Stories about: Christopher Walsh

Gene active before birth regulates brain folding, speech motor development

SCN3A, linked to polymicrogyria, regulates speech motor development
ILLUSTRATIONS: RICHARD SMITH/BOSTON CHILDREN’S HOSPITAL

A handful of families from around the world with a rare brain malformation called polymicrogyria have led scientists to discover a new gene that helps us speak and swallow.

The gene, SCN3A, is turned “on” primarily during fetal brain development. When it’s mutated, a language area of the brain known as the perisylvian cortex develops multiple abnormally small folds, appearing bumpy. People with polymicrogyria in this region often have impaired oral motor development, including difficulties with swallowing, tongue movement and articulating words — especially if the polymicrogyria affects both sides of the brain.

The new study, published today in Neuron, ties together human genetics, measurements of electrical currents generated by neurons, studies of ferrets and more to start to connect the dots between SCN3A, the brain malformation and the oral motor impairment.

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Gene mutation in children with microcephaly reveals an essential ingredient for brain development

This electron microscope image shows two multivesicular bodies in the dendrites of neighboring neurons in the cerebellum of a normal mouse. Each contains vesicles bearing sonic hedgehog. (Michael Coulter/Boston Children’s Hospital)

In 2012, researchers in the Boston Children’s Hospital lab of Christopher Walsh, MD, PhD, reported a study of three unrelated families that had children with microcephaly. All had smaller-than-normal brains — both the cerebrum and the cerebellum were reduced in size— and all had mutations that knocked out the function of a gene called CHMP1A.

It was clear that CHMP1A is needed for the brain to grow to its proper dimensions. But the study stopped there.

“Then I came along, and my goal was to figure out what this gene is doing in brain during development, and why, when you lose it, you have a small brain,” says Michael Coulter, MD, PhD, who joined the Walsh lab as a student in 2012.

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Mutant ferrets and kids with microcephaly shed light on brain evolution

ASPM, ferrets, microcephaly and brain evolution
Fawn Gracey illustration

Mouse brains are tiny and smooth. Ferret brains are larger and convoluted. And ferrets, members of the weasel family, could provide the missing link in understanding how we humans acquired our big brains.

Children with microcephaly, whose brains are abnormally small, have a part in the story too. Microcephaly is notorious for its link to the Zika virus, but it can also be caused by mutations in various genes. Some of these genes have been shown to be essential for growth of the cerebral cortex, the part of our brain that handles higher-order thinking.

Reporting in Nature today, a team led by Christopher A. Walsh, MD, PhD, of Boston Children’s Hospital and Byoung-Il Bae, PhD, at Yale University, inactivated the most common recessive microcephaly gene, ASPM, in ferrets. This replicated microcephaly and allowed the team to study what regulates brain size.

“I’m trained as a neurologist, and study kids with developmental brain diseases,” said Walsh in a press release from the Howard Hughes Medical Institute, which gave him a boost to his usual budget to support this work. “I never thought I’d be peering into the evolutionary history of humankind.”

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Mutations accumulate in our brain cells as we age. Do they explain cognitive loss?

the aging brain - do DNA mutations in neurons account for cognitive loss?

Scientists have long wondered whether somatic, or non-inherited, mutations play a role in aging and brain degeneration. But until recently, there was no good technology to test this idea.

Enter whole-genome sequencing of individual neurons. This fairly new technique has shown that our brain cells have a great deal of DNA diversity, making neurons somewhat like snowflakes. In a study published online today in Science, the same single-neuron technique provides strong evidence that our brains acquire genetic mutations over time.

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Late-breaking mutations may play an important role in autism

somatic mutations in autism may occur at different times in the embryo
Post-zygotic mutations, which arise spontaneously in an embryonic cell after sperm meets egg, are important players in autism spectrum disorder, a large study suggests.

Over the past decade, mutations to more than 60 different genes have been linked with autism spectrum disorder (ASD), including de novo mutations, which occur spontaneously and aren’t inherited. But much of autism still remains unexplained.

A new study of nearly 6,000 families implicates a hard-to-find category of de novo mutations: those that occur after conception, and therefore affect only a subset of cells. Findings were published today in Nature Neuroscience.

