Boy Or Girl? It’s In The Father’s Genes

A study of hundreds of years of family trees suggests a man’s genes play a role in him having sons or daughters. Men inherit a tendency to have more sons or more daughters from their parents. This means that a man with many brothers is more likely to have sons, while a man with many sisters is more likely to have daughters.

A simplified diagram in which men either have only sons, only daughters, or equal numbers of each, though in reality it is less clear cut.

A Newcastle University study involving thousands of families is helping prospective parents work out whether they are likely to have sons or daughters.

The work by Corry Gellatly, a research scientist at the university, has shown that men inherit a tendency to have more sons or more daughters from their parents. This means that a man with many brothers is more likely to have sons, while a man with many sisters is more likely to have daughters.

The research involved a study of 927 family trees containing information on 556,387 people from North America and Europe going back to 1600.

“The family tree study showed that whether you’re likely to have a boy or a girl is inherited. We now know that men are more likely to have sons if they have more brothers but are more likely to have daughters if they have more sisters. However, in women, you just can’t predict it,” Mr Gellatly explains.

Men determine the sex of a baby depending on whether their sperm is carrying an X or Y chromosome. An X chromosome combines with the mother’s X chromosome to make a baby girl (XX) and a Y chromosome will combine with the mother’s to make a boy (XY).

The Newcastle University study suggests that an as-yet undiscovered gene controls whether a man’s sperm contains more X or more Y chromosomes, which affects the sex of his children. On a larger scale, the number of men with more X sperm compared to the number of men with more Y sperm affects the sex ratio of children born each year.

Sons or daughters?

A gene consists of two parts, known as alleles, one inherited from each parent. In his paper, Mr Gellatly demonstrates that it is likely men carry two different types of allele, which results in three possible combinations in a gene that controls the ratio of X and Y sperm;

  • Men with the first combination, known as mm, produce more Y sperm and have more sons.
  • The second, known as mf, produce a roughly equal number of X and Y sperm and have an approximately equal number of sons and daughters.
  • The third, known as ff produce more X sperm and have more daughters.

“The gene that is passed on from both parents, which causes some men to have more sons and some to have more daughters, may explain why we see the number of men and women roughly balanced in a population. If there are too many males in the population, for example, females will more easily find a mate, so men who have more daughters will pass on more of their genes, causing more females to be born in later generations,” says Newcastle University researcher Mr Gellatly.

More boys born after the wars

In many of the countries that fought in the World Wars, there was a sudden increase in the number of boys born afterwards. The year after World War I ended, an extra two boys were born for every 100 girls in the UK, compared to the year before the war started. The gene, which Mr Gellatly has described in his research, could explain why this happened.

As the odds were in favour of men with more sons seeing a son return from the war, those sons were more likely to father boys themselves because they inherited that tendency from their fathers. In contrast, men with more daughters may have lost their only sons in the war and those sons would have been more likely to father girls. This would explain why the men that survived the war were more likely to have male children, which resulted in the boy-baby boom.

In most countries, for as long as records have been kept, more boys than girls have been born. In the UK and US, for example, there are currently about 105 males born for every 100 females.

It is well-documented that more males die in childhood and before they are old enough to have children. So in the same way that the gene may cause more boys to be born after wars, it may also cause more boys to be born each year.

How does the gene work?

The trees (above) illustrate how the gene works. It is a simplified example, in which men either have only sons, only daughters, or equal numbers of each, though in reality it is less clear cut. It shows that although the gene has no effect in females, they also carry the gene and pass it to their children.

In the first family tree (A) the grandfather is mm, so all his children are male. He only passes on the m allele, so his children are more likely to have the mm combination of alleles themselves. As a result, those sons may also have only sons (as shown). The grandsons have the mf combination of alleles, because they inherited an m from their father and an f from their mother. As a result, they have an equal number of sons and daughters (the great grandchildren).

In the second tree (B) the grandfather is ff, so all his children are female, they have the ff combination of alleles because their father and mother were both ff. One of the female children has her own children with a male who has the mm combination of alleles. That male determines the sex of the children, so the grandchildren are all male. The grandsons have the mf combination of alleles, because they inherited an m from their father and f from their mother. As a result, they have an equal number of sons and daughters (the great-grandchildren).


Editing Out Blood Disease

Gene therapy successful in 22 patients with severe form of the blood disorder beta-thalassemia


In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in the clinic, an international team of investigators has announced that gene therapy can be safe and effective for patients with a severe form of the blood disorder beta-thalassemia.

