Possible association between glyphosate exposure and autism spectrum disorder (ASD)

Human complex diseases represent a phenotype (trait) that reflects the combination of: [a] genetics (e.g., DNA sequence variants); [b] epigenetics (chromosomal changes other than DNA sequence alterations); [c] environmental factors (pesticides, chemical pollutants); [d] endogenous influences (diabetes, heart disease); and [e] differences in one’s microbiome. Autism spectrum disorder (ASD) is a great example of a very complex disease trait that is certainly polygenic, plus influenced by epigenetic and environmental factors, and perhaps even by variability in the microbiome. Many genome-wide association studies (GWAS) have identified a number of low-effect genes, noncoding DNA loci, repetitive DNA sequences, and changes in DNA methylation that show correlations with ASD. Clinically, ASD is a developmental disorder that presents as severe social and communication impairment, combined with limited or focused interests and repetitive-type behaviors.

The prevalence of ASD has been exploding since the mid-1960s, rising from about one case of autism per 20,000 patients (in ~1960) to one case of ASD in 44 children today (~460 per 20,000(!!). One important caveat is that diagnosis of ASD is MUCH broader than it was, 60+ years ago. Throughout my clinical pediatrics training in the 1960s, I can remember only one ASD patient among the thousands of patients I was in contact with during those years.

The attached paper focuses on a possibly significant contribution of an environmental factor during pregnancy in ASD etiology. Proposed environmental chemicals that might cause ASD include: selective serotonin reuptake inhibitors (SSRIs), pesticides, herbicides, phthalates, polychlorinated biphenyls, solvents, air pollutants, fragrances, and heavy metals. For example, increases in the widely-used chemical, glyphosate [N-(phosphonomethyl)glycine], the active ingredient in the herbicide Roundup, were reported to be associated with increases in ASD rates over the same period — reported in the US public school system. Authors cite a population-based case-control study in California, showing the risk of ASD was associated with use of glyphosate (odds ratio = 1.16). For ASD children with intellectual disability, estimated odds ratios were higher with prenatal exposure to glyphosate (odds ratio = 1.33). These reports suggest that possible relationships between glyphosate and ASD should be explored in animal models.

Epidemiological studies implicate in utero maternal immune activation (MIA), playing a key role in the etiology of developmental disorders such as ASD; also, there are a number of positive associations between maternal infections or inflammatory biomarkers and ASD. Collectively, it is suggested that MIA during pregnancy can increase the risk of developmental disorders such as ASD in offspring. Authors [in the attached paper] show that soluble epoxide hydrolase (sEH), participating in metabolism of polyunsaturated

fatty acids (PFAs) might be involved in genesis of ASD in mouse offspring, following MIA; authors also found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. [Authors state the dose of glyphosate is “0.098% in drinking water,” but authors should report what that computes to, in mg per kg per day]

Authors found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring; in addition, they discovered decreased levels of epoxy-fatty acids [e.g., 8,9-EpETrE] in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure — which would be consistent with increased activity of sEH in the offspring. Moreover, authors found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) during pregnancy from embryonic day-5 (E5) to postnatal day 21 (P21) prevented ASD-like behaviors (e.g., social interaction deficits and increased grooming time) in the juvenile offspring after maternal glyphosate exposure.

These findings suggest that maternal “exposure to high levels of glyphosate” — causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring mice, and that increased activity of sEH might play a role in ASD-like behaviors in offspring due to maternal glyphosate exposure. Authors suggest that “sEH might therefore be considered as a target for ASD in offspring,” following maternal stress from environmental exposure to contaminants. This study is a good example of gene-environment interactions, the recurrent theme of these GEITP blogs. 😊

COMMENTS:Hi Dan, Thanks for sending this around. There are several strong candidates which may play a role in the horrendous increase in ASD. And I agree that improved diagnosis is only a small part of the puzzle. Air pollution and other environmental pollution might play some role.

Much of the research has been conducted using PURE glyphosate (i.e., the active ingredient which is what is required for pesticide testing). The problem is that it may be the formulations that are part of the problem. Anyhow, lots of interesting work happening now on glyphosate — demonstrating that it is NOT innocuous to humans. LSB

COMMENT: Dan, I just did a back-of-the-envelope calculation on doses of glyphosate used in this ASD study:

They used ~1,000 ppm (million) in drinking water. The levels in tap water range from 85-330 ppt (trillion) — which means the dose they used is 3- to 12-million times higher than the average level found in tap water.

The difference with respect to food is more reasonable and that is likely the major glyphosate exposure clinically. The acceptable daily intake (ADI) for glyphosate is 0.5 ppm; therefore, the dose they used in mice (without allometric correction) is 2,000 times the human ADI.

Is this study relevant to toxicology? It irritates me that the authors use descriptors in the Abstract such as “…suggest that maternal exposure…” whereas in the title, the authors state: “Maternal glyphosate exposure CAUSES autism-like…” Association is NOT causation — even if this paper gets published in Proc Natl Acad Sci USA !! DW

COMMENT: This is GREAT, Dave. I saw the authors described in the text their treatment as “0.008% in drinking water” — where did you find all the additional details about the regimen used? DWN
COMMENT: Dan: I was going by the information in their Supplemental Materials section — “In this study, we used commercially available RoundupⓇ Maxload [48% (w/v) glyphosate (N-phosphonomethylglycine) potassium salt, having 52% other ingredients such as water and surfactant. [Lot #11946898. Nissan Chemical Corporation, Tokyo, Japan]. Previous studies used drinking water containing 0.38% (w/v) glyphosate (expressed as free base: 1% RoundupⓇ), during pregnancy and lactation, equivalent to 50 mg/kg/day of glyphosate (1,2). This corresponds to 1/20th of the glyphosate no-observed-adverse-effect level, as described previously (3). Therefore, water or formulated glyphosate [or 0.1, 0.25, 0.50, 0.75, 1.0 % RoundupⓇ] was given to the pregnant mice from E5 to P21 (weaning).”

“Measurement of glyphosate in the blood. Water or 0.098% (w/v) formulated glyphosate was given to pregnant mice from E5 to P21, as described above.”

The glyphosate dose of 0.1% would be 1000 ppm, and that is what I used, to compare with the reported levels in tap water (85-330 ppt). If mice drink 4 mL water/day at 0.1%, that would be 4 mg/day or 160 mg/kg for a 25 g mouse.

If the doses were between 0.1% and 1% of a formula containing 48% glyphosate, that would be about 2 mg/day (80 mg/kg), i.e., 20 mg/day (800 mg/kg).

The acceptable daily intake (ADI) for humans in food is 0.5 ppm or 0.5 x 10-7 g/g food. If a human eats 1,800 g food/day, that works out to 0.9 mg/day glyphosate, or 0.013 mg /kg for a 70-kg human. So, whatever the dose they actually used, it is many orders of magnitude higher than the human ADI. If my math is off, I will blame it on being quarantined in this pandemic, going on now, for more than 2 years. ☹ DW

COMMENT: I had intended to emphasize the authors’ use of the word “causes” in the title of their article (notice in the subject line of this email, it more conservatively says “possible association,” which is much more scientifically accurate thing to say). Kudos to Professor David Williams for bringing this topic up. Far too often, authors see a correlation — and immediately assume it is the cause-and-effect. “Possible association” is the much more accurate way to describe any observed correlation.

