A harmful genetic mutation can increase the likelihood of disease, but it does not always determine the outcome. In some cases, people carry mutations associated with genetic disorders yet remain healthy.
Understanding why is at the center of research led by Jamie Nichols, PhD, associate professor in the Department of Craniofacial, Oral and Materials Sciences at the CU Anschutz School of Dental Medicine.
Nichols has secured a five-year, $2.58 million grant renewal from the National Institute of Dental and Craniofacial Research (NIDCR) to continue his project, “Mechanisms of Developmental Buffering.” The continued funding will allow his lab to investigate the biological mechanisms that enable some individuals to withstand the effects of mutations that cause disease in others.
“Developmental buffering is a widely observed phenomenon where some individuals can tolerate or overcome a genetic mutation that causes problems in other individuals,” Nichols said. “The underlying mechanisms have remained mysterious, and we’ve developed a system to understand them.”
The long-term goal is to uncover principles that could help researchers better understand genetic risk in people.
Understanding Why Genetic Mutations Have Different Outcomes
To investigate developmental buffering, Nichols and his team turned to zebrafish, a well-established model for studying development and genetics.
“We hope that by understanding how a zebrafish model can overcome a genetic problem, someday those concepts could extend to humans with genetic disorders,” Nichols said.
They began with zebrafish carrying the same mutation but showing substantially different outcomes. Even among full siblings, some were dramatically affected while others were able to tolerate the mutation.
Using selective breeding, the researchers developed strains that reliably respond differently to the mutation. One is tolerant and the other is sensitive. Comparing the two provides the lab with a way to identify the mechanisms that may allow one group to compensate for the genetic disruption.
Investigating the Genetics Behind Developmental Buffering
That work has already revealed an important clue: Some tolerant zebrafish appear to rely on duplicate versions of the affected gene.
“We found that one major mechanism is the use of ‘backup copies’ of the broken gene,” Nichols said. “We hypothesize that these duplicate versions of the gene are no longer required but can do the job when pressed into action.”
The next phase of the research will dig deeper into how that backup system works.
Over the next five years, the team plans to investigate how duplicate genes are activated when they are needed and how they remain capable of performing their original function despite millions of years of evolutionary change.
Answering those questions could provide a more complete picture of the relationship between a genetic mutation and its actual effects.
What Developmental Buffering Could Mean for Craniofacial Disorders
Even people with nearly identical genetics can experience different outcomes. Nichols points to reports of identical twins in which one twin develops cleft lip and palate while the other does not.
“In this case the genes are the same in both individuals, but one is buffered while the other isn’t,” he said.
Understanding the mechanisms behind those differences could ultimately help researchers make better predictions about craniofacial genetic disorders and other conditions.
“I imagine a future where we could sequence individuals and have better predictions of genetic risk,” Nichols said. “Further, maybe someday we could apply what we learn about how a zebrafish overcomes a mutation to help a human overcome a deleterious mutation.”
Advancing Developmental Biology Research
The renewed funding also allows Nichols’ lab to build on the work of its previous funding period, which resulted in eight high-impact publications, while continuing to train the next generation of researchers.
For Nichols, the next five years are as much about the people conducting the science as the questions they are pursuing.
He said, “I have a talented and committed group of trainees in my laboratory, and I’m excited to watch them grow, and for the discoveries they will make along the way.”
The next phase of the research will continue probing one of genetics’ fundamental questions: not simply how mutations cause disease, but how biology can sometimes find a way around them.