Led by Philippe Leboulch, lecturer in medicine, part-time, at Harvard Medical School and a sponsored collaborator in the Brigham and Women’s Hospital Division of Genetics, an international research team reports that a one-time treatment with the gene therapy known as LentiGlobin BB305 vector reduced or eliminated the need for blood transfusions in 22 patients with severe beta-thalassemia.

The results have been published in The New England Journal of Medicine.

“It was always our hope to bring our research findings to patients,” said Leboulch, whose primary appointment has transitioned to the University of Paris as professor of medicine and institute director. “We have taken our work from the lab, through preclinical models and past the proof-of-principle stage and are now able to gauge its effectiveness in patients with this disease. It is immensely gratifying.”

Restoring hemoglobin production

Beta-thalassemia is a genetic disorder that impairs the body’s ability to produce a key component of hemoglobin, the protein in red blood cells that carries oxygen to organs and tissue. Beta-thalassemia and sickle-cell disease are related disorders—both hamper hemoglobin production and can have lifelong repercussions.

From toddlerhood on, people with the most severe forms of beta-thalassemia require monthly blood transfusions to replenish their red blood cell supplies along with iron chelation to remove extra iron from the body.

As a postdoctoral fellow at Massachusetts Institute of Technology, Leboulch began researching a therapeutic approach to compensate for the genetic mutations that lead to both sickle-cell disease and beta-thalassemia. In the 1990s, Leboulch joined HMS and Brigham and Women’s, where he continued his work to develop a viral carrier, or vector, that could insert genetic instructions into a patient’s own blood stem cells and restore hemoglobin production.

Leboulch and colleagues hoped that introducing the altered stem cells back into people would allow the cells to make enough hemoglobin, eliminating the need for blood transfusions.

Leboulch and colleagues studied the vector, LentiGlobin, in pre-clinical models, publishing results from mouse studies in Science. In 2010, Leboulch and his collaborator, Marina Cavazzana of University Paris-Descartes, published a paper in Nature detailing the success of using LentiGlobin to genetically correct cells and transplant them into a single beta-thalassemia patient. Last year, they published in NEJM on a successful gene therapy of the first sickle-cell anemia patient using the same vector.

Blood transfusions no more

In the newly published NEJM study, Leboulch, Cavazzana and their colleagues teamed up with a second group of U.S. and international clinical investigators in Australia and Thailand to share data and results from their respective phase II clinical trials.

In total, the two teams treated 22 patients at six different sites around the world. Among nine patients with the most severe form of beta-thalassemia, the one-time treatment reduced the need for red-blood cell transfusions by 73 percent. Three of the nine subsequently discontinued transfusions altogether. Twelve of the 13 patients with a slightly less severe form of the disease no longer needed any blood transfusions after treatment.

The team reports no safety concerns—treatment-related adverse effects were typical of those seen in patients who receive transplants of their own stem cells.

“When you have an anecdote of a single patient, you never know if it will be confirmed. Here, with a multi-center trial in a larger number of patients, we see a convergence of results, and we can measure the magnitude of the therapeutic effect,” said Leboulch.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” he added. “But there is also hope with protocol modifications we have introduced in our phase III trials.”

Based on these results, two pre-drug marketing phase III clinical trials have begun.

Patents on the LentiGlobin BB305 vector are owned by Bluebird Bio, which also sponsored the study. Leboulch is one of the co-founders of Bluebird Bio.

Motherless, designer baby specter increases

Two developing reproductive technologies — one that could facilitate motherless babies and another that could open the door to so-called designer babies — have drawn warnings from Christian ethicists.

In one experiment, researchers at the UK’s University of Bath altered unfertilized mouse eggs so they took on properties like “ordinary” cells, such as skin cells, the BBC reported. Then they created mouse embryos by fertilizing the altered eggs with sperm cells, leading scientists to speculate that two human men, or even one man, may one day be able to conceive a child with similar technology using sperm and another donated body cell.

A separate experiment in Sweden has achieved genetic modification of “healthy human embryos,” which were then destroyed, NPR reported. Lead researcher Fredrik Lanner said he is seeking to help treat infertility, prevent miscarriages and treat diseases. But critics say the research could lead to genetically made-to-order babies and the introduction of new diseases into the human genepool.

Both experiments have troubling ethical implications, Union University bioethicist C. Ben Mitchell said.

“The biblical ideal for procreation is one man, one woman, in a one-flesh relationship, in which children are received as a gift,” Mitchell told Baptist Press in written comments. “Every violation of that ideal results in human trauma and heartache, whether through adultery, divorce or death.