As with >90% (or probably >99%) of all toxicological studies, authors choose a dose WAY beyond “environmental reality,” in order to find “an effect.” This paper is a great example of this. In My Humble Opinion, this paper should never have been published — at least not in the high-visibility prestigious Proc Natl Acad Sci USA journal. ☹

What are the likely causes of ASD? Clearly, it must be a polygenic disease — with dozens if not hundreds of genes, each contributing a “small-effect” to the phenotype. In addition, to explain the incredible increase in frequency of this disease in the Western World since 1970, there must be epigenetic effects (the time for this increase to appear, i.e., <50 years, is way too short for DNA mutations to be involved). Environmental factors, lifestyle suspects, include things around us today — that were not there 50-60 years ago: e.g., [a] steady and excessive exposure of TV, electronic games and fast-moving videos to children almost from birth; [b] dietary changes (today there is so much “fast foods,” excessive sugar, and lack of a nutritious well-balanced diet); and [c] tendency of teachers, school counselors and parents diagnosing every transient behavioral defect in every school kid as “likely having ASD.” DwN COMMENT: Wow, this discussion is very harsh on the authors. I think the authors mentioned that their results in animals are “not readily translated into human populations,” because the concentration they used here was way higher than environmental levels. The purpose of this study was to demonstrate that glyphosate (at some level of exposure) could cause behavioral disorders that are similar to an ASD-like phenotype (for example, “arsenic causes cancers”). Based on their study, I believe it is safe to say glyphosate "is associated with" ASD-like symptoms in mice — at the concentrations at which the authors chose to use. ZL COMMENT: Findings in a mouse model, or any other nonhuman model for that matter, means nothing more than a hypothesis — unless the model has been validated in clinical studies with human patients. We at P & G lost many millions of dollars, trying to develop new drugs for humans, based on animal preclinical work. We saw many more failures, compared to successes. Academicians who publish these preclinical studies are only interested in getting their names in lights. And, of course, their University PR departments trump up the potential value. R D'A COMMENT: All of this is an interesting discussion — especially because the renewal assessment report of glyphosate is now on the board of the European Food Safety Authority (EFSA). Their license should be either renewed or discarded in the EU by the end of this year. Evaluation by the EFSA is a huge effort; we have thousands of pages and public opinions comprising more than 2,000 comments. ☹ OP **[Read emails from oldest to newest]** This email-chain just keeps going and going. Maybe there is lots to ventilate about? Here are two more of the latest comments. One from the Editor of Critical Reviews in Toxicology. And this last one is from Dr,, Jim Adams, who has a sobering message from “someone in the trenches” — a general practitioner for 40+ years. 😊 I hope everyone enjoys his frankness, honesty and humor as much as I do. 😊 —DwN COMMENT: J A I’ve been saving the Roundup emails and now I feel that I am at a point where I can attempt to sound off — which is the point of my reply to this, and other, related trends in modern problem-solving that crosses many fields of interest. (I’ll try not to ramble too much.) Every day in my practice, I see people who haven’t been diagnosed — even after thousands of dollars of tests, or they have had their problems solved by thousands of dollars of medications. If it’s a broken bone, no problem. If it’s fatigue or one of the myriad chronic pain or even more obvious illnesses almost always based on obesity — not so easy. Medicine has become compartmentalized. If you take “fatigue” to a cardiologist, you get thousands of dollars of cardiac tests. If you send “fatigue” to an internist, you get another set of tests, and a CAT scan or two. If you send “fatigue” to one of the “second-tier practitioners,” you get a repeat of some of the above — plus a sleep study and more and more pills that are like throwing darts in the darkness of failed knee-jerk approaches to complex problems. So finally, for all our deviations from normal hard work and the struggles over the millennia that kept us from becoming walking eggplants or other vegetables, the “alternate” problem-solvers get a shot: psychiatry, functional medicine, dietary guides, and a whole host of herbal incantations, etc. Then, maybe watching TV before bed — turns out to be the “real cause." This mirrors, in a sense, the Roundup studies, wherein the millions of chemicals floating around become targets, “searches for causality,” — especially if a company like Monsanto with deep pockets is involved. Let’s consider all the food additives, chemicals in cosmetics, herbicides and pesticides. Why not add PVC pipe, residuals of all food processing, and, more realistically, every new and old drug or potion on the market? For example, take psychostimulants for children who can’t do well in school. The adverse effect studies extend at best two years…!! We're talking about habit-forming drugs that alter brain structure, and there is no feasible way to look at subtle, or not-so-subtle, mental or physical effects 20 years from now. Now, add in statins, etc. How can one account for possible drug effects and combination-drug long-term effects from something as minute as the amount of Roundup sprayed on weeds…?? Then, I have this problem with all pesticide and herbicide fears. I live in the Mississippi Delta — where airplanes have sprayed every imaginable chemical directly in the air, since I was 10 years old. You smell them all spring, summer and fall while riding down the highways. When I was age 10, I stood in my T-shirt and marked the rows for airplanes flying over my head, smearing my glasses with 2-4-D (remember dioxin?) and every chemical, except Paraquat, a chemical we all knew “was toxic.” (My brother uses Paraquat in spray rigs every year to spray the stuff on the ground, as if that’s safer.) What’s my obvious point? If chemicals for bugs and weeds are truly toxic, it would seem to me that those of us in the Mississippi Delta with 60 years of intense, yearly exposure, second only to the crop-dusters and spray-rig-tractor drivers, should be more valid study subjects than rats. My friends and I rode our bikes in the DDT fog sprayers as children. But then, this returns to paragraph one. We know nothing. We have science groomed by ulterior motives…money mostly…and hysteria. None of us is as brilliant as a Cray Computer, and we are simply throwing darts in darkness to invent answers — using clever tools and tests — all depending on our particular fields of interest. Yet, from another viewpoint, are we all like the doctors, including myself years ago, who are more like college kids smoking pot…”I’ve done it, and it’s hasn’t killed me yet?” We assume safety if there aren’t visible or palpable immediate adverse effects. There is a pill for everything. And by the way, despite the use of an incredible array of pesticides, some sprayed over the entire city overhead by airplanes at night during summer, when our mosquitoes are horrid. Right now, at 6 am in Cleveland, Mississippi, it sounds like a songbird sanctuary, and by sunrise, the air will be literally filled with insects flying or crawling over every square inch of territory in my back yard. I don’t know if the Joni Mitchell lyric “Give me spots on my apples, but leave the birds and the bees” is an intelligent assessment of reality or not. I, by the way, keep bees in my back yard, and they’re buzzing around and surviving just fine. In summary, I’m 72 years old, and I have been breathing high doses of every evil chemical imaginable, and it’s done no harm that I can see. (This is an old photo below…well, I did have to have a few plastic surgeries over the years.) From: RM Subject: Fw: California regulators changing language on glyphosate and cancer risk Dan: I have followed the recent exchanges on your blog. I have stayed on the sidelines — because I received a lot of flak — related to articles by Willliams et al. on “glyphosate's potential carcinogenicity,” which I chose to accept for publication and it got published in Critical Reviews in Toxicology; and I refused to retract them in response to requests from IARC and others. You will find the attached article of interest. I am sure you recognize Carey Gillam has a vested position. Keep up the great work that you do — in communicating and discussing these high-profile issues(!!) Best regards, RM COMMENT: Let me add to the firestorm…As a proud member of the National Academy of Schmoozers, I could not agree more with Fred. I’m continually dismayed by the number of so-called toxicology studies that draw ‘disconcerting’ conclusions for human health — based on in vitro (and sometines in vivo) studies that use doses/concentrations that are 1,000 times to, sometimes, 10s-of-thousands of times, higher than could ever conceivably be achieved from ‘environmental’ exposures. Imagine if drug safety assessment were based on observed effects on in vitro studies that required doses thousands of times higher than physiological-based pharmacokinetic modeling and simulation (PBPK) therapeutic concentrations. We would have no new drugs….the Glyphosate ‘controversy’ is just the tip of this toxicology iceberg…. ☹ COMMENT: [Read emails from oldest to newest]** Lastly, to bring this email-chain into perspective and full-circle, the short video clip [attached] of a small toddler on a farm shows an example of a child who is completely aware of his surroundings and acts appropriately when challenged by a cow. No doubt the child’s parents have been using glyphosate on their farm, and their entire family has been exposed. Even during her pregnancy with this child, the toddler was likely exposed to this herbicide in utero. But, as you can see here — he does NOT show any evidence of ASD. 😊😉😉 DwN Nebert, Daniel (nebertdw) Sent: Wednesday, April 13, 2022 5:22 PM The raging firestorm of GLYPHOSATE — continueth, including claims of an association and possible causation not only to ASD but also to cancer. For many years, I’ve been aware of this political battle and fraudulent (glyphosate-cancer) “scientific” studies and claims. Sound science (following The Scientific Method *) continues to be replaced by government opinion and policy, and this trend seems to be accelerating during these past 2-3 decades. Why? Perhaps this has to do with the internet? or social media? or incompetent teaching of the latest generation of students? I just don’t know. DwN *The six steps of The Scientific Method include: 1) ask a question; 2) learn what is already known about the topic; 3) construct a hypothesis; 4) experiment to test the hypothesis (including repeat experiments to confirm the same result); 5) analyze data from the experiments and draw conclusions; 6) communicate the results to others. [Repeat Steps 1 through 6 again and again.] From: GeK Dear Dr. Nebert, Jim Enstrom included me on the correspondence involving you, David Williams, and others regarding the PNAS paper linking glyphosate exposure and ASD. Since there was no direct mention of cancer in the email exchange, I wanted to make you aware – if you are not already aware – of the unfortunate controversy that has been raging for seven years regarding the claim of carcinogenicity of glyphosate. The controversy stems from IARC’s 2015 determination that glyphosate is a “probable carcinogen.” (This initial publication was followed several years later by IARC Monograph 112, which reached the same conclusion.) IARC based its conclusion of probable carcinogenicity solely on animal (rodent) studies, which it judged to constitute sufficient evidence (whereas the epidemiologic evidence was judged to be insufficient). However, the Agency’s evaluation of the rodent studies has been criticized on the grounds that the wrong statistical test was used to assess dose-response trends, erroneously declaring certain positive trends statistically significant. In addition, where comparable inverse trends occurred, these were ignored. Other irregularities have been documented by Reuters reporter, Kate Kelland, who found that non-carcinogenic findings were edited out in successive drafts. There is also the appearance of a serious conflict of interest on the part of Christopher Portier, who served as an invited guest on the Working Group but, who was also influential in IARC’s 2014 decision to evaluate glyphosate. Within days of the publication of IARC's conclusion in March, 2015, Portier signed a lucrative contract to act as a litigation consultant for two law firms that were preparing to sue Monsanto on behalf of glyphosate cancer victims. Regarding the epidemiology, most studies have been case-control studies of occupational groups exposed to glyphosate. Many of these were conducted when glyphosate was less widely used and exposure would have been low. An association of glyphosate with non-Hodgkin’s lymphoma (NHL) was found in some of these studies. It is noteworthy that IARC ignored the results of the large prospective cohort study, the Agricultural Health Study [AHS], conducted by NCI among 54,000 pesticide applicators. Although the latest results regarding glyphosate were not published until 2018, the results of the analyses involving glyphosate had circulated far earlier, and, furthermore, the head of the Working Group that evaluated glyphosate, Aaron Blair, was one of the lead researchers on the AHS, who would have been intimately aware of the results. The overall conclusion from the AHS analysis was as follows: “In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes.” Recently, together with two colleagues, I published an updated meta-analysis of epidemiologic studies of glyphosate exposure and NHL. Using updated information from the case-control studies, where available, and examining the five different latency conditions considered in the AHS analyses, we found no association of glyphosate exposure with risk of NHL. Given your interest in carcinogenesis and your comments on the toxicology of glyphosate, I wanted to draw your attention to the situation regarding glyphosate and cancer. This question has serious implications for agriculture, where glyphosate has been enormously useful to farmers, providing an environmentally benign means of controlling weeds and increasing yields, enabling no-till cultivation. Activists, litigators, and politicians have taken IARC’s glyphosate determination as gospel, and this has provided the basis for four (by my count) successful lawsuits in California against Monsanto and its successor company, Bayer. In addition, local jurisdictions and states (such as the state of Maine) are considering banning glyphosate, based on IARC’s verdict. In this juggernaut, the judgment of 17 other national and international health/regulatory agencies, which have found glyphosate to be non-carcinogenic and to not pose a risk to the general population, is blithely ignored. In other words, carefully-conducted reviews, including those of the U.S. EPA, Health Canada, and the European Food Safety Authority, among others, are simply deemed to be of no weight — when counterpoised to IARC’s seriously flawed (some would say, fraudulent) conclusion.

