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Gene-editing technology uncovers genetic link to infertility

A woman's silhouette with the DNA double helix and letters of A T C GInfertility - difficulty getting or staying pregnant - can come at a high financial and emotional cost. Couples experiencing infertility may resort to ever-more expensive and stressful procedures, such as in vitro fertilization, while experiencing disappointment, sadness or even shame.

This burden affects many: The U.S. Department of Health and Human Services and the U.S. Centers for Disease Control and Prevention estimate that about 6 million women and 4 million men experience some form of infertility in the United States. Of these, about 50 percent of cases are thought to be due to genetic factors. Now, new research techniques are yielding insights into the genetic roots of infertility.

The August Genome Advance of the Month looks at a study in the Proceedings of the National Academy of Sciences that begins to untangle the complex genetic picture of infertility, using both genetic sleuthing and cutting-edge, gene-editing technology in a process researchers dubbed a "reverse genetics approach."

Reproduction is a highly complex process. It involves the orchestration of hormones and body parts that work to create the egg or sperm cells that package our DNA, the genetic material that makes up our 20,000 genes, to be passed along to our children. The genome is composed of DNA and organized into genes, which are small sections of DNA that are like recipes telling our cells how to grow and function.

This intricate process, which involves a particular subset of genes, sometimes fails and leads to infertility. Previous genetics research has had limited success in finding the genes or mutations responsible for infertility. To address this challenge, Drs. Priti Singh and John Schimenti at Cornell University in Ithaca, New York, decided to work backwards. Using a novel and rigorous multi-pronged approach to study the possible genetic causes of infertility in humans, they recreated that infertility in mice, which are about 85 percent genetically the same as humans.

The investigators first looked at a large database of genetic mutations that have been observed in humans. They restricted their search to uncommon mutations seen in genes that are active during meiosis, the process by which our bodies prepare our egg or sperm cells. The team then winnowed a list of potentially important mutations from the database by plugging them into specialized software that predicts whether a mutation is harmful or benign. Using the results of this software, the team chose four likely harmful mutations in four genes that might lead to infertility. Still, they wanted to check these computer results in a live model.

To do this, the team bred mice with the specific mutations that mimic the known mutations in humans using a new gene-editing technology called CRISPR-Cas9, which act like biological scissors that can be programmed to cut DNA at specific points. The CRISPR-Cas9 system supplies a small copy of the mutated DNA to be inserted, which will usually be incorporated when the cell repairs the introduced DNA cuts. Knowing this, the researchers designed a new strip of DNA with the known human mutation in it, et voilĂ : a human mutation in a mouse gene.

The team then bred the mice that tested positive for the new gene mutation to find out if the mutations were harmful. They discovered that one of the four mutations led to infertility. This means that in some cases, infertility may be the result of a single gene mutation.

This may seem illogical. After all, how can someone have a child if they have a mutation in an infertility gene? One possible explanation for this is that certain genes work only in egg production while others work only in sperm production. The team proposed that a father could pass on a female infertility gene mutation, and vice-versa.

Another outcome of this research is that it demonstrates that CRISPR-Cas9 can help scientists determine whether a gene linked to a condition actually causes that condition. This tool could then be applied to any gene and its mutations, giving genetics researchers a powerful and precise tool to study genetic conditions.

Unlike previous research with knockout mice, where an entire gene is rendered non-functional, this approach provides a more detailed view of the function involved by introducing a single change in the gene to see how or if the gene's function changes. This is the difference between deleting a recipe in a cookbook and changing a single character in the text of the recipe from one teaspoon of baking soda to zero teaspoons. In the first, the baker can no longer bake banana bread; in the latter, the bread can be made, but it will not rise.

Now that it is known that this specific change can lead to infertility in mice, other researchers can perform more detailed genetics studies to see if the particular mutation is in fact seen in people with infertility. Moreover, the methods used to produce these results can help researchers and clinicians pinpoint genetic factors that lead to complex conditions beyond infertility.

Read the study:

Singh, P., & Schimenti, J. C. The genetics of human infertility by functional interrogation of SNPs in mice. Proceedings of the National Academy of Sciences, 112(33), 10401-10436. 2015. [PubMed]

Posted: September 29, 2015

Last updated: September 29, 2015