Possible function found for intronic RNA segments (in yeast) ???

The present GEITP topic here is something that might revolutionize our thinking about RNA processing in all eukaryotes (i.e. organisms such as yeast or human having chromosomal pairs, as opposed to prokaryotes such as bacteria that have single unpaired chromosomes). RNA molecules that are newly transcribed from DNA — contain intron and exon sequences. Introns are excised by means of a process called “RNA splicing”, during which the remaining exon sequences are joined together (ligated) to form mature messenger RNA (mRNA), which is then translated into protein. RNA splicing releases a lariat-shaped intron that is rapidly converted (debranched) to a linear form, and then degraded. Much of what we know about the molecular machinery — the spliceosome and its associated factors — and the mechanisms of splicing has come from genetic and biochemical experiments using baker’s yeast (Saccharomyces cerevisiae).

Many studies have suggested that most yeast introns can be removed with little consequence for the cell. Two articles [see attached] now challenge this view — by showing that introns help yeast cells in culture to sense a lack of essential nutrients in their growth medium and to adjust the rate of cell growth to adapt to this change in environment. Although the splicing machinery has been highly conserved during evolution, we must keep in mind that gene architecture is complex and varies across organisms.

However, the yeast genome is highly streamlined — in comparison with those of most other eukaryotes (i.e. the group of organisms that include plants, fungi and animals). Approximately 5% of protein-coding genes in yeast contain introns, and only nine genes contain more than one intron. By contrast, 90% of genes in mammals contain introns, with an average of eight introns per gene. In yeast, as in other organisms, “introns have been viewed as an dispensable by-product of exon ligation”, because of their rapid degradation after splicing.

Authors [see first article] systematically deleted all known introns in yeast genes. In most cases, cells with all introns deleted — growth was found to be impaired — when nutrients are depleted; this effect of introns on growth is not linked to expression of the host gene, and was reproduced even when translation of the host mRNA into protein was blocked. Authors found that introns promote resistance to starvation by enhancing the repression of ribosomal protein genes downstream of the nutrient-sensing TORC1 (yeast equivalent of the mammalian Target Of Rapamycin Complex-1, a protein complex that functions, also in mammals, as a nutrient/energy/redox sensor and controls protein synthesis) and PKA (protein kinase-A, which is mammals has functions such as regulation of glycogen, sugar, and lipid metabolism) pathways.

Authors [see 2nd article] excised 34 introns in yeast and found that — despite being rapidly degraded in log-phase growth — the introns accumulated as linear RNAs, under conditions of either saturated-growth, or other stresses that cause prolonged inhibition of TORC1. Introns that became stabilized — remained associated with components of the spliceosome, and differed from other spliceosomal introns in having a short distance between their lariat branch point and the 3′ splice site (which is necessary and sufficient for their stabilization).

Deletion of these introns is therefore disadvantageous in saturated conditions and causes aberrantly high growth rates in yeast that are chronically challenged with the TORC1 inhibitor (rapamycin). Re-introduction of native, or engineered, stable introns suppresses this aberrant rapamycin response. Thus, excised introns function within the TOR growth-signalling network of S. cerevisiae and, more generally, excised spliceosomal introns appear to have biological functions. Collectively, the data from both papers reveal functions for introns — which might help to explain their evolutionary preservation in genes, and the results uncover regulatory mechanisms of cell adaptations to starvation. Lastly, as is commonly the case, “if it happens in yeast, don’t be surprised if it also happens in mammals including humans.” )

DwN

Nature 31 Jan 2o19; 565: 606–611 & 612–617 [two articles] & 578-579 [editorial]

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Can Big Science Be Too Big?

This article is from the Science section of the New York Times this last week. I had the “gut feeling” that this was true, but now we have an actual mathematically quantifiable study to demonstrate this conclusion.

DwN
A new study finds that small teams of researchers do more innovative work than large teams do.
Modern science is largely a team sport, and over the past few decades the makeup of those teams has shifted, from small groups of collaborators to ever larger consortiums, with rosters far longer than that of the New England Patriots. Answering big questions often requires scientists and institutions to pool resources and data, whether the research involves detecting gravitational waves in deep space, or sorting out the genetics of brain development.

But that shift has prompted scientists to examine the relative merits of small groups versus large ones. Is supersizing research projects the most efficient way to advance knowledge? What is gained and what, if anything, is lost?

Now they have at least the beginning of an answer. In the largest analysis of the issue thus far, investigators have found that the smaller the research team working on a problem, the more likely it was to generate innovative solutions. Large consortiums are still important drivers of progress, but they are best suited to confirming or consolidating novel findings, rather than generating them.