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A Paleolithic Raw Bar, and a Human ‘Brush with Extinction’

This article from Medscape, just received today, is about “evolution” and had such an intriguing title — that I had to begin reading it. And once I began reading it (it’s written very breezily and it’s enjoyable to read), I could not stop. And I think this is worthwhile information to share with all of GEITP. The topic includes climate, diet, and human gene evolution. In fact, at one point, I wondered about a possible relationship between this topic — and autism spectrum disorder (i.e., the Western World diet of today versus that of 50-70 years ago). 😊


A Paleolithic Raw Bar, and a Human ‘Brush with Extinction’

Bret S. Stetka, MD
March 25, 2021

This essay is adapted from the newly released book A History of the Human Brain: From the Sea Sponge to CRISPR, How Our Brain Evolved.

“He was a bold man that first ate an oyster.”

—Jonathan Swift

That man or, just as likely, that woman may have done so out of necessity. It was either eat this glistening, gray blob of briny goo. Or perish.

Beginning 190,000 years ago, a glacial age we identify today as Marine Isotope Stage 6, or MIS6, had set in, cooling and drying out much of the planet. There was widespread drought, leaving the African plains a harsher, more barren substrate for survival — an arena of competition, desperation, and starvation for many species, including Homo sapiens. Some estimates have the Sapien population dipping to just a few hundred people during MIS6. Like other apes today, we were an endangered species. But through some nexus of intelligence, ecological exploitation, and luck, we managed. Anthropologists argue over what part of Africa would’ve been hospitable enough to rescue Homo sapiens from Darwinian oblivion. Arizona State University archeologist Curtis Marean believes the continent’s southern shore is a good candidate.

For two decades, Marean has overseen excavations at a site called Pinnacle Point on the South African coast. The region has over 9000 plant species, including the world’s most diverse population of geophytes, plants with underground energy-storage organs like bulbs, tubers, and rhizomes. These subterranean stores are rich in calories and carbohydrates, and, by virtue of being buried, are protected from most other species (save the occasional tool-wielding chimpanzee). They are also adapted to cold climates and, when cooked, easily digested. All in all, a coup for hunter-gatherers.

The other enticement at Pinnacle Point could be found with a few easy steps toward the sea. Mollusks. Geological samples from MIS6 show South Africa’s shores were packed with mussels, oysters, clams, and a variety of sea snails. We almost certainly turned to them for nutrition.

Marean’s research suggests that, sometime around 160,000 years ago, at least one group of Homo sapiens began supplementing their terrestrial diet by exploiting the region’s rich shellfish beds. This is the oldest evidence to date of humans consistently feasting on seafood — easy, predictable, immobile calories. No hunting required. As inland Africa dried up, learning to shuck mussels and oysters was a key adaptation to coastal living, one that supported our later migration out of the continent.

Marean believes the change in behavior was possible thanks to our already keen brains, which supported an ability to track tides, especially spring tides. Spring tides occur twice a month with each new and full moon and result in the greatest difference between high and low tidewaters. The people of Pinnacle Point learned to exploit this cycle. “By tracking tides, we would have had easy, reliable access to high-quality proteins and fats from shellfish every two weeks as the ocean receded,” he says. “Whereas you can’t rely on land animals to always be in the same place at the same time.” Work by Jan De Vynck, a professor at Nelson Mandela University in South Africa, supports this idea, showing that foraging shellfish beds under optimal tidal conditions can yield a staggering 3500 calories per hour!

“I don’t know if we owe our existence to seafood, but it was certainly important for the population that Curtis studies. That place is full of mussels,” says Ian Tattersall, curator emeritus with the American Museum of Natural History in New York City, New York.

“And I like the idea that during a population bottleneck, we got creative and learned how to focus on marine resources.” Innovations, Tattersall explains, typically occur in small, fixed populations. Large populations have too much genetic inertia to support radical innovation; the status quo is enough to survive. “If you’re looking for evolutionary innovation, you have to look at smaller groups.”

MIS6 wasn’t the only near-extinction in our past. During the Pleistocene epoch, roughly 2.5 million to 12,000 years ago, humans tended to maintain a small population, hovering around a million and later growing to maybe eight million at most. Periodically, our numbers dipped as climate shifts, natural disasters, and food shortages brought us dangerously close to extinction. Modern humans are descended from the hardy survivors of these bottlenecks.

One especially dire stretch occurred around one million years ago. Our effective population (the number of breeding individuals) shriveled to around 18,000, smaller than that of other apes at the time. Worse, our genetic diversity — the insurance policy on evolutionary success and the ability to adapt — plummeted. A similar near-extinction may have occurred around 75,000 years ago, the result of a massive volcanic eruption in Sumatra.

