with a normal male. When the female carried the bad copy, there were fewer births.
Further research revealed this is because aneuploidy was generated in the egg and passed on to the single-cell zygote that forms when a sperm fertilizes an egg. And this led to the loss of the embryo.
"This work certainly points to Bub1 having a role in maternal age-induced fertility issues," said Venkatachalam. "Now that we know the gene seems to have this role, the next big question is why, and we hope to continue the research in that direction."
"Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice" was published in the July 13-17, 2009 online early edition of the Proceedings of the National Academy of Sciences. Funding for the work came from UT Knoxville's Department of Biochemistry, Cellular and Molecular Biology and the U.S. Department of Energy.