The new research, published on Wednesday in the journal Nature, is the latest contribution from an emerging branch of work known as the science of science — the study of how, when and through whom knowledge advances. The results could have wide-ranging implications for individual investigators, the academic centers that employ them and the government agencies that provide so much of the financing.

“There has been a huge amount of debate in the scientific community about the effects of moving to larger research teams,” said Albert Lazlo Barabasi, a professor of network science at Northeastern University, who was not involved in the research. “This new paper gives us a way to resolve the debate. It’s an enormous contribution.”

In the study, a trio of investigators led by James A. Evans, a sociologist at the University of Chicago, mined selections from three vast databases: the Web of Science, using more than 42 million articles published since 1950; the United States Patent and Trademark Office, with 5 million patents granted since 1976; and GitHub, with 16 million software projects posted since 2011.

By working backward, the research team, which included Dashun Wang of Northwestern University and Lingfei Wu of the University of Chicago, analyzed the pattern of citations generated by each paper or project. The content of the citations was the crucial indicator, not their number. Truly original contributions, such as Einstein’s general theory of relativity, published in 1915, are cited extensively by later papers. But, notably, those later papers do not cite the same research that the original did: that work marks a clean break from the past.

More incremental articles, by contrast, tend to be widely cited by later papers, but they are referenced along with a sizable chunk of their own citation list. These papers represent not a sharp bend in the river, but a steady, deepening stream.

Based on these differences in citation content, Dr. Evans and his team rated papers and projects on a measure of “disruption.” Nobel Prize-winning papers tended to cluster at the top of this disruption scale; they were also more likely to be mentioned by current leaders in each field of science, in phone surveys by the research team.

When the team correlated this disruption rating to the size of the group responsible for the project or paper, they found a clear pattern: smaller groups were more likely to produce novel findings than larger ones. Those novel contributions usually took a year or so to catch on, after which larger research teams did the work of consolidating the ideas and solidifying the evidence.

“You might ask what is large, and what is small,” said Dr. Evans. “Well, the answer is that this relationship holds no matter where you cut the number: between one person and two, between ten and twenty, between 25 and 26.”

It also holds within every field in science, whether physics, psychology, computer science, mathematics, or zoology, he added: “You see it within field, within topics. And two-thirds of the effect we found is within the individual. That means that if I’m writing a paper, and I partner with one other person, or two, the result is less disruptive with each person I add.”

Psychologists have found that people working in larger groups tend to generate fewer ideas than when they work in smaller groups, or when working alone, and become less receptive to ideas from outside. Why that would be — isn’t entirely clear, but it runs counter to intuition, said Suparna Rajaram, a professor of psychology at Stony Brook University.

“We find that the product of three individuals working separately is greater than if those three people collaborate as a group,” Dr. Rajaram said. “When brainstorming, people produce fewer ideas when working in groups than when working alone.”

There are upsides to working in groups, Dr. Rajaram said. Over time, group members learn a lot from each other, and incorporate that knowledge. “But overall, this new study provides findings on a large scale that are consistent with the underlying principles of our work,” she said.

It makes sense that science has shifted toward a large-team model. Large teams have clout; they typically include a number of prominent, influential figures at big-name institutions. They attract some of the best younger scientists, who gain a career boost by signing on. And these trends, in turn, lead to more published papers, promotions, grants and tenured positions.

The new study suggests that a different kind of funding approach may be needed, one that takes more risk and spends the time and money to support promising individuals and small groups, Dr. Evans said.

“Think of it like venture capitalists do,” he said. “They expect a 5 percent success rate, and they try to minimize the correlation between the businesses they fund. They have a portfolio, one that gives them a higher risk-tolerance level, and also higher payoffs.”

Benedict Carey has been a science reporter for The Times since 2004. He has also written three books, “How We Learn” about the cognitive science of learning; “Poison Most Vial” and “Island of the Unknowns,” science mysteries for middle schoolers.

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Aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease

As these GEITP pages have discussed previously, the ligand-activated transcription factor aryl hydrocarbon receptor (AHR), is one of 110 members of the human BHLH gene superfamily of sensors that continuously monitor incoming signals (both exogenous and endogenous i.e. from both outside, and within, the organism) that can affect each cell type, one way or another (these signals include oxygen tension, redox potential, temperature, osmotic pressure, and many types of endogenous and exogenous chemicals). Cells are constantly adapting and responding to these molecular signals in their micromilieu — provided by environment, diet, commensal flora (i.e. all beneficial virus-bactera-fungus that live synergistically within our bodies), and host metabolism. AHR is a member of a BHLH subset, called the basic helix-loop-helix periodic circadian protein (Per)–AHR nuclear translocator (ARNT)–single-minded protein (Sim) (bHLH/PAS), which comprises ~30 members.