Our smarts and adaptability helped us endure these tough times — omnivorism helped us survive scarcity.
A Sea of Vitamins

Both Marean and Tattersall agree that the Homo sapiens hanging on in southern Africa couldn’t have lived entirely on shellfish. Most likely they also spent time hunting and foraging roots inland, making pilgrimages to the sea during spring tides. Marean believes coastal cuisine may have allowed a paltry human population to hang on until climate change led to more hospitable terrain. He’s not entirely sold on the idea that marine life was necessarily a driver of human brain evolution.

By the time we incorporated seafood into our diets, we were already smart, our brains shaped through millennia of selection for intelligence. “Being a marine forager requires a certain degree of sophisticated smarts,” he says. It requires tracking the lunar cycle and planning excursions to the coast at the right times. Shellfish were simply another source of calories.

Unless you ask Michael Crawford.

Crawford is a professor at Imperial College London and a strident believer that our brains are those of sea creatures. Sort of.

In 1972, he co-published a paper concluding that the brain is structurally and functionally dependent on an omega-3 fatty acid called docosahexaenoic acid, or DHA. The human brain is composed of nearly 60% fat, so it’s not surprising that certain fats are important to brain health. Nearly 50 years after Crawford’s study, omega-3 supplements are now a multi-billion-dollar business.

Omega-3’s, or more formally, omega-3 polyunsaturated fatty acids (PUFAs), are essential fats, meaning they aren’t produced by the body and must be obtained through diet. We get them from vegetable oils, nuts, seeds, and animals that eat such things. But take an informal poll, and you’ll find most people probably associate omega-fatty acids with fish and other seafood.

The animal brain evolved ~600 million years ago in the ocean and was dependent on DHA…

In the 1970s and 1980s, scientists took notice of the low rates of heart disease in Eskimo communities. Research linked their cardiovascular health to a high-fish diet (though fish cannot produce omega-3’s, they source them from algae), and eventually the medical and scientific communities began to rethink fat. Study after study found omega-3 fatty acids to be healthy. They were linked with a lower risk for heart disease and overall mortality. All those decades of parents forcing various fish oils on their grimacing children now had some science behind them. There is such a thing as a good fat.

Recent studies show that some of omega-3s’ purported health benefits were exaggerated, but they do appear to benefit the brain — especially DHA and eicosapentaenoic acid, or EPA. Omega fats provide structure to neuronal cell membranes and are crucial in neuron-to-neuron communication. They increase levels of a protein called brain-derived neurotrophic factor (BDNF), which supports neuronal growth and survival. A growing body of evidence shows omega-3 supplementation may slow down the process of neurodegeneration, the gradual deterioration of the brain that results in Alzheimer disease and other forms of dementia.

Popping a daily omega-3 supplement or, better still, eating a seafood-rich diet, may increase blood flow to the brain. In 2019, the International Society for Nutritional Psychiatry Research recommended omega-3’s as an adjunct therapy for major depressive disorder. PUFAs appear to reduce the risk for, and severity of, mood disorders such as depression and to boost attention in children with ADHD as effectively as drug therapies.

Many researchers claim there would’ve been plenty of DHA available on land to support early humans, and marine foods were just one of many sources.

Not Crawford.

He believes that brain development and function are not only dependent on DHA but, in fact, DHA sourced from the sea was critical to mammalian brain evolution. “The animal brain evolved 600 million years ago in the ocean and was dependent on DHA, as well as compounds such as iodine, which is also in short supply on land,” he says. “To build a brain, you need these building blocks, which were rich at sea and on rocky shores.”

Crawford cites his early biochemical work showing DHA isn’t readily accessible from the muscle tissue of land animals. Using DHA tagged with a radioactive isotope, he and his colleagues in the 1970s found that “ready-made” DHA, like that found in shellfish, is incorporated into the developing rat brain with 10-fold greater efficiency than plant- and land animal–sourced DHA, where it exists as its metabolic precursor, alpha-linoleic acid. “I’m afraid the idea that ample DHA was available from the fats of animals on the savanna is just not true,” he disputes. According to Crawford, our tiny, wormlike ancestors were able to evolve primitive nervous systems and flit through the silt thanks to the abundance of healthy fat to be had by living in the ocean and consuming algae.

For over 40 years, Crawford has argued that rising rates of mental illness are a result of post–World War II dietary changes, especially the move toward land-sourced food and the medical community’s subsequent support of low-fat diets. He feels that omega-3’s from seafood were critical to humans’ rapid neural march toward higher cognition, and are therefore critical to brain health. “The continued rise in mental illness is an incredibly important threat to mankind and society, and moving away from marine foods is a major contributor,” says Crawford.

University of Sherbrooke physiology professor Stephen Cunnane tends to agree that aquatically sourced nutrients were crucial to human evolution. It’s the importance of coastal living he’s not sure about. He believes hominins would’ve incorporated fish from lakes and rivers into their diet for millions of years. In his view, it wasn’t just omega-3’s that contributed to our big brains, but a cluster of nutrients found in fish: iodine, iron, zinc, copper, and selenium among them. “I think DHA was hugely important to our evolution and brain health, but I don’t think it was a magic bullet all by itself,” he says. “Numerous other nutrients found in fish and shellfish were very probably important too and are now known to be good for the brain.”

Marean agrees. “Accessing the marine food chain could have had a huge impact on fertility, survival, and overall health, including brain health, in part, due to the high return on omega-3 fatty acids and other nutrients.” But, he speculates, before MIS6, hominins would have had access to plenty of brain-healthy terrestrial nutrition, including meat from animals that consumed omega-3-rich plants and grains.

Cunnane agrees with Marean to a degree. He’s confident that higher intelligence evolved gradually over millions of years as mutations inching the cognitive needle forward conferred survival and reproductive advantages — but he maintains that certain advantages like, say, being able to shuck an oyster, allowed an already intelligent brain to thrive.

Foraging marine life in the waters off of Africa likely played an important role in keeping some of our ancestors alive and supported our subsequent propagation throughout the world. By this point, the human brain was already a marvel of consciousness and computing, not too dissimilar to the one we carry around today.

In all likelihood, Pleistocene humans probably got their nutrients and calories wherever they could. If we lived inland, we hunted. Maybe we speared the occasional catfish. We sourced nutrients from fruits, leaves, and nuts. A few times a month, those of us near the coast enjoyed a feast of mussels and oysters. 😊

COMMENT: Hi Dan, Thanks for sharing this entertaining essay; I have two minor comments.
This hypothesis of the ancient African Homo Sapiens populations staying close to the coastline, for regular seafood feasts is exactly the same hypothesis proposed for the Australian aboriginals during times of severe climate and drought. Those people arrived from (current) Indonesia/Papua New Guinea more than ~40 000 years ago, and were believed to have stayed largely along the coastal regions. While some of the population gradually moved inland — where they invented the boomerang for hunting purposes — the major portion of aboriginals remained along the coast and enjoyed frequent “oyster parties.”

Regarding the Eskimo diet; to my knowledge, Greenland Eskimos started eating fish and other small seafood only rather recently. Their traditional diet was whales and other marine mammals. I don’t know how much PUFAs are present in whale meat and whale fat (blubber).
Cheers, M

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Omicron variant largely avoids antibodies produced by present vaccines ??

The SARS-CoV-2 B.1.1.529 (omicron) variant contains 15 mutations in the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies — requires immediate investigation. Authors [see attached] used high-throughput yeast display screening to determine the profiles of RBD-escaping mutations for 247 human anti-RBD neutralizing antibodies and showed that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F) — a grouping that is highly concordant with knowledge-based structural classifications.

Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups: [a] Neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and
Q493R; [b] Antibodies in group E (e.g., S309) and [c] Antibodies in group F (e.g., CR3022), which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by
G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes.

In total, >85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was

greatly undermined by Omicron — whereas VIR-7831 and DXP-604 still functioned at a diminished efficacy. Together, these data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus-conserved-region will remain most effective. Authors’ state that their results “will advance the development of antibody-based drugs and vaccines against Omicron and future variants.”