“The use of reproductive technologies that end up destroying unborn human beings is a clear harm. If we defy the procreative relationship by creating parentless babies, there is likewise clear harm. Even if we could justify the outcome, think of the human carnage on the way to the goal. Countless human beings — generated at the hands of researchers — would die in the process of trying to perfect the techniques. The end does not justify the means when the means are immoral,” said Mitchell, Union’s provost and Graves Professor of Moral Philosophy.

Conception without eggs?

The British experiment, reported Sept. 13 in the journal Nature Communications, is only a first step toward motherless human babies, with researcher Tony Perry calling such a prospect “speculative and fanciful” at present, according to the BBC.

Still, Charles Patrick, a Southwestern Baptist Theological Seminary vice president who holds a Ph.D. in chemical and biomedical engineering, warned of skewing God’s plan for procreation described in Genesis 1-2.

“Just because we can develop a reproductive technology does not mandate that we must develop the technology,” Patrick told BP. “It seems unwise to develop reproductive technologies that preclude the use of sperm or eggs.”

“First, and to be scientifically honest, much of what occurs when a sperm and egg unite continues to be a mystery. There are potential errors with dangerous consequences that may occur when cells are ‘tricked’ into functioning in a manner not natural for them,” he said in written comments. “Second, reproductive technologies that remove either the egg or the sperm open the cultural door further to a genderless society.”

Additionally, creating babies without either egg or sperm cells “would provide childless couples yet another ‘extraordinary means’ distraction from adoption. Adoption is clearly espoused and modeled throughout Scripture,” Patrick said.

R. Albert Mohler Jr., president of Southern Baptist Theological Seminary, said the University of Bath research illustrates society’s quest to redefine “everything about sex and reproduction and marriage and gender.”

The sexual revolution, Mohler said Sept. 22 on his podcast The Briefing, has necessitated “a technological revolution” whose proponents seek reproduction “without marriage, and in this case … without women.”

Genetically made to order?

The Swedish research uses a genetic engineering innovation to “edit” healthy embryos’ DNA for what NPR deemed the first time ever. British scientists have said they will begin similar experiments later this year.

Thus far, at least 12 embryos — which were donated by couples who generated them as part of the in vitro fertilization process — have been modified, and researchers have vowed to destroy all modified embryos no later than their 14th day of life.

Patrick called any “use and destruction of human embryos” unethical because it “does not preserve the worth, dignity and value of human life defined in Genesis 1-2.” Yet “even if there were not a sanctity of life issue, there are other issues to consider in opening the epigenetic black box.”

“For instance, although there is the promise of correcting devastating diseases, there is equally the specter of creating designer babies or other non-therapeutic modifications and of introducing unintended consequences in the human germline,” Patrick said.

“Man was mandated in Genesis to be a steward of creation, and emphasis throughout Scripture is placed on restoring what God originally purposed in His creation. Hence, there is a general biblical warrant for scientific advances and technologies that restore,” he said.

“However, there is not clear biblical permission to manipulate genes toward perfection. Gene editing cannot reverse what sin and resulting human depravity wrought to God’s perfected creation. There is a flesh-spirit aspect that gene editing does not and cannot incorporate,” Patrick said.

Mohler wondered aloud Sept. 23 in The Briefing, “How long will it be before the bumper sticker on the back of the SUV says, ‘My child is genetically enhanced?’ … That day might after all not be so far in our future.”

5 Things To Know About In-Home Genetic Testing

Recently,  in-home genetic testing kits, such as 23andMe and Color, were granted FDA authorization to provide direct to consumer, no prescription needed, in-home genetic testing. On the surface, this seems very attractive. Genetic mutations are thought to account for 5-10% of all cancer diagnoses ( As we learn more about how genetics influence our cancer risk, more individuals may want to learn about their own genetic make-up and how to reduce their risk for developing cancer. These tests offer the convenience of performing the test at home. Here are five things you should think about BEFORE undergoing ANY kind of genetic testing.

1. Genetic testing should NOT be taken lightly.

It isn’t just a simple “spit into a vial” process. Assessing genetic risk also includes taking a complete family and personal health history, as well as counseling and education about the test results, after the test is completed. Genetic counseling and genetic testing go hand in hand. It is essential that you receive education associated with your results, as well as counseling about talking to your family about your results. 23andMe only offers referrals to genetic counselors in your geographic area, not actual counseling services. Color offers “professional genetic counseling.”

2. Genetic testing is complex.

There are over 50 hereditary cancers, each with multiple potential gene mutations. For example, BRCA is associated with a higher risk of ovarian cancer, breast cancer and prostate cancer. These in home kits only test for only three genetic variants associated with BRCA mutations – yet many more exist. The mutations that are included in this test tend to be associated with individuals with Ashkenazi Jewish heritage. While these tests may be helpful for people from this population, others who undergo the test may receive a false sense of security with a negative test result. It doesn’t necessarily mean the test is negative and you don’t have the mutation—it just means you don’t have one of these three mutations. These tests do not test for any other cancer related gene mutations.