Table 1

Summary of organs, systems,cell functions, and developmental biology in which AHR-signaling is involved. Location AHR-signaling pathway involvement

Central nervous system — Development of brain and nervous system; Neurogenesis; Neuronal cell development; Cardiorespiratory brainstem – development in ventrolateral medulla; “Brain-gut-microbiome”

Eye — Ciliary body formation and function; Thyroid-associated eye disease

Gastrointestinal tract — Development of GI tract; Rectal prolapse during aging; “Brain-gut-microbiome”

Heart — Development of heart organ; Cardiovascular physiology; Atherogenesis; Cardiomyogenesis; Cardiorespiratory — functions

Hematological system — Development of blood cell-forming system; Hematopoiesis; Activation or suppression of erythroid development

Immune system — Immune system development; The immune response; Innate immunity; Pro-inflammatory response; Anti-inflammatory response; Immunomodulatory effects

Inner ear — Development of the cochlea

Kidney — Development of the kidney; Hypertension

Liver — Development of liver organ; Hyperlipidemia; Glucose and lipid metabolism; Hepatic steatosis

Musculoskeletal system — Transmesoderm ? osteoblast transition; Bone formation; Osteoclastogenesis

Pancreas — Development of pancreas; Beta-cell regulation; Pancreatic fibrosis

Endocrine system — Serum lowered testosterone levels; Infertility; Mammary gland duct cell epithelial hyperplasia; Degenerative changes in testis; Gerrm-cell apoptosis; Endometriosis

Reproductive system — Development of male and female sex organs; Spermatogenesis; Fertility

Respiratory tract– Development of respiratory tract; Disruption of GABA-ergic transmission defects; Cardiorespiratory function

Vascular system — Angiogenesis; Atherosclerotic plaque formation

Skin– Barrier physiology; Atopic dermatitis

Cellular functions — Cell migration; Cell adhesion; Circadian rhythmicity

DNA changes — DNA synthesis; DNA repair; DNA-adduct formation; Mutagenesis

Oxidative stress — Mitochondrial ROS formation; Anti-oxidant protection against ROS formation; Mitochondrial H2O2 production; Crosstalk with hypoxia and HIF-signaling pathways; Transforming growth factor-signaling pathways; MID1-PP2A-CDC25B-CDK1 signaling pathway regulating mitosis

Tumor cells– Growth suppression; Tumor initiation; Tumor promotion

ES cell basic functions — Ectoderm ? epithelium transition; Cell adhesion; Cell-cycle regulation; Apoptosis; Cavitation during morula? blastula formation; Activator of Rho/Rac GTPases; WNT-signaling pathways; Homeobox-signaling pathways

Other basic functions — Transgenerational inheritance; Epigenetic effects; Chromatin remodeling; Histone modification; Aging-related and degenerative diseases

After discovery of the Per locus (in the fly) in 1971, AHR was the second bHLH/PAS member discovered 3 years later; AHR is now known to carry out functions in virtually every cell-type of the body — resulting in regulation of critical life processes, as well as protecting against disease and causing disease [reviewed in Progr Lipid Res 2017; 67: 38-57]. In the attached review, authors describe updated information about AHR participation in the immune response. Authors suggest that “studying AHR regulation and function is likely to reveal unknown biological processes and may guide the development of novel therapeutic interventions.” My opinion strongly disagrees with this suggestion: i.e. any gene/gene product expressed from the fertilized cell and embryonic stems cells — and then throughout development and all the way to carrying out critical life functions in virtually every cell-type — will be a difficult drug target (down- or up-regulating AHR, other than only specifically that one cell type, will lead to many so-called ‘off-targets’ that might cause detrimental clinical effects).

Authors [see attached review] summarize current knowledge on the role of AHR in autoimmune disorders and cancer of the central nervous system (CNS). AHR is described as a transcription factor that integrates environmental, dietary, microbial, and metabolic cues to control complex transcriptional programs in a ligand-specific, cell-type-specific, and context-specific manner. Authors update and recapitulate current knowledge of AHR and the transcriptional pathways it controls in the immune system. Lastly, authors discuss the purported role of AHR in autoimmune diseases and neoplasia (cancer) of the CNS, with special focus on the gut immune system, the brain-gut-microbiome axis, and the “therapeutic potential of targeting AHR” in neurological disorders.
DwN
Nat Rev Immunol 4 Feb 2o19; doi: 10.1038/s41577-019-0125-8. [Epub ahead of print]

COMMENT:
Nancy, this is an excellent point you make, which needs to be scrutinized closely. No doubt my opinion (which has changed, over the decades) has been strongly influenced by advances in developmental biology research over the past two decades. We now know that a relatively small subset of genes (perhaps 150? 200? 400?) become expressed in [a] the fertilized zygote and/or pluripotent embryonic stem cells, whereas the vast majority of genes are [b] first expressed later during embryogenesis, or during fetogenesis in specific organs/tissues, or in the neonatal period and beyond. The key difference, in my mind, is that AHR is in the former category, whereas steroid receptors (and other successful druggable targets) are in the latter category.