This is one paper in the 24 Feb issue of Nature; five more papers on this similar topic are published in sequence [see below]. 😊
Nature 24 Feb 2022; 602: 657-664
But also see: pp 654-656, 664-670, 671-675, 676-681 & 682-688

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**HGNC Newsletter** Winter 2022

Some of you will find the 2022 Winter HGNC NewsLetter relevant and of interest. 😊

Winter newsletter 2022

Newsletters · 24 Feb 2022
Thanks to our Scientific Advisory Board

We would like to thank all the members of our SAB for attending our (mostly virtual) annual meeting from 27-28th January. We hope that we might be able to host a less virtual version in the future! We were pleased to welcome our new board member, Cecilia Arighi, who works within several different protein information projects, including UniProt, Protein Ontology and BioCreative. While Professor Helen Firth has rotated off the board, we are delighted that she has agreed to remain associated with HGNC as our Clinical Advisor.
Play ‘Genele’ – the gene symbol guessing game

How many of you have tried Genele, the fun gene symbol guessing game made by Dr Andrew Holding? It might just remind you of a popular word guessing game that has taken the world by storm in the last few months ;-). We love Genele so much that we have linked to it from our home page. So take a break for a few minutes daily to guess the gene symbol – go on, you can even use genenames.org to help you out a little!

Progress on the VGNC project

We now have more than ~108,500 genes approved in total for our VGNC project, with 14,019 cat genes, 16,751 chimpanzee genes, 16,856 cattle genes, 15,567 dog genes, 15,704 horse genes, 14,677 Rhesus macaque genes and 13,898 pig genes with approved VGNC symbols. This includes over 6,000 new VGNC genes within the last year! Below is a graph showing our progress with each core species.
Wanted – a new VGNC full stack developer

We are currently advertising for a new full stack developer to work on our VGNC project. The closing date is 10th March, so please notify anybody you know that might be interested in this position!
Update on genes with the ‘stable’ tag

We have 2821 gene symbols tagged as ‘stable’ as of February 23rd 2022, an increase of 209 since our Autumn newsletter. Examples of genes within the new stable set include NHEJ1, the causative gene for Severe combined immunodeficiency with microcephaly growth retardation, and sensitivity to ionizing radiation, NKX6-2, the causative gene for Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy and KNG1, the causative gene for High molecular weight kininogen deficiency.

In order for a gene to be marked as stable, an HGNC curator manually reviews the gene symbol to check that this is unlikely to ever be changed in future. During the review of the 209 genes that were marked as stable in the last quarter, no gene symbols were changed and the descriptive names of just seven genes were altered. In most cases this was to make the name more functionally informative – For example, the gene name of NUBPL was updated from “nucleotide binding protein like” to “NUBP iron-sulfur cluster assembly factor, mitochondrial”; EPG5 was updated from “ectopic P-granules autophagy protein 5 homolog” to “ectopic P-granules 5 autophagy tethering factor”; CD3E was updated from “CD3e molecule” to “CD3 epsilon subunit of T-cell receptor” and CD3G was updated from “CD3g molecule” to “CD3 gamma subunit of T-cell receptor complex”.
Updates to placeholder symbols

Since the last newsletter we have continued to work on updating C#orf symbols where possible. The following symbols were all updated based on data in publications:

C11orf49 -> CSTPP1, centriolar satellite-associated tubulin polyglutamylase complex regulator 1
C7orf26 -> INTS15, integrator complex subunit 15
C9orf116 -> PIERCE1, piercer of microtubule wall 1
C15orf65 -> PIERCE2, piercer of microtubule wall 2
C7orf61 -> SPACDR, sperm acrosome developmental regulator

The nomenclature of the FAM71 family was updated following a consultation with researchers working on these genes. The symbol “GARI” had been published for FAM71F2 but this was not a suitable gene symbol for approval because it is a poor search term and is similar to the approved symbol GAR1. The community agreed upon “GARIN” for “golgi associated RAB2 interactor” as a suitable alternative root symbol for the FAM71 family. For genes where the function of the encoded protein has not been confirmed as a golgi associated RAB2 interactor, the term “family member” was added into the gene name. The updates were as follows:

FAM71F2 -> GARIN1A, golgi associated RAB2 interactor 1A
FAM71F1 -> GARIN1B, golgi associated RAB2 interactor 1B
FAM71D -> GARIN2, golgi associated RAB2 interactor 2
FAM71B -> GARIN3, golgi associated RAB2 interactor 3
FAM71A -> GARIN4, golgi associated RAB2 interactor family member 4
FAM71E1 -> GARIN5A, golgi associated RAB2 interactor 5A
FAM71E2 -> GARIN5B, golgi associated RAB2 interactor family member 5B
FAM71C -> GARIN6, golgi associated RAB2 interactor family member 6

Gene Symbols in the News

We bring news of two gene therapy stories, the first is the successful treatment of sickle cell disease via gene editing of the BCL11A gene to switch adults to making fetal hemoglobin rather than the affected adult hemoglobin that causes the red blood cells to ‘sickle’. The treatment is so successful that patients have not needed hospital visits since. The second is in earlier stages and is the first attempt to treat Tay-Sachs disease, caused by mutation of the HEXA gene. A low dose of treatment was delivered to the brain and spine of two young girls, who are now clinically stable with slowed or no disease progression. Further studies will use higher doses of treatment.

A new as yet unnamed neurodevelopmental disorder has been identified that is caused by mutation of the PAX5 gene. After discovering a mutation in one patient, researchers used GeneMatcher to find another 15 patients with PAX5 mutations who all exhibited similar characteristics of developmental delay, intellectual disability and autism spectrum disorder.

An SNP located within a chemokine receptor cluster that affects expression of CCR1, CCR2, CCR3 and CCR5 has been shown to increase the risk of severe COVID-19 disease but lower the risk of becoming infected with HIV. Interestingly, this SNP was inherited from Neanderthals and rose in frequency over 10,000 years ago, suggesting that this may have been due to selective pressure from a virus infecting humans around this time, such as smallpox.

Finally we bring news of a gene variant identified in dog that is responsible for the small size in breeds such as chihuahua and miniature schnauzers. The mutation is carried on a long non-coding RNA gene that is antisense to the insulin-growth factor-1 protein coding IGF1 gene.

Braschi B, Omran H, Witman G.B, Pazour, G.J, Pfister, K.K, Bruford, E.A, King, S.M. Consensus nomenclature for dyneins and associated assembly factors. J Cell Biol. 2022 Feb 7;221(2):e202109014. Epub 2022 Jan 10. PMID: 35006274 PMCID: PMC8754002 DOI: 10.1083/jcb.202109014. Please also read the accompanying guest blog post by Dr Stephen M. King Naming Dynein Components and their Cytoplasmic Associated Factors.

Ho M, Thompson B, Fisk JN, Nebert DW, Bruford EA, Vasiliou V, Bunick CG. Update of the keratin gene family: evolution, tissue-specific expression patterns, and relevance to clinical disorders. Hum Genomics. 2022 Jan 6;16(1):1. DOI: 10.1186/s40246-021-00374-9. PMID: 34991727. PMCID: PMC8733776

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The Military-Industrial-Academic-Political-Scientific Complex

The Military-Industrial-Academic-Political-Scientific Complex

J. Scott Turner

January 24, 2022

Sixty-one years ago, just before leaving office, Dwight D. Eisenhower delivered his farewell address. The most remembered and oft-quoted sentence of that address was an admonition:

In the councils of government, we must guard against the acquisition of unwarranted influence, whether sought or unsought, by the military-industrial complex.

I remember the phrase “military-industrial complex” as a big thing in the sixties. Through that lens, wars were not fought for reasons of compelling national interest, they were fought to enrich defense contractors. It became a convenient trope to the protest culture of the sixties, framing everything from environmental degradation (enriching chemical companies) to public health (enriching pharmaceutical companies) to automobile safety (enriching automobile companies). In all its forms, the innumerable “etc-industrial complexes” were the leavening for protest and political activism, all variations on the same theme: an unseemly and closed relationship of government with favored businesses — and the interests of ordinary people be damned.

Eisenhower had a deeper point, though, sometimes forgotten. It wasn’t just a cabal of military and defense contractors that worried Eisenhower; it was that an emerging “scientific-technological elite,” propped up by burgeoning public spending, would come to dominate, not serve, public policy. The deepening penetration of government funding into the sciences would similarly undermine the value of the sciences. Speaking of the ”technological revolution” then ongoing, Eisenhower wrote:

research has become central . . . more formalized, complex, and costly. A steadily increasing share is conducted for, by, or at the direction of, the Federal government.

. . . the free university, historically the fountainhead of free ideas and scientific discovery, has experienced a revolution in the conduct of research. Partly because of the huge costs involved, a government contract becomes virtually a substitute for intellectual curiosity. . .