3. Genetic testing IS typically covered by insurance, if you have a strong family history that suggests higher cancer risk. 

23andMe and Color are not covered by insurance. The current cost for 23andMe is $199 (this includes more than just cancer targeted genetic testing for BRCA mutations), for Color it is $99 (this is only for BRCA mutations).

Under the Affordable Care Act (ACA), genetic testing for BRCA 1 and 2 must be covered by insurance plans when there is a strong family history of BRCA associated cancers.

4. Privacy and confidentiality guidelines for health protected information may be questionable with in-home testing kits.

The test results generated by 23andMe and Color are maintained by these companies. They are not part of your medical record and thus MAY NOT be covered under HIPPA guidelines. While this company does not share your genetic test results, they can sell your personal information to third parties who may want to include you in research or market other products to you.

5. Genetic testing results are protected under the Genetic Information Nondiscrimination Act (GINA).

GINA protects family health history, the results of genetic tests, the use of genetic counseling/genetic services and individuals participating in genetic research from being discriminated against by health insurers or employers. This includes results from in-home testing kits. However, genetic testing information is not protected by GINA if you are attempting to purchase life insurance. Genetic information CAN be used during the medical investigation/under-writing process for a life insurance policy..

Talk to your healthcare provider before undergoing ANY genetic testing. Ask questions about your risk, your family history, and your own personal behaviors that may influence your cancer risk. While 23andMe and Color may offer a “jumping off point” or introduction to testing for genetic mutations, they are hardly foolproof and may produce false negatives and/or misinformation. Ultimately, it is buyer beware with in home genetic testing and an educated consumer “is the best customer.”

For more information about genetic risk and cancer, visit Facing our Risk of Cancer Empowered (FORCE).

Synesthesia’s Molecular Roots Traced Back to Rare DNA Mutations

For people with auditory-visual synesthesia, striking a piano key may ignite visions of turquoise geometric patterns or a twanging guitar string could create the sensation of billowing orange foam. Many aspects of life may feel like a sober LSD trip for people who experience this neurological phenomenon, and in a study published Monday in the Proceedings of the National Academy of Sciences, scientists came one step closer to characterizing exactly who these people are.

In a statement released Monday, scientists from the Max Planck Institute for Psycholinguists and the University of Cambridge report a discovery that they hope will eventually “explain the biology of synaesthesia.”

Previous brain-imaging studies have demonstrated that the visual areas of synesthetes’ brains are more active and that synesthetes have altered cortical wiring at the embryo stage, but until now scientists haven’t been able to trace the phenomenon back to its molecular roots. In the new paper, they show that auditory-visual synesthetes — one of at least 60 known sense variants — carry variants of genes related to the development of neural connections and cell migrations. Characterizing these genes, the authors write, is the first step in understanding how a person’s genes influences these extrasensory associations.

synesthesia, Pharrell Williams
When Pharrell Williams listens to Earth, Wind, and Fire he sees baby blue.

Synesthesia is known to run in families, so the scientists examined DNA samples belonging to several generations of three families with multiple cases of auditory-visual synesthesia. Using genomic sequencing, the scientists searched the DNA for changes that altered the way genes code for proteins. There were consistent variations on genes associated with cell migration and axogenesis, the process that enables brain cells to wire up to their correct partners — a consistent theme across all three families. Six genes were altered within these synesthetes: COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2.

“These results are consistent with the neuroimaging-based hypothesis about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences,” the scientists write.

Frank Ocean
Lorde says her synesthesia helped her write “Melodrama.”

Now that these genes have been identified, the scientists hope to better understand how and when they turn on during development and affect the way the brain is wired. Of course, there’s still a huge amount to learn when it comes to understanding how people can experience something as spectacular as the blending of color and sound. That’s why the team behind this study has put out the call for other synesthetes — especially families of them — to come and participate in future studies. The scientists have also created this short quiz that people can use to test for the ability: If you pass, you join the just one percent of folks who pulsate with the involuntary cross-activation of their senses.

7 Traits Kids Get From Their Fathers

7 Traits Kids Get From Their Fathers

Scientists Are Annoyed by This Pretty Big Flaw in The New DNA Emoji

They had one job (╯°□°)╯︵ ┻━┻

Unicode, the standards body that decides which emojis we all need on our phones and laptops, is finally adding a bunch of science emojis to the mix, including DNA – but there’s confusion over the style of the doodle that will eventually get used.

