Tag: Genomics

Mutations in Sperm May Reveal Risk for Autism

Credit: Martin Breuss, UC San Diego Health
In this illustration of sperm mosaicism, mutated sperm are depicted in red.

Researchers Use SDSC’s ‘Comet’ Supercomputer to Analyze Genome Sequences

While the causes of autism spectrum disorder (ASD) are not fully understood, researchers believe both genetics and environment play a role. In some cases, the disorder is linked to de novo mutations that appear only in the child and are not inherited from either parent’s DNA.

In a recent study published in Nature Medicine, an international team of scientists led by researchers at University of California San Diego School of Medicine describe a method to measure disease-causing mutations found only in the sperm of the father, providing a more accurate assessment of ASD risk in future children.

“Autism afflicts one in 59 children and we know that a significant portion is caused by these de novo DNA mutations, yet we are still blind to when and where these mutations will occur,” said co-senior author Jonathan Sebat, professor and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. “With our new study, we can trace some of these mutations back to the father, and we can directly assess the risk of these same mutations occurring again in future children.”

The research team used the Comet supercomputer based at the San Diego Supercomputer Center, an Organized Research Unit of UC San Diego, to align the whole genome sequences. “We called variants on the sequences and also detected de novo variants using Comet for these samples,” explained Danny Antaki, a UC San Diego Neurosciences postdoctoral scholar. “In short, Comet provided the foundation for the larger experiment as we were able to find the de novos that we wanted to analyze in sperm with the data generated on the supercomputer.”

Recent studies suggest gene-damaging de novo mutations are involved in at least 10 to 30 percent of ASD cases, with the number of mutations rising with the father’s age at time of conception. De novo mutations occur spontaneously in parents’ sperm or eggs or during fertilization. The mutation is then present in each cell as the fertilized egg divides.

Studies now point to male sperm as a particularly important source of these mutations, with the chance of the mutation recurring within the same family generally estimated at 1 to 3 percent.

“However, such estimates are not based on actual knowledge of the risk in an individual family, but instead are based on frequencies in the general population,” said co-senior study author Joseph Gleeson, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “When a disease-causing mutation occurs for the first time in a family, the probability that it could happen again in future offspring is not known. Thus, families must make a decision with a great deal of uncertainty.”

For their study, Gleeson, Sebat, and colleagues analyzed the sperm of eight fathers who were already parents of children with ASD. The goal was to look for the presence of multiple, genetically different material in cells in the same person, a phenomenon called mosaicism. Using deep whole genome sequencing, they found variants in offspring that were matched only in the fathers’ sperm.

“While medical textbooks teach us that every cell in the body has an identical copy of DNA, this is fundamentally not correct,” said first author Martin Breuss, an assistant project scientist in Gleeson’s lab. “Mutations occur every time a cell divides, so no two cells in the body are genetically identical. Mosaicism can cause cancer or can be silent in the body. If a mutation occurs early in development, then it will be shared by many cells within the body. But if a mutation happens just in sperm, then it can show up in a future child but not cause any disease in the father.”

The researchers determined that disease-causing mutations were present in up to 15 percent of the fathers’ sperm cells, information that could not be determined through other means, such as blood samples.

“My laboratory has a long-standing interest in understanding the origins of pediatric brain disease, and how mutations contribute to disease in a child,” said Gleeson. “We previously showed that mosaicism in a child can lead to diseases like epilepsy. Here, we show that mosaicism in one of parents is at least as important when thinking about genetic counseling.”

If developed into a clinical test, the researchers said fathers could have their sperm studied to determine their precise risk of recurrence in future children. The methods might also be applied to men that haven’t had children yet, but who want to know the risk of having a child with a disease.

About UC San Diego Health

UC San Diego Health, comprising a comprehensive health system throughout San Diego County, UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, is one of five academic medical systems within the University of California system. We are committed to improving patient care while also researching new treatments and training tomorrow’s doctors and pharmacists. For more than 50 years, our renowned clinicians and scientists have made advances in numerous fields, including minimally invasive surgeries, personalized cancer therapy, cardiovascular treatment and surgery, transplantation and the early detection of autism.

About SDSC

As an Organized Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s petascale Comet supercomputer is a key resource within the National Science Foundation’s XSEDE (eXtreme Science and Engineering Discovery Environment) program.

The rare genetic disorder identified in only three people worldwide

Condition causes severe neuro degeneration in infants

Photo by Drew Hays

A team of South Australian researchers has cracked a rare gene variant for a disorder that sees a normal healthy child start to lose muscle tone and motor skills, ultimately losing the capacity to walk and use language. The children go on to experience epileptic encephalopathy and cycles of serious gastric disruption, including severe vomiting. 

The condition has an onset at between 12 and 14 months.

Using a genomics approach, where a patient’s entire DNA sequence is examined, University of South Australia PhD student Alicia Byrne made the significant find, identified in just three infants worldwide, two of those in one South Australian family.   

“When we started working with this local family, the disorder the children presented with had never been described but since our research began there has been one more case identified,” Byrne says.

“We discovered that the children carried genetic changes which meant they were unable to absorb vital B group vitamins, which are essential for normal development and function of the nervous system.”

While the Adelaide family tragically lost one child to this disorder, with the cause now identified, the family’s paediatric neurologist at the Women’s and Children’s Hospital in Adelaide, Dr Nicholas Smith, and colleagues were able to devise a targeted therapy to overcome the problem.

Dr Smith, a senior lecturer in paediatric medicine at the University of Adelaide, says the treatment has made a huge difference.

“For the family’s second child, weekly injections of the B group vitamins in which he is deficient have been able to halt and even reverse some of the impacts of this devastating disease,” Dr Smith says.

Byrne’s PhD supervisor, UniSA Adjunct Professor at the Centre for Cancer Biology, Hamish Scott says, ironically, rare diseases are actually a broad and significant area of genomics research.

“While a rare genetic disease may only impact a handful of people, what we are quickly understanding in our work on the human genome is that there are myriad different rare diseases,” he says.

“Genomic research opens an important path in identifying and, with strong partnerships such as we have here in South Australia between universities, government and our hospitals, in developing personalised precision medicine to treat rare diseases.” 

“In addition, the work we do in understanding genes and how they make the body work, constantly informs human biology and provides deeper understandings of human health that have population-wide relevance.” 

“Our goal is to develop genomic testing so that children can be diagnosed at or before birth and treatments can be delivered as early as possible.”