The prospect of domination of the nation’s scholars by Federal employment, project allocations, and the power of money is ever present and is gravely to be regarded.

[emphasis mine]

Just one year later, recognizing Eisenhower’s warning of the corrupting influence of growing federal support of research universities, Senator William Fulbright began to speak of the “military-industrial-academic complex.” Fulbright’s concern was primarily over what he regarded as the militarization of academic research, but it’s worth remembering that Eisenhower was warning that the pursuit of federal money would prevail over the curiosity-driven search for knowledge that is the beating heart of the ethos of scientific research.

Shift now to the present day. The “scientific and technological elite” Eisenhower warned about is clearly here, deeply entrenched and wielding enormous power. David Eisenhower, currently a professor in the Annenberg School for Communications, sees the entrenched scientific elite operating in public health authorities’ intervention into civil government. They ostentatiously wear the mask of “science,” but behind that mask lurks a tangled web of collusion between government scientists, non-governmental organizations (NGOs), and foreign governments — all fueled by enormous and unaccountable streams of federal cash.

The technological elites, for their part, have aggrandized such power and influence that they serve as the censorship wing of the scientific elite, and more broadly of the electoral interests of one political party over the other. The enormous federal expenditures for scientific research in the universities that worried Eisenhower in 1961 have continued to grow with nary a blip. In 1961, total federal expenditure for university research was $595 million. Presently, it is more than $50 billion. Among the items we have purchased with that largesse is a stridently politicized and partisan “science” that serves the interests of the “scientific and technological elite” rather than the dispassionate source of knowledge that we, the taxpayers who support the whole edifice, were promised.

The military-industrial complex that so worried Eisenhower has not gone away. Instead, it has morphed into a military-industrial-academic-scientific-political complex that is coming more and more to resemble the corporatism underpinning Italian fascism: a “partnership” of government, industry, and academy that puts its collective interests ahead of individuals. Eisenhower warned that the externalities of federal financial incentives could eventually destroy the ethos of the “solitary inventor, tinkering in his shop.” Despite Eisenhower’s admonition, we continue to hurtle down this highway at ever-increasing speed.

Where is the off-ramp?

Dr. J. Scott Turner is Director of the Diversity in the Sciences Project for the National Association of Scholars.

COMMENT: Thanks Dan,

The Military-Industrial Complex was bad enough, but when research is becoming so colored — by the desire to patent every little trivial discovery — then the collaborative spirit gets lost. No sharing of data, and no real exchange of ideas or problem-solving anymore. This is very sad! ☹

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FW: Effects of Lockdowns on COVID-19 Mortality: Literature Review & Meta-Analysis

I’ll try to cover this topic from a statistical and logical standpoint — and not from any political ramifications. This systematic review of the literature and meta-analysis were designed by: Professor Steve H. Hanke, Founder and Co-Director of The Johns Hopkins Institute for Applied Economics, Global Health, & the Study of Business Enterprise, Baltimore, MD, USA; Jonas Herby, MA economics, Special Advisor at Center for Political Studies in Copenhagen, Denmark; and Lars Jonung, Professor Emeritus in Economics at Lund University, Sweden. [See attached 62-page publication.] This topic is (tangentially?) related to gene-environment interactions. 😊

They wished to determine whether there is empirical evidence to support the hypothesis (“belief”) that “lockdowns” decrease COVID-19 mortality. Lockdowns are defined as “the imposition of at least one compulsory, non-pharmaceutical intervention (NPI); NPIs are any government mandate that directly restricts people’s possibilities, such as policies that limit internal movement, close schools and businesses, and ban international travel.”

This study employed a systematic search and screening procedure in which 18,590 studies were identified that could potentially address the hypothesis posed. After three levels of screening, 34 studies ultimately qualified. Of those 34 eligible studies, 24 qualified for inclusion in their meta-analysis. These 24 studies were separated into three groups: lockdown stringency index, shelter-in-place-orders (SIPOs), and specific NPI studies. Analysis of each of these three groups supported the conclusion that lockdowns have had little, to no, effect on COVID-19 mortality. More specifically, stringency index studies revealed that lockdowns in Europe and the United States only reduced COVID-19 mortality by 0.2% on average. SIPOs were also ineffective, only diminishing COVID-19 mortality by 2.9% on average. Specific NPI studies also find no broad-based evidence of noticeable effects on COVID-19 mortality.

Whereas this meta-analysis concludes that lockdowns have had little to no public health effects, they have imposed enormous economic hardships and social costs — at locations where they have been adopted. Consequently, authors conclude that lockdown policies are ill-founded; and they should be rejected as a “pandemic policy instrument.” ☹

Please study these 62 pages meticulously; there will be a quiz on this, next Friday morning. 😉

COMMENT: RP Hence, the Swedish model might be a better approach — if we ever have such a pandemic again?

COMMENT: WM Diminishing mortality is not the same as ‘having little to no public health effects.’ Although ‘NPIs’ may have short-term benefits, such as decreased hospitalization rates, which should lessen the impact on non-Covid patients and certainly decrease stress and drop-outs among health care workers, we unfortunately know very little about long-term ‘public health effects.’ Distinguishing effects of ‘NPIs’ from effects of immunizations will be very difficult, because the same populations either favor or oppose both. Long-term medical effects are already being seen in adult patients and in infants born to COVID-infected mothers.

A retrospective “meta-analysis” of 24 studies “cherry-picked?” from 18,590 studies does not strike me as having scientifically valid predictive value. The greatest weakness that physicians, healthcare workers, and health policy makers exhibit — is a profound reluctance to admit “WE DON’T KNOW.” Advocates on both ends of the political spectrum about COVID policy would be wise to remember that we just don’t know most of the answers (and probably will not know for many years).
In the words of one of America’s most noted philosophers, Yogi Berra, “It’s tough to make predictions … especially about the future.”

COMMENT: R D’A his study was headline news on the Drudge Report the other day. I hope they also undertake a study on mask wearing. Surely the data behind the studies selected are dirty; surely the authors know this. I wonder how the statisticians dealt with that.
I am not going to plow through 62 pages. Right off the bat, I wonder how good the death counts are — when hospitals are being offered $35,000 for each death coded as COVID-related.

COMMENT CBG – HANK YOU for sending this to everyone. This study has been slammed by Forbes (and also on Twitter, but there are many cogent arguments against this paper). I suspect that at least one of the authors is seeking to use this to support his ongoing argument against lockdowns in Sweden. This study would have been more credible if it had involved expertise beyond economists, and if it involved people who were truly objective and dispassionate.
NPIs could also include a mandate to wear a mask. But still very interesting to read.
Thanks again and warmest regards

COMMENT M I-H Yes, Sweden chose the right approach to this pandemic — from the very beginning..!!! No lockdowns, masks always optional, never mandated.

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HGNC Newsletter Autumn 2021

Some of you will be interested in the latest news in the Human Gene Nomenclature Committee (HGNC) autumn issue ot their NewsLetter.

Autumn newsletter 2021

Newsletters · 26 Nov 2021
New links to GenCC

We are pleased to announce that HGNC now displays links from our Symbol Reports to curated gene-disease relationships in the GenCC (The Gene Curation Coalition) database. The HGNC is a member of the GenCC project that brings together multiple groups that are either directly involved in gene-disease curation or that promote standards needed to support this curation. Genes reported as being associated with disease by the GenCC project are on the HGNC’s priority list for gene symbol stabilisation.

The new links to GenCC can be found in the Clinical Resources section of our Symbol Reports, as shown for the ATXN1 Symbol Report below:

Recommendations for reporting gene fusions

HGNC has worked with the scientific community to determine a new standard for describing human fusion genes – recommending the use of a double colon (::) to separate the two gene symbols involved in the gene fusion, e.g., BCR::ABL1. You can read our new article, “HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions” for full details as to why the double colon was chosen. In brief, gene fusions in the majority of publications have been denoted by use of either a hyphen (-) or a forward slash (/), but these two characters can result in confusion as they are used to denote many other concepts, such as readthrough transcripts and pathway descriptions.