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What genetic changes gave us the human brain? A $10 million center aims to find out

genes and human brain evolution

How did our distinctive brains evolve? What genetic changes, coupled with natural selection, gave us language? What allowed modern humans to form complex societies, pursue science, create art?

While we have some understanding of the genes that differentiate us from other primates, that knowledge cannot fully explain human brain evolution. But with a $10 million grant to some of Boston’s most highly evolved minds in genetics, genomics, neuroscience and human evolution, some answers may emerge in the coming years.

The Seattle-based Paul G. Allen Frontiers Group today announced the creation of an Allen Discovery Center for Human Brain Evolution at Boston Children’s Hospital and Harvard Medical School. It will be led by Christopher A. Walsh, MD, PhD, chief of the Division of Genetics and Genomics at Boston Children’s and a Howard Hughes Medical Institute investigator.

“To understand when and how our modern brains evolved, we need to take a multi-pronged approach that will reflect how evolution works in nature, and identifies how experience and environment affect the genes that gave rise to modern human behavior,” Walsh says.

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Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.

Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.

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Human brain evolution holds clues about autism… and vice versa

human brain evolution autism Human Accelerated Regions
Humans evolved to become more social and cognitively advanced, thanks to genetic changes in regions such as HARs — the child with autism spectrum disorder (ASD) being the exception. While mutations in protein-coding genes continue to be explored in ASD (indicated by the red ribbon of RNA), the scientists at far left are suggesting that mutations in regulatory elements (the histones , in green, and their modifications shown in yellow) may be important in both ASD and human evolution. (Illustration: Kenneth Xavier Probst)

Starting in 2006, comparative genomic studies have identified small regions of the human genome known as Human Accelerated Regions, or HARs, that diverged relatively rapidly from those of chimpanzees — our closest living relatives — during human evolution.

Our genomes contain about 2,700 HAR sequences. And as reported today in Cell, these sequences are often active in the brain and contain a variety of mutations implicated in autism and other neurodevelopmental disorders.

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Brain samples show a wealth of single-letter and somatic mutations in autism

somatic mutations in autismDisease-causing mutations can be incredibly subtle: Sometimes a single-letter change in a gene or a so-called somatic mutation (affecting only some of the body’s cells) can be enough. Researchers report this week in Neuron that both kinds of mutations — easily missed on standard blood and saliva testing — play a role in autism spectrum disorder (ASD).

Scientists have suspected a role for these mutations in brain disorders, but the technology to find them has only recently come online. Sampling brain tissue is the most likely way to find them, but brain biopsies aren’t something you do every day.

In their study, a team led by Christopher Walsh, MD, PhD, and Alissa D’Gama, of Boston Children’s Hospital and Harvard Medical School, tapped several brain banks — the NIH’s NeuroBioBank, the Oxford (U.K.) Brain Bank and Autism BrainNet — to gather brain tissue from more than 100 deceased individuals, some neurotypical and some with ASD.

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DNA diversity in the brain: Somatic mutations reveal a neuron’s history

neurons somatic mutations
Neurons are more like snowflakes–no two alike–than anyone realized.

Walt Whitman’s famous line, “I am large, I contain multitudes,” has gained a new level of biological relevance in neuroscience.

As we grow, our brain cells develop different genomes from one another, according to new research from Harvard Medical School and Boston Children’s Hospital. The study, published last week in Science, provides the most definitive evidence yet that somatic (post-conception) mutations exist in significant numbers in the brains of healthy people—about 1,500 in each of the neurons they sampled.

The finding confirms previous suspicions and lays the foundation for exploring the role of these non-inherited mutations in human development and disease. Already, the researchers have found evidence that the mutations occur more often in the genes a neuron uses most. And they been able to trace brain-cell lineages based on mutation patterns.

“This work is a proof of principle that if we had unlimited resources, we could actually decode the whole pattern of development of the human brain,” says co-senior investigator Christopher Walsh, MD, PhD, the HMS Bullard Professor of Pediatrics and Neurology and chief of the Division of Genetics and Genomics at Boston Children’s. “These mutations are durable memory for where a cell came from and what it has been up to. I believe this method will also tell us a lot about healthy and unhealthy aging as well as what makes our brains different from those of other animals.”

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