Genetics and age

Infertility is widely defined as a disease of either male or female reproductive systems, or both, if pregnancy is not achieved after 12 months of unprotected sex. An estimated 7% of men and 10% of women are infertile. With thousands of genes involved in male and female reproduction, any number of things can go wrong.

From a genetic perspective, errors in chromosome replication followed by mistakes during sperm and egg production can all result in infertility. Frequently, genetics also underlies structural defects of the reproductive system that impair fertility in both men and women.

Female reproductive aging, a research focus of Stowers Investigator Jennifer Gerton, Ph.D., begins decades before other organ systems start to decline with age. Reproductive function falls precipitously in women by their mid to late thirties before completely ceasing at menopause.

Socioeconomic and lifestyle factors are contributing to many women choosing to have children later in life, and the risk factors for infertility, birth defects, and miscarriages increase with age. Research indicates that a cellular decline in egg quality and not quantity is the primary cause.

The Gerton Lab investigates the cellular and molecular mechanisms associated with reproductive aging in women, such as how ovarian tissues change over time, and how this process affects fertility. A long-term goal is to help increase our understanding of reproductive health to help women make more informed health decisions and to identify new ways to improve women’s health and fertility.

Although far more research addresses female infertility, there is growing evidence of a paternal age factor associated with offspring having birth defects or cognitive conditions. Because procreation, at least in humans, takes two, fertility or the lack thereof must be considered for both sexes.

Meiosis and the formation of eggs and sperm

While physiological conditions that impact the structure and function of various reproductive organs can be a source of infertility, the fundamental genetic and age-related factors impacting fertility frequently point to faults in meiosis, the specialized cell division that gives rise to sperm and eggs.

Meiosis comprises a series of distinct steps that produce cells with half the usual number of chromosomes. That way, when an egg is fertilized by a sperm cell, the two half-sets of chromosomes come together to form a full set in the embryo. Understanding the steps of meiosis is a primary focus of Stowers Investigator Scott Hawley, Ph.D.

First, chromosomes are duplicated and must correctly match up in pairs. Next up, the pairs of maternal and paternal chromosomes literally connect. Then pieces of these chromosomes are swapped between pairs, a process called recombination. In the last steps which occur during two rounds of cell division, the chromosomes must pull apart from each other and separate into four different cells. Each step in the series is like a coordinated dance, until something missteps.

The Hawley Lab’s research seeks to uncover the molecular and mechanistic underpinnings for how meiosis works. Down the road, insights from this work may have applications for reproductive medicine and personalized healthcare or treatments. “Personalized knowledge provides people with power—power to make informed decisions about their individual circumstances and potentially on the steps needed to overcome infertility,” said Hawley.

Infertility and evolution

Meiosis has been evolutionarily conserved over hundreds of millions of years, perhaps even longer, and across many different species. Infertility is largely due to errors during meiosis that give rise to reproductive cells with incorrect numbers of chromosomes.

Infertility is also linked to the presence of certain rule-breaking “selfish” genes in a population’s genome that decrease its health and fertility. Stowers Associate Investigator SaraH Zanders, Ph.D., studies how selfish genes bend reproductive rules to ensure their persistence in offspring. Generally, inheritance can be viewed like the flip of a coin, but there are exceptions – and a growing awareness that certain genes stack odds in their favor. This occurs across many species at the expense of fertility.

By using simple single-celled yeast to investigate mechanisms governing selfish gene function and how organisms evolve processes to suppress these, research from the Zanders Lab may provide hope for understanding how these elements can be identified as sources of infertility.

Foundational research at the Stowers Institute is leading to a greater understanding of the many factors governing infertility with the goal of improving health, healthy outcomes, and providing hope for people facing this challenge.

Learn more about the impact of our infertility research at the Stowers Institute here.