As usual, the HGNC has been collaborating and communicating with as many other groups and resources as possible to ensure that this standardisation is supported and applied across the biomedical sphere. The new recommendation for use of the double colon is supported by:

HGVS (Human Genome Variation Society)
ISCN (International System for human Cytogenetic Nomenclature)
WHO Classification of Tumors
Atlas of Genetics and Cytogenetics in Oncology and Haematology
Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer
Tumor Fusion Gene Data Portal

Update on genes with the ‘stable’ tag

HGNC curators have been working hard to continue adding the ‘stable’ tag to genes in the last quarter. As of November 19th 2021, we have 2612 stable symbols — an increase of 169 since our previous newsletter. As described in our September blog post Stability in the time of COVID-19, we have recently been prioritising review of the nomenclature of genes linked to COVID-19.

Not surprisingly, the number of publications associated with these genes has greatly increased since the beginning of 2020; for example, the symbol ACE2 appears in PubMed 3586 times in 2020 and 3941 times so far in 2021, compared to 157 times in 2018 and 173 times in 2019. We used the COVID-19 UniProtKB webpage as our source of human genes related to COVID-19. The 81 proteins encoded by the human genome listed on that webpage include immune related genes, transcription factors, enzymes and receptors: we have been able to add the stable tag to over 85% of the relevant gene symbols. The symbol stability review has resulted in the change of just one gene symbol in the last quarter — since the publication of the blog post, we have now updated PHB (HGNC:8912) to the more search-friendly symbol PHB1, with the added advantage that the human gene symbol is now consistent with the yeast PHB1 and nematode worm phb-1 gene symbols.
Updates to placeholder symbols

Over the last three months, the HGNC has been able to update a number of C#orf symbols to symbols with the root CFAP# (based on the identification of the gene as the ortholog of a gene with the FAP#, flagellar associated protein, nomenclature in Chlamydomonas), there has been a further update — based on identification of the gene product as part of a complex, and one based on a change of locus type from protein-coding to long non-coding RNA:

C9orf135 -> CFAP95, cilia and flagella associated protein 95
C1orf158 -> CFAP107, cilia and flagella associated protein 107
C1orf189 -> CFAP141, cilia and flagella associated protein 141
C1orf194 -> CFAP276, cilia and flagella associated protein 276
C5orf51 -> RIMOC1, RAB7A interacting MON1-CCZ1 complex subunit 1
C11orf45 -> KCNJ5-AS1, KCNJ5 antisense RNA 1

New gene groups

We have worked on our Nuclear hormone receptors gene group hierarchy to make the subgroups consistent with the IUPHAR/BPS Guide to Pharmacology nuclear hormone receptor pages. This group now has the following subgroups (as displayed on the Nuclear hormone receptors gene group page):

An example subgroup, Estrogen receptors (ESR), is shown below. The link to the appropriate IUPHAR page is found towards the bottom of the Gene group report:

Gene Symbols in the News

A new study may explain why certain apes, including humans, do not have tails — these apes have an Alu element insertion within a noncoding region of the TBXT (T-box transcription factor T) gene, while this insertion is not found in primates that have tails.

A study has identified the olfactory receptor that is necessary for us to detect caramel-type smells. The OR5M3-encoded receptor is activated by only two odorants, furaneol, which allows us to smell caramel notes in food such as coffee and strawberries, and homofuraneol, which gives a caramel-type smell to durian and other fruits.

In many parts of the world, humans are growing taller and reaching puberty at an earlier age. New research pins the MC3R (melanocortin 3 receptor) gene, which encodes a receptor expressed in the brain, as the link between accessibility of food and this accelerated growth and development.

In COVID-19 news, a variant of the previously little-studied LZTFL1 (leucine zipper transcription factor-like 1) gene, which is present in a higher proportion in people of South Asian descent, has been associated with a doubling in risk of death from COVID-19. The current hypothesis for this association is that the risky LZTFL1 variant blocks a protective mechanism in lung cells that would reduce the amount of ACE2 protein on the lung cell surface.

A different gene, APOL1 (apolipoprotein-like 1), has been associated with more severe COVID-19 disease in African Americans, based on a study of patients admitted to the Hospital of the University of Pennsylvania. The same gene variant was also linked to increased risk of developing sepsis.

A separate study on young, critically ill patients with COVID-19 who had no known underlying health conditions used machine learning to identify genes that were more active in these patients. One of the identified loci was the ADAM9 (ADAM metallopeptidase domain 9) gene; in vitro studies suggest that higher levels of the ADAM9 gene product is associated with an increase in SARS-CoV-2 virus duplication.
Relevant publication:

Braschi B, Seal RL, Tweedie S, Jones TEM, Bruford EA. The risks of using unapproved gene symbols. Am J Hum Genet 2021 Oct 7; 108(10): 1813-1816. doi:10.1016/j.ajhg.2021.09.004 PMID:34626580

Please also see our companion blog post to this article “The risks of using unapproved symbols”.

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Masks Work to Prevent COVID-19


Looks like “masks might help to some extent, and of course depending on the type of mask.” This article today from MedScape.
Large Study Affirms What We Already Know: Masks Work to Prevent COVID-19
Brenda Goodman, MA
September 03, 2021

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action (IPA), a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions — or local governmental districts in Bangladesh — and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that if anything, we think that that is a substantial underestimate,” Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they only tested people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that among people who had symptoms, only one third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers ― two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared to 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50 to 60 years who wore surgical masks were 23% less likely to test positive for COVID compared to their peers who didn’t were masks. For people older than 60, the reduction in risk was greater — 35%.

Rigorous Research
The study took place over a period of 8 weeks in each district. The interventions were rolled out iwaves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym ― NORM.

N, for no-cost masks;
O, for offering information through the video and local leaders;
R, for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wearing it correctly;
M, for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Styczynski said that nothing else ― neither text message reminders, nor signs posted in public places, nor local incentives ― moved the needle on mask wearing.

Saving Lives and Money

The study found that the strategy was cost-effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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Time to sober up

Finally, we have the analysis by a rational “applied economist.” More than 40 years of precise satellite-measured global atmospheric temperatures — have concluded that the “warming” is 0.14 deg.C per decade [which seems reasonable, given that the planet is just coming out of the (1300-1870 A.D.) Little Ice Age].

Is each taxpaying citizen in the Western World willing to pay $10,000 or $100,000 per year to “save the planet from this horrible calamity?” And right now, Earth is much cooler than the three “Warm Periods” that are known to have existed during just the last 3500 years. Let’s get real…

The rise or fall of climate change mitigation

By David L. Debertin

Applied economist and therefore social scientist [retired]

I have become convinced that whether or not the public is willing to invest a lot of their personal income or favor spending a lot of tax dollars on strategies aligned with the climate change activists will depend not on data and science related to things such as sea level change, measurement of melting glaciers, the status of the polar bears, whether or not hurricanes, floods and tornados have become more or less frequent on average or any of the rest of the stuff we see plastered all over the media each and every day, but rather something much simpler. Instead, what concerns most of the public is what I call a set of “kitchen table” issues. Can I keep doing what I have been doing, pretty much, or will this mean that the cost of what I want to continue to do will rise significantly even accounting for the usual inflation over time?

People love it when something costs less and less over time in inflation-adjusted dollars. That has happened for goods such as personal computers and flat-panel TV sets. The consequence of this is that people quickly bought up a lot more computers and TV sets than they might have purchased if either of these cost ever more and more even for the same speed and quality. Indeed, a lot of economic growth hinges on people getting more and more for less and less, as measured in inflation-adjusted dollars.

Given that, the public generally is rightfully wary of any technology that keeps costing more and more to do the same or less than before. For example, if electricity from wind and solar ends up costing more and more per kilowatt hour than electricity made by using coal and natural gas, and as a consequence, heating and cooling a home, keeps costing more and more even when measured in inflation-adjusted dollars, the vast majority of consumers are not going to push for a conversion from fossil fuels to wind and solar. Now if the technology were such that the wind and solar electricity kept costing less and less than the electricity coming from fossil fuels, that is another matter entirely, and conversion by both the public and the power suppliers would be rapid.

The vast majority of the public care nothing for esoteric arguments related to computer simulations of how the earth would be if the global temperature rose by 1.5 degrees C. If the fossil to renewable conversion also reduces the amounts of additional carbon dioxide going into the atmosphere, fine, but the public is not naïve enough to believe that if the US converted all electricity production were moved from fossil fuels to solar., that the mitigation in the rise in global temperature is going to be even noticeable from anywhere in the world. Maybe instead of 1.5 degrees because the US adopted all- renewable electricity then instead of rising 2 degrees C, the global temperature rose only 1.99995 degrees C on account of the extreme steps US residents took but so what? Most of the rest of the world still gets most of its electricity by burning fossil fuels and these countries are not in a financial position to convert to a higher-cost method.