That’s because one of the samples shown by Unicode and Emojipedia shows DNA strands twisting to the left, as they do on the less common Z-DNA.

For the most common B-DNA structure, the one that is responsible for the origins of life, the twists should be right-handed.

The difference isn’t easy to spot at first, but it’s crucial in dictating the way the ladders of DNA are structured – it’s like going down a spiral staircase clockwise or anticlockwise, with one state the complete mirror image of the other.

dna emojis 2The new emoji, as imagined by Emojipedia.

Scientists love accuracy more than most, and so the new symbol sample has caused some frustrated reactions on Twitter, as Gizmodo reports.

Researchers have been quick to point out that Unicode and Emojipedia has gone for a spiral that twists in the wrong direction – or at least in the more obscure, less common direction.

However, the original draft of the new emojis for 2018 had the DNA emoji twisting in the correct way, so it seems there’s some confusion about which one will eventually get used.

dna emojis 3The original Unicode draft.

If you’re struggling to understand what we mean, point your index finger away from you, push out your hand and rotate your finger in a clockwise direction – you’re drawing DNA in the air. If you rotate your finger anticlockwise, you’re drawing Z-DNA.

All is not lost though: Apple, Google, Microsoft, Samsung and the rest all design their own emoji styles on top of whatever Unicode puts forward – that’s why emojis look different from device to device and app to app.

So there’s still hope these tech giants may not totally stuff up, and the final emoji designs on our devices will end up spiralling the right way.

In the meantime, scientists are busy pointing out the mistake. It may not matter too much in the grand scheme of things, but if you’re going to have a DNA emoji, you might as well make sure you get it right.

Other science-related emojis in the list of 157 new ones rolling out this year include a magnet, a test tube, and a petri dish (there’s a full list at Emojipedia). Before too long then, you should be able to have much more meaningful emoji-based science conversations with your friends.

DNA’s double-helical structure, which creates the twisting pattern, was discovered way back in 1953, with a right-handed spiral.

Since then scientists have wondered what caused that right-handed bias. One idea is that cosmic rays destroyed the left-handed ancestors of DNA on the early Earth, but at the moment we really don’t know for sure.

What we do know is that DNA should have a right-handed spiral, and flipping it over to show a mirror image is wrong – just as wrong as trying to exactly duplicate the actions of a right hand with a left hand.

This isn’t the first time this mistake has been made – the same error has appeared in textbooks and in graphics many times in the past – and we can’t get too angry when we’re getting skateboards and kangaroos added to our emoji vocabulary.

Now though, you should all know what to look out for. When the emojis eventually land on your phone, take a close look to see which way the DNA strand is twisted.

Debating Whether Next-Gen Sequencing Should Be Applied Universally in Metastatic Breast Cancer

Large list of potentially targetable genes, but what about outcomes?

Interest is great in genomically informed targeted therapy, with the goal of identifying genomic alterations that (1) are drivers of tumor growth and progression in individual patients to individualize therapy; and (2) are targetable directly or indirectly with approved or investigational agents.

But should all women diagnosed with metastatic breast cancer undergo next-generation sequencing (NGS)? The question was debated by two experts at the most recent San Antonio Breast Cancer Symposium.

Yes, said Funda Meric-Bernstam, MD, chair of Breast Cancer Research at the University of Texas MD Anderson Cancer Center in Houston. Genomic testing should be part of the clinical management, and should be considered in all patients with metastatic breast cancer and adequate performance status who have an interest in clinical trials.

A large list of genes are potentially targetable in breast cancer, she said, pointing to PIK3CA, Akt, HER2, TRK and other rare alterations.

Several PI3K inhibitors are in clinical trials to target PIK3CA, with “emerging hope in upcoming inhibitors such as alpelisib in combination with fulvestrant” in PIK3CA-altered advanced breast cancer, she said. Activating Akt mutations, usually E17K, are most commonly found in hormone receptor-positive breast cancer. Objective responses have been elicited with the catalytic inhibitor AZD5363 as monotherapy in patients with estrogen receptor-positive AktE17K-mutant breast cancer and is now being studied in combination with fulvestrant. Ipatasertib, another Akt inhibitor, combined with paclitaxel in patients with PIK3 pathway aberrations increased progression-free survival to 9.0 months, compared with 4.9 months with paclitaxel alone in a phase II study.

HER2 is a proven genetic target, Meric-Bernstam said, noting that some patients who are HER2-negative on initial screening are subsequently found to be HER2-positive on NGS of another or newer sample. “We’re not sure if this is genomic evolution or heterogeneity or technical issues with the first testing, and we’re not as sure of the therapeutic sensitivity in this context, especially if it represents heterogeneity.”

