Stories about: Christopher Walsh

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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Mapping mosaicism: Tracing subtle mutations in our brains

brain genetic mosaicism
(Erik Jacobsen, Threestory Studio. Used with permission.)

DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.

Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.

Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.

“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.”

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“Deep sequencing” finds hidden causes of brain disorders

brain malformations sequencing mosaicism
New methods can find a mutation that strikes just 1 in 10 cells.

It’s become clear that our DNA is far from identical from cell to cell and that disease-causing mutations can happen in some of our cells and not others, arising at some point after we’re conceived. These so-called somatic mutations—affecting just a percentage of cells—are subtle and easy to overlook, even with next-generation genomic sequencing. And they could be more important in neurologic and psychiatric disorders than we thought.

“There are two kinds of somatic mutations that get missed,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital. “One is mutations that are limited to specific tissues: If we do a blood test, but the mutation is only in the brain, we won’t find it. Other mutations may be in all tissues but in only a fraction of the cells—a mosaic pattern. These could be detectable through a blood test in the clinic but aren’t common enough to be easily detectable.”

That’s where deep sequencing comes in. Reporting last month in The New England Journal of Medicine, Walsh and postdoctoral fellow Saumya Jamuar, MD, used the technique in 158 patients with brain malformations of unknown genetic cause, some from Walsh’s clinic, who had symptoms such as seizures, intellectual disability and speech and language impairments.

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