Stories about: genetics

Using mitochondrial DNA to trace cells’ family trees

tracing cell family relationships with mitochondrial DNA
(IMAGE: ADOBE STOCK)

Second in a two-part series on mitochondria. See part 1.

Recent advances in single-cell genomics have made it possible to study individual cells and learn how they develop into specialized cells. However, we have only limited information on cells’ origins and how they’re related to the other cells around them.

Meanwhile, efforts to understand more about how cells differentiate and divide have looked at whole cell categories at a time, offering little knowledge of individual cells.

“It’s like looking at the statistics for a college — you can determine what the average student is like, but you have no idea what any one individual student is doing,” says Vijay Sankaran, MD, PhD, a hematologist at Boston Children’s Hospital. “Learning about cellular relationships is critical — it can help us understand how many stem cells give rise to any tissue in our body, what cell types cancers emerge from, or how some cells can be dysfunctional in particular diseases.”

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Gene panel helps investigate sudden unexpected death in children

Thousands of cases of sudden unexplaied death (SUDP) occur each year.
(PHOTO: ADOBESTOCK)

Almost 10 percent of pediatric deaths occur suddenly and without explanation. In this terrible situation, the first question many parents have is “Why?” For most, answers never come.

Childhood deaths that cannot be explained by traditional autopsy and death-scene investigation are referred to as sudden unexplained deaths in pediatrics (SUDP). In children, these deaths are more common than those from either cardiac disease or cancer and typically occur in infancy or early childhood.

Robert’s Program at Boston Children’s Hospital, co-founded by Richard Goldstein, MD, and Hannah Kinney, MD, is adding a genetic approach to the search for answers.

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Newborn DNA sequencing finds actionable disease risks in nearly 10% of enrolled babies

BabySeq study sequenced the DNA of 159 newborns
(PHOTO: AdobeStock)

Current newborn screening tests a baby’s blood for several dozen known, treatable conditions. Can full-on DNA sequencing at birth add more benefit? Interpreting sequencing results is complex: having a genetic variant doesn’t always mean having the disease, and many of the conditions identified may not currently be treatable.

To explore what DNA sequencing might turn up, the BabySeq study, an NIH-funded project, was in launched in 2015. A team led by Ozge Ceyhan-Birsoy, PhD of Partners HealthCare and Alan H. Beggs, PhD, now reports the comprehensive results of whole-exome sequencing in 159 infants. Their analysis is published in the American Journal of Human Genetics.

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After 80 years, genetic causes of Diamond-Blackfan anemia come into view

Vijay Sankaran, MD and a patient with Diamond-Blackfan anemia
Hematologist Vijay Sankaran with Jack Farwell (PHOTO: MICHAEL GODERRE / BOSTON CHILDREN’S HOSPITAL)

In 1938, Louis K. Diamond, MD, and Kenneth Blackfan, MD, at Boston Children’s Hospital described a severe congenital anemia that they termed “hypoplastic” (literally, “underdeveloped”) because of the bone marrow’s inability to produce mature, functioning red blood cells. Eighty years later, the multiple genetic origins of this highly rare disease, now known as Diamond-Blackfan anemia, or DBA, are finally coming into view.

The largest study to date, published recently in the American Journal of Human Genetics, raises as many questions as it answers. But in the meantime, it provides a genetic explanation for nearly 80 percent of patients.

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Super suppressor: Boosting a gene that stifles tumor growth

Researchers have packaged a tumor suppressor into a therapeutic nanoparticle.
Researchers have packaged a tumor suppressor into a therapeutic nanoparticle. IMAGE: ISLAM, ET AL.

Most of the time, cancer cells do a combination of two things: they overexpress genes that drive tumor growth and they lose normal genes that typically suppress tumors. No two tumors are exactly alike, but some combination of these two effects is usually what results in cancer. Now, for the first time, researchers have shown that it’s possible to treat cancer by delivering a gene that naturally suppresses tumors.

Researchers from Boston Children’s Hospital, Brigham and Women’s Hospital and Memorial Sloan Kettering Cancer Center combined their cancer biology and nanomaterials expertise and developed a therapeutic capable of delivering a tumor suppressor gene known as PTEN, the loss of which can allow tumors to grow unchecked.

In several preclinical models, their PTENboosting therapeutic was able to inhibit tumor growth. Their findings were published yesterday in Nature Biomedical Engineering.

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Why are males more prone to bladder cancer than females?

A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females.
A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females. IMAGE: ADOBE STOCK

New research helps explain why men are three to five times more likely to develop bladder cancer than women.

Using mouse models and human patient data, Boston Children’s Hospital researchers in the urology department, Xue Sean Li, PhD, and Satoshi Kaneko, PhD, found that inherent genomic differences contribute to the contrast in bladder cancer rate between males and females.

