The biological research of UC Santa Cruz’s Needhi Bhalla to determine the molecular motions at the heart of heredity has yielded a new discovery: The proper transfer of genetic materials depends on two key proteins that choreograph the delicate dance between chromosomes when sexual-reproduction cells divide.
When cells split to create eggs and sperm, they must undergo a crucial process called "meiotic crossover recombination." This mechanism ensures that genetic material is properly shuffled between chromosomes, preventing errors that could lead to disorders such as miscarriages, infertility, birth defects, and even cancer.
This process also results in the endearing transfer of traits that parents see in their children. And beyond contributing to parental pride, Bhalla says meiotic crossover recombination is fundamental for human evolution by promoting genetic diversity. That's why the identification of two specific proteins that play central roles in controlling how and where these crossovers happen is so significant.
"Thirty percent of miscarriages are because the embryo doesn't have the correct number of chromosomes," said Bhalla, a professor of molecular, cell, and developmental biology (MCD Bio). "Because meiotic crossover recombination is essential to get the right number of chromosomes, you'd think it was a stable and predictable process. But it's actually an incredibly delicate and responsive mechanism that is very heavily regulated to look straightforward."
Chromosomal crossing guards
Through lab studies on the roundworm C. elegans, Bhalla's team discovered that a protein known as PCH-2 plays an important role in regulating crossover events. While scientists have long recognized its importance, the protein's precise function hasn't been well understood.
This study now shows that PCH-2 acts against crossover formation in a controlled manner at different stages of cell division. Initially, it limits the number of potential crossover sites, preventing an excessive number of crossovers from forming too early. Later, it ensures that at least some crossovers occur, a process known as crossover assurance, the researchers found.
As Bhalla explains, every cell undergoing the sexual-reproduction process of meiosis must make critical decisions regarding crossover events. Hundreds of potential crossover sites exist within a single cell, but only a limited number become actual crossovers. This selection process is crucial for maintaining genetic integrity. If crossovers fail to occur properly, essential genetic information can be lost, mutations can arise, or chromosomes can partition incorrectly—leading to dire consequences for the organism.
The study further revealed that PCH-2 interacts with another protein, HIM-3, which helps organize chromosomes during meiosis. Together, these proteins fine-tune the crossover process, ensuring both efficiency and accuracy. "The placement of crossovers is just as crucial as their presence. If crossovers occur near the ends of chromosomes, they tend to be less stable than those positioned more internally," Bhalla said. "Our findings highlight the necessity of precise control over both crossover number and distribution."
Impact on human health
One of the most promising applications of this research is in the development of molecular diagnostics. Similar to how cancer diagnostics allow for early detection and treatment decisions, Bhalla said the discoveries her team made could pave the way for genetic tests that assess infertility risks or the likelihood of recurrent miscarriages. Such a diagnostic tool could provide crucial information for patients and physicians, enabling them to explore fertility interventions such as in vitro fertilization, surrogacy, or other reproductive-assistance options.
"This intricate, highly regulated process ensures the successful continuation of life across generations," Bhalla said.
The paper's other authors were undergraduates in Bhalla's lab. They include Valery Ortiz, a graduate student at Scripps Research Institute whose undergraduate work at UC Santa Cruz was supported by the university ACCESS program, which funded community college students to do scientific research and then supported their transfer to a UC campus.
Co-author Alberto Herrera received a MARC grant through the Science Division's STEM Diversity Research office. Maryke Grobler was an undergrad in Bhalla's lab and is now doing graduate research in the lab of Olena Vaske, an MCD Bio assistant professor at UC Santa Cruz. Elias Logari, also an undergraduate in Bhalla's lab, is currently applying to ophthalmology programs.
This research was primarily supported with a MIRA grant from the National Institutes of Health's National Institute of General Medical Sciences.