If the tumor is HER2 amplified on NGS, validation is not needed to institute HER2-directed therapy. If the tumor is not amplified on NGS, the patient may still have a lower level of amplification or overexpression. “There’s a lot of enthusiasm about exploring HER2 mutations as a target.”

A few years ago, activating HER2 mutations were discovered in HER2-negative breast cancer. In a series of 5,605 women with breast cancer who underwent genomic profiling, 10.6% had HER2 amplifications, 2.4% had HER2 mutations, and 0.7% had co-occurring HER2 amplification and mutation, she continued. A few agents have already been approved in the HER space, with neratinib being the most prominent.

A very rare alteration found in several tumor types including breast cancer is TRK fusions. As presented at the 2017 ASCO annual meeting, in a phase I/II basket trial of patients with TRK (tropomyosin receptor kinase) fusions, almost all patients treated with the pan-TRK inhibitor larotrectinib had an objective response, which proved durable. Meric-Bernstam explained that TRK fusions are pathognomonic in secretory breast cancer, which constitutes less than 1% of breast cancers. “Because they are rare in breast cancer, I am not going to advocate for TRK fusion testing across the board for this reason, but if you do have a secretory breast cancer patient, please do TRK fusion testing.”

Not performing NGS means that patients with rare alterations cannot be entered into genotype-selected clinical trials, she argued.

ESR1, another current clinically relevant mutation, is rarely found in primary breast cancer but is commonly found in the metastatic setting. Evidence suggests that as ESR1 mutations accumulate with further treatment, there may be some value in retesting or performing liquid biopsy. An ESR1 mutation may affect the choice of therapy; an improved PFS was obtained with the use of fulvestrant compared with exemestane in breast cancer patients with ESR1 mutations, which was not the case in the patient who were ESR1 wild type.

Outcomes Not Altered, Potential Pitfalls Remain

The debater taking the other side at the symposium, Fabrice André, MD, of Gustave Roussy Cancer Center in Villejuif, France, said the key question is whether in the context of routine practice, NGS should be considered for detection of somatic mutations. At least as of yet, he said, no such rationale exists.

At present, no drug approved for use in the treatment of breast cancer requires a genomic test, he reminded listeners. “The reason is because the current way of interpreting DNA sequencing is not useful in metastatic breast cancers, and is potentially deleterious.”

Although NGS has been able to detect alterations in PIK3CA, Atk1, ERBB2, and ESR1 for which objective responses have been observed with the use of targeted therapy in early phase study, their detection did not improve outcome. Progression-free survival in these studies ranged from 5 to 8 months, which was not superior to standard of care. Further, these alterations can be detected by polymerase chain reaction (PCR) assays on circulating tumor DNA, which would be less expensive than NGS, he said.

In the case of sensitivity to PD-1 inhibitors such as pembrolizumab, accelerated approval of the agent was granted in those patients with microsatellite instability-high or mismatch repair-deficient solid tumors. The companion diagnostic for this purpose is immunohistochemistry or PCR, not NGS, said André. “Keep in mind that breast cancer with microsatellite instability is extremely rare — something like 1% and mostly in triple-negative breast cancer.”

The largest commercially available NGS panel can detect about 300 targetable genomic alterations. The issue here is that large gene panels report targetable alterations that are not relevant or for which the wrong drug may be recommended. Therefore, NGS reports can be deleterious because they recommend ineffective therapy and deny effective therapies, he said — one illustration of the wrong target, for example, is fibroblast growth factor receptor (FGFR)1/2 amplification for which an FGFR may be recommended. Nogova et al reported an objective response rate of 0% in patients with breast cancer and FGFR1/2 amplification.

Two large clinical trials in which large gene panels were used had efficacy as the primary endpoint, and in both cases, the targeted drugs matched to the genomic alteration detected by NGS failed to improve PFS.

Finally, said André, the reporting of large panels of genes leads to major ethical, regulatory, and financial issues that have not yet been sorted out. For example, in comparing results obtained from different NGS vendors, the overlap in genomic alterations is sometimes poor. Another pitfall is that somatic genetic testing in patients with advanced cancer may also detect previously unrecognized pathogenic germline variants.

Furthermore, he said, with genomic testing the likelihood of finding a drug matched to a genomic alteration is low. Although sequencing is inexpensive, it generates additional cost for biopsies and potentially the off-label use of expensive drugs.

Nature, Meet Nurture

Single-cell analysis reveals dramatic landscape of genetic changes in the brain after visual stimulation

A “brainbow” of cerebral cortex neurons labeled with different colors.