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A perfect genetic hit: New gene mutation implicated in rare congenital diarrhea

Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.
Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.

When the 1-year-old boy arrived from overseas, he was relying on total parenteral nutrition — a way of bypassing the digestive system to provide nutrients and calories completely intravenously — to survive. From the time of his birth, he had experienced unexplainable diarrhea. Answers were desperately needed.

Sequencing his genes in search of clues, neonatologists and collaborators at the Manton Center for Orphan Disease Research at Boston Children’s Hospital identified a new gene mutation responsible for chronic congenital diarrhea — even finding a similar mutation in two other children as well.

Using patient-derived intestinal organoids in the laboratory, the team discovered that the newly-identified gene mutation, WNT2B, appears to stifle intestinal stem cells’ normal function and growth. The findings were published in the American Journal of Human Genetics.

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Getting a grip on genetic loops

Chromatin is housed inside the nucleus. A new discovery about its physical arrangement could pave the way for new therapeutics.
Artist’s rendering of chromatin, which is housed inside the nuclei of mammalian cells. A new discovery about its physical arrangement could pave the way for new therapeutics.

A new discovery about the spatial orientation and physical interactions of our genes provides a promising step forward in our ability to design custom antibodies. This, in turn, could revolutionize the fields of vaccine development and infection control.

“We are beginning to understand the full biological impact that the physical structure and movement of our genes play in regulating health and development,” says Frederick Alt, PhD, director of the Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM) and the senior author of the new study, published in the latest issue of Cell.

Recent years of research by Alt and others in the field of molecular biology have revealed that it’s not just our genes themselves that determine health and disease states. It’s also the three-dimensional arrangement of our genes that plays a role in keeping genetic harmony. Failure of these structures may trigger genetic mutations or genome rearrangements leading to catastrophe.

The importance of genetic loops

Crammed inside the nucleus, chromatin, the chains of DNA and proteins that make up our chromosomes, is arranged in extensive loop arrangements. These loop configurations physically confine segments of genes that ought to work together in a close proximity to one another, increasingly their ability to work in tandem.

“All the genes contained inside one loop have a greater than random chance of coming together,” says Suvi Jain, PhD, a postdoctoral researcher in Alt’s lab and a co-first author on the study.

Meanwhile, genes that ought to stay apart remain blocked from reaching each other, held physically apart inside our chromosomes by the loop structures of our chromatin.

But while many chromatin loops are hardwired into certain formations throughout all our cells, it turns out that some types of cells, such as certain immune cells, are more prone to re-arrangement of these loops.

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Phenylketonuria without the ‘phe’: Enzyme therapy offers chance at a better life

Kaylee Goodwin credits pegvaliase for changing her life — including her engagement.
Kaylee Goodwin credits pegvaliase for changing her life — including her engagement. “It’s to the point where I don’t even think I have PKU anymore,” she says.

Kaylee Goodwin, 29, has struggled her whole life to control her blood levels of “phe” — the amino acid known as phenylalanine. “I was told that if my levels were controlled, I would be able to think more clearly and feel better overall,” she says.

Goodwin was born with phenylketonuria (PKU), a genetic metabolic disorder affecting roughly 1 in 16,000 newborns. Her body can’t break down phe because of a genetic mutation disabling the necessary enzyme, phenylalanine hydroxylase (PAH).

If left untreated, phe accumulates in the brain, causing intellectual disability and seizures. But starting in the early 1960s, newborn screening programs have been able to test for PKU. Goodwin tested positive and was prescribed a special phe-free diet by Harvey Levy, MD, at Boston Children’s Hospital.

Through the diet, Goodwin has dodged serious brain damage and was able to attend college and start a career as a dancer and actress. But because phe is in nearly all naturally occurring proteins, she couldn’t eat meat, eggs, dairy products, legumes, most grains and many fruits and vegetables. Instead, she had to consume a foul-tasting amino acid formula.

“I spent my entire life carrying special foods and medical formula around with me, and weighing and measuring foods,” she says.

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Mothers’ life experiences may affect their newborns’ telomeres — especially boys’

mother and newborn with telomeres

A new study adds to a growing body of evidence that mothers’ experiences affect their babies’ chromosomes. For the first time, it also shows a gender difference — with male babies more susceptible to maternal influence. And it even implicates experiences dating back to the mother’s own childhood.

The study, led by psychologist Michelle Bosquet Enlow, PhD, at Boston Children’s Hospital, may help explain why stress can have intergenerational effects within a family. It was published last month in the journal Psychoneuroendocrinology.

The researchers enrolled 151 socioeconomically diverse mothers and their infants, all born at Beth Israel Deaconess Medical Center in Boston. The mothers completed in-depth interviews during pregnancy. Cord blood was collected from the newborns so that their chromosomes could be examined — and in particular, the little caps at their tips known as telomeres.

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