Still, the activists in the US are very self-absorbed and pleased with themselves in showing the world how the public is better off using expensive electricity not the cheap stuff like that the people in India and China use. The global temperature changed only a trivial amount after spending billions and billions of money in the US was simply for show.

A number of years ago none other than resource economists at UC Berkeley did a study that revealed the primary motivation homeowners had for putting solar panels of their houses was not because they were doing something to limit climate change or making an attempt to save the planet, nor for that matter saving money on electricity. The primary reason was to communicate to their neighbors that they too were environmentalists concerned for the planet. The solar panels, fundamentally, were an ego trip to impress the neighbors up the block. It mattered not that they actually accomplished anything positive other than impressing the neighbors and communicating to them their core liberal values.

Newsom has announced that after a certain date, lawn mowers, blowers and other lawn maintenance tools could no longer be sold in California if they are gasoline-powered. These tools must be electric-powered (with electricity from wind and solar power, of course). Much of California is known for having million-dollar+ houses on postage stamp-sized lots. I think you could find a battery-powered lawn mower that might be able to do 1/3 of an acre on a single charge, but that would be pressing it. No matter, Californians generally cannot afford to live on 1/3 acre lots anyway, and anyone who can afford to spend 3 million on a home on a third acre probably is wealthy enough to hire a gardener, and what the gardener must use is not the homeowner’s problem!

Apparently, the kinds of lawn care equipment that owners of larger than city-sized lots ordinarily use has yet to attract the attention of the governor. Still, once the banning of the sale of new lawn mowers and blowers that run on fossil fuels, I expect a thriving on-line market for only very slightly used gas-powered equipment popping up, and a booming business for California mechanics capable of keeping the old gas mower running for yet another season or two.

These proclamations by leaders regarding what can and cannot be sold new are always very interesting. I guess California now thinks they can put a specific date on when the last new fossil fuel-powered vehicle can be sold in the state as well. But equally interesting is that generally these proclamations usually do not apply to vehicles a person already owns or to private transactions involving the sale of used vehicles. Is the governor of California really going to tell me I can’t sell my fossil fuel-powered vehicle to a neighbor of mine but must junk it instead? And if the moratorium applies only to new vehicles, how many miles does a new vehicle have to be driven before it is no longer new but qualifies as used. And aren’t the mechanics going to have great businesses keeping fossil-fuel powered vehicles running well past their expiration dates? California could end up being “Cuba-west”. My motor vehicle is even older than my gasoline-powered lawn mower!

At some point all of this merely becomes silly. California has long been a lab for half-baked political pronouncements with the idea that if Californians are forced to do it, they will somehow start a trend that the rest of the US will follow in a year or two. But people in a lot of other states seem to react very negatively to pronouncements from On-High, federal or state.

All-electric-vehicles (EVs) for everyone in the world? Why? How do those work in states where wintertime temperatures routinely go to -20 degrees F or lower? What is the range on an electric vehicle if the outdoor temperature is -20F not 70F? Are you serious if you think the range numbers based on a 70-degree day — are the same when the outdoor temperature is -20F? Do you really think the public is that stupid? That batteries generally perform less well in cold temperatures is well-known science and anyone who thinks otherwise is in fact a “science denier.”

I actually have a lot of confidence in the ability of the public to sort this all out, and veto all the ideas that are stupid whether they involve stuff the government is forcing or the neighbor is trying to do. The public will dump politicians promoting crazy stuff, eventually, at least most of the time. Right now, if the developed nations did all the things the activists are promoting, chances are the global temperature would not be affected by more than an inconsequential amount. The activists really do not want to believe this, instead thinking it is merely a matter of the public getting engaged in order to “save the planet from climate change.” No proof of that, whatsoever! The activists are delusionary, treating closely-held values as if they had somehow magically morphed into scientific fact.

Climate Derangement Syndrome

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Researchers discover a gene that doubles risk of death from COVID-19

This should be of interest to some of you. As is often the case in Gene-Environment Interactions, patients having a particular allelic variant of their LZTFI gene, exhibit a different response to the incoming signal (i.e., SARS-CoV-2 virus) that causes COVID-19. That such “genetic differences in response” would be found has been predicted by various research groups including [Godri Pollitt KJ et al., COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission. Hum Genomics May 2020; 14: 17. doi: 10.1186/s40246-020-00267-3 PMID: 32398162].

The cutting-edge techology used to find this regulatory gene (with the help of artificial intelligence; AI) is noteworthy, as this features a whole new avenue of investigative approach to genomic medicine. 😊 This article, just out of embargo today, will appear within the next few days in Nature Genetics.


Researchers discover a gene that doubles risk of death from COVID-19
Scientists at Oxford University have identified the gene responsible for doubling the risk of respiratory failure from COVID-19. Sixty percent of people with South Asian ancestry carry the high-risk genetic signal, partly explaining the excess deaths seen in some UK communities, and the impact of COVID-19 in the Indian subcontinent.

Previous work has already identified a stretch of DNA on chromosome 3 which doubled the risk of adults under 65 of dying from COVID. However, scientists did not know how this genetic signal worked to increase the risk, nor the exact genetic change that was responsible.

In a study published in Nature Genetics, a team lead by Profs. James Davies and Jim Hughes at the University of Oxford’s MRC Weatherall Institute of Molecular Medicine used cutting-edge technology to work out which gene was causing the effect, and how it was doing so.

Study co-lead Prof Jim Hughes, Professor of Gene Regulation, said: ‘The reason this has proved so difficult to work out, is that the previously identified genetic signal affects the “dark matter” of the genome. We found that the increased risk is not because of a difference in gene coding for a protein, but because of a difference in regulatory DNA that makes a switch to turn a gene on. It’s much harder to detect the gene which is affected by this kind of indirect switch effect.’

The team trained an artificial intelligence (AI) algorithm to analyze huge quantities of genetic data from hundreds of types of cells from all parts of the body, to show that the genetic signal is likely to affect cells in the lung. Then using a highly accurate technique they had only just developed, the researchers could zoom down on the DNA at the genetic signal. This examines the way that the billions of DNA letters fold up to fit inside a cell to pinpoint the specific gene that was being controlled by the sequence causing the greater risk of developing severe COVID-19.

Dr Damien Downes, who led the laboratory work from the Hughes research group, said: ‘Surprisingly, because several other genes were suspected, the data showed that a relatively unstudied gene called LZTFL1 (leucine zipper transcription factor-like 1) causes the effect.’

The researchers found that the higher risk variant of the gene probably prevents the cells lining airways and the lungs from responding to the virus properly. But, importantly, it doesn’t affect the immune system, so the researchers expect people carrying this version of the gene to respond normally to vaccines.

The researchers are also hopeful that drugs and other therapies could target the pathway preventing the lung lining from transforming to less specialised cells — raising the possibility of new treatments customized for those most likely to develop severe symptoms.

Study co-lead Prof James Davies, who worked as an NHS Consultant in Intensive Care Medicine during the pandemic and is an Associate Professor of Genomics at Oxford University’s Radcliffe Department of Medicine, said: ‘The genetic factor we have found explains why some people get very seriously ill after coronavirus infection. It shows that the way in which the lung responds to the infection is critical. This is important because most treatments have focussed on changing the way in which the immune system reacts to the virus.’

Sixty percent of people with South Asian ancestry carried this higher-risk version of the gene, compared to 15 percent of those with European ancestry – explaining in part the higher death rates and hospitalisations in the former group. The study also found that 2 percent of people with Afro-Caribbean ancestry carried the higher risk genotype, meaning that this genetic factor does not completely explain the higher death rates reported for black and minority ethnic communities.

Prof Davies explained: ‘The higher risk DNA code is found more commonly in some black and minority ethnic communities, but not in others. Socioeconomic factors are also likely to be important in explaining why some communities have been particularly badly affected by the COVID-19 pandemic.

‘Although we cannot change our genetics, our results show that the people with the higher risk gene are likely to particularly benefit from vaccination. Since the genetic signal affects the lung rather than the immune system, it means that the increased risk should be cancelled out by the vaccine.’

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