“Nature and nurture is a convenient jingle of words, for it separates under two distinct heads the innumerable elements of which personality is composed. Nature is all that a man brings with himself into the world; nurture is every influence from without that affects him after his birth.” – Francis Galton, cousin of Charles Darwin, 1874.

Is it nature or nurture that ultimately shapes a human? Are actions and behaviors a result of genes or environment?

Variations of these questions have been explored by countless philosophers and scientists across millennia.

Yet, as biologists continue to better understand the mechanisms that underlie brain function, it is increasingly apparent that this long-debated dichotomy may be no dichotomy at all.

In a study published in Nature Neuroscience on Jan. 21, neuroscientists and systems biologists from Harvard Medical School reveal just how inexorably interwoven nature and nurture are.

Using novel technologies developed at HMS, the team looked at how a single sensory experience affects gene expression in the brain by analyzing more than 114,000 individual cells in the mouse visual cortex before and after exposure to light.

Their findings revealed a dramatic and diverse landscape of gene expression changes across all cell types, involving 611 different genes, many linked to neural connectivity and the brain’s ability to rewire itself to learn and adapt.

The results offer insights into how bursts of neuronal activity that last only milliseconds trigger lasting changes in the brain, and open new fields of exploration for efforts to understand how the brain works.

“What we found is, in a sense, amazing. In response to visual stimulation, virtually every cell in the visual cortex is responding in a different way,” said co-senior author Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and chair of the Department of Neurobiology at HMS.

“This in essence addresses the long-asked question about nature and nurture: Is it genes or environment? It’s both, and this is how they come together,” he said.

One out of many

Neuroscientists have known that stimuli—sensory experiences such as touch or sound, metabolic changes, injury and other environmental experiences—can trigger the activation of genetic programs within the brain.

Composed of a vast array of different cells, the brain depends on a complex orchestra of cellular functions to carry out its tasks. Scientists have long sought to understand how individual cells respond to various stimuli. However, due to technological limitations, previous genetic studies largely focused on mixed populations of cells, obscuring critical nuances in cellular behavior.

To build a more comprehensive picture, Greenberg teamed with co-corresponding author Bernardo Sabatini, the Alice and Rodman W. Moorhead III Professor of Neurobiology at HMS, and Allon Klein, assistant professor of systems biology at HMS.

Spearheaded by co-lead authors Sinisa Hrvatin, a postdoctoral fellow in the Greenberg lab, Daniel Hochbaum, a postdoctoral fellow in the Sabatini lab and M. Aurel Nagy, an MD-PhD student in the Greenberg lab, the researchers first housed mice in complete darkness to quiet the visual cortex, the area of the brain that controls vision.

They then exposed the mice to light and studied how it affected genes within the brain. Using technology developed by the Klein lab known as inDrops, they tracked which genes got turned on or off in tens of thousands of individual cells before and after light exposure.

The team found significant changes in gene expression after light exposure in all cell types in the visual cortex—both neurons and, unexpectedly, non-neuronal cells such as astrocytes, macrophages and muscle cells that line blood vessels in the brain.

Roughly 50 to 70 percent of excitatory neurons, for example, exhibited changes regardless of their location or function. Remarkably, the authors said, a large proportion of non-neuronal cells—almost half of all astrocytes, for example—also exhibited changes.

The team identified thousands of genes with altered expression patterns after light exposure, and 611 genes that had at least two-fold increases or decreases.

Many of these genes have been previously linked to structural remodeling in the brain, suggesting that virtually the entire visual cortex, including the vasculature and muscle cell types, may undergo genetically controlled rewiring in response to a sensory experience.

There has been some controversy among neuroscientists over whether gene expression could functionally control plasticity or connectivity between neurons.

“I think our study strongly suggests that this is the case, and that each cell has a unique genetic program that’s tailored to the function of a given cell within a neural circuit,” Greenberg said.

Goldmine of questions

These findings open a wide range of avenues for further study, the authors said. For example, how genetic programs affect the function of specific cell types, how they vary early or later in life and how dysfunction in these programs might contribute to disease, all of which could help scientists learn more about the fundamental workings of the brain.

“Experience and environmental stimuli appear to almost constantly affect gene expression and function throughout the brain. This may help us to understand how processes such as learning and memory formation, which require long-term changes in the brain, arise from the short bursts of electrical activity through which neurons signal to each other,” Greenberg said.

One especially interesting area of inquiry, according to Greenberg, includes the regulatory elements that control the expression of genes in response to sensory experience. In a paper published earlier this year in Molecular Cell, he and his team explored the activity of the FOS/JUN protein complex, which is expressed across many different cell types in the brain but appears to regulate unique programs in each different cell type.

Identifying the regulatory elements that control gene expression is critical because they may account for differences in brain function from one human to another, and may also underlie disorders such as autism, schizophrenia and bipolar disease, the researchers said.

“We’re sitting on a goldmine of questions that can help us better understand how the brain works,” Greenberg said. “And there is a whole field of exploration waiting to be tapped.”

New tool tracks down distant regulators of gene expression, upends expectations

Gene enhancers light up in distinctive patterns in different cell types in a fruit fly.

To put things simply, Harvard Medical School researcher Karen Adelman studies DNA “to see how genes get messed up in disease.”

Sometimes that means investigating mutations in the genes that make proteins. In sickle cell anemia, for example, a mutated gene builds improperly shaped hemoglobin that sticks together and reduces the ability of red blood cells to carry oxygen.

Adelman’s interest, however, lies in how otherwise normal genes are expressed—turned on or off—in the wrong amounts, at the wrong times or in the wrong tissues.

In the past few years, scientists have begun to appreciate how often these instructions come from DNA segments called enhancers located far from the genes they influence. Children can be born without a pancreas when a mutation in an enhancer disrupts the “go” signal to a gene 25,000 DNA bases away that is supposed to start growing the organ.

Mutations in these distant enhancers are increasingly being linked to many other diseases, including congenital heart diseases, type 2 diabetes, cancers and immunological disorders.

The problem? “There’s no good way to find those enhancers,” said Adelman, professor of biological chemistry and molecular pharmacology at HMS. “If something’s wrong, we don’t know where to look.”

That is now changing. Adelman and colleagues reported this week in Genes & Development that they repurposed a tool they developed in 2010, Start-seq, to generate maps of enhancers that are active in a given tissue type, disease or set of environmental conditions.

Adelman believes Start-seq will help researchers seeking the sources of disrupted gene expression as well as those trying to understand how enhancers work normally.

“How do enhancers give the right instructions in embryonic development and go wrong in cancer?” she said. “Not only is this stuff fascinating to explore, but we also need to answer these questions if we ever want to alter enhancers, such as to treat disease.”

Already, the team has made a surprising discovery that blurs the distinction between enhancers and the genes they regulate.

Who transcribes the transcribers?

Like the rest of her peers, Adelman was taught in school that enhancers simply send instructions, in the form of transcription machinery, to the genes they want to “switch on.” The machines copy the genes’ DNA into RNA and use that as a blueprint to build proteins.

But in 2010, researchers led by Michael Greenberg, the Nathan Marsh Pusey Professor and head of the Department of Neurobiology at HMS, discovered that enhancers in brain cells also spawn RNAs as they do their jobs—only these RNAs are tiny and short-lived, and they don’t code for proteins.

Since then, the community has debated: How common is this phenomenon? What purpose, if any, do the little RNAs serve?

Adelman and colleagues took advantage of the unique qualities of these RNAs to locate enhancers and get some answers.

“These RNAs are very different from the ones made at genes,” Adelman explained. “They’re generated, they fall off and then they’re quickly degraded. We developed a technique to find them when they’re still stuck to the enhancers.”

Rescued from the scrap heap

The Start-seq technique begins with cell samples. The researchers wash away long, mature RNAs and keep ones that are still stuck to the genome. They then pluck out short RNAs that have a chemical tag characteristic of RNA-construction machinery found at genes and enhancers.

Finally, the team sequences these RNAs, revealing where each came from on the genome.

The result: a list of just about every enhancer that was active at the time the sample was taken, along with their exact genetic sequences. While not perfect, Start-seq returns fewer false positives and false negatives than previous enhancer-detection methods, the authors found.

Poised to dive into the genetics and transcription dynamics that drive enhancers, the researchers can already answer one burning question: Around 95 percent of enhancers make RNA.

“This means transcription at enhancers and protein-coding genes have much more in common than we appreciated,” said Adelman. “Philosophically it makes sense—and it helps explain why protein-coding genes can act as enhancers—but it still turns things on their head quite a bit.”

The good news, she said, is that the vast knowledge scientists have gathered about control of protein-coding genes can now be applied to learning how enhancers work.

Community resource

The team is working to automate Start-seq so they can make it available to researchers throughout the HMS community and beyond.

The tool should enable people to search for overlaps between enhancer activity and genetic variants to tease out which variants might contribute to the biological phenomenon they’re studying, whether that is Parkinson’s disease or the differentiation of stem cells.

“We have plenty of neighbors who are hoping to identify relevant enhancers in their disease models,” Adelman said. “We hope to shine the flashlight on the right parts of the genome for them.”

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