Perhaps it was just serendipity (dumb luck) during my 50+ year career, but my lab stumbled onto the discovery of (not one, but) two such genes in the former category: Ahr (mouse) and AHR (human) and then Slc39a8 (mouse) and SLC39A8 (its human ortholog). Because AHR is expressed in the fertilized zygote and therefore “expressible, as needed” in virtually every cell-type beyond that (i.e. during embryogenesis, fetogenesis, neonatal period and later) — it plays critical “yin-yang” roles in essentially every cell-type and organ [as summarized in table (below) from the 2o17 review]. The same story is still developing (but is probably two decades behind) — for the SLC39A8 (ZIP8) transporter of divalent cations. Therefore, Nancy, to answer your question: any inhibition or overexpression of AHR in one cell-type is VERY likely to perturb AHR regulation in other cell-types (so-called “off-targets”), often leading to undesirable, or lethal, side-effects.

For the sake of grant-writing and discussing in invited reviews, however, it’s always helpful for the Principal Investigator/Author to propose clinical relevance, translational research, and benefitting humankind. These terms bring in more research money in the future.

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Two or more diet beverages a day is linked to high risk of stroke, heart attacks

Two or more diet beverages a day is linked to high risk of stroke, heart attacks
Nebert, Daniel (nebertdw)

For a change-of-pace on these GEITP pages, below is a perplexing article today from CNN_News.com, describing an epidemiology study. Needless to say, “Correlation does not prove causation” — although these data are very interesting. And troubling. Artificial sweeteners are definitely interacting with clinically relevant genetic pathways and/or 2nd-messenger signaling, probably (directly or indirectly) in the central nervous system, which then interferes with normal endocrine regulatory functions.

Drinking two or more diet beverages a day linked to high risk of stroke, heart attacks

By Sandee LaMotte, CNN
1:23 PM ET, Fri February 15, 2019

(CNN) More bad news for diet soda lovers: Drinking two or more of any kind of artificially sweetened drinks a day is linked to an increased risk of clot-based strokes, heart attacks and early death in women over age 50, according to a new study by the American Heart Association and American Stroke Association.

The risks were highest for women with no history of heart disease or diabetes and women who were obese or African-American.

Previous research has shown a link between diet beverages and stroke, dementia, Type 2 diabetes, obesity and metabolic syndrome, which can lead to heart disease and diabetes.

“This is another confirmatory study showing a relationship between artificially sweetened beverages and vascular risks. While we cannot show causation, this is a yellow flag to pay attention to these findings,” said American Academy of Neurology President Dr. Ralph Sacco, who was not involved in the latest study.

“What is it about these diet drinks?” asked lead study author Yasmin Mossavar-Rahmani, an associate professor of clinical epidemiology and population health at the Albert Einstein College of Medicine in the Bronx, New York. “Is it something about the sweeteners? Are they doing something to our gut health and metabolism? These are questions we need answered.”

Weight and race increased risk

More than 80,000 postmenopausal US women participating in the Women’s Health Initiative, a long-term national study, were asked how often they drank one 12-fluid-ounce serving of diet beverage over the previous three months. Their health outcomes were tracked for an average of 11.9 years, Mossavar-Rahmani said.

“Previous studies have focused on the bigger picture of cardiovascular disease,” she said. “Our study focused on the most common type of stroke, ischemic stroke and its subtypes, one of which was small-vessel blockage. The other interesting thing about our study is that we looked at who is more vulnerable.”

After controlling for lifestyle factors, the study found that women who consumed two or more artificially sweetened beverages each day were 31% more likely to have a clot-based stroke, 29% more likely to have heart disease and 16% more likely to die from any cause than women who drank diet beverages less than once a week or not at all.

The analysis then looked at women with no history of heart disease and diabetes, which are key risk factors for stroke. The risks rose dramatically if those women were obese or African-American.

“Women who, at the onset of our study, didn’t have any heart disease or diabetes and were obese, were twice as likely to have a clot-based or ischemic stroke,” Mossavar-Rahmani said.

There was no such stroke linkage to women who were of normal weight or overweight. Overweight is defined as having a body mass index of 25 to 30, while obesity is over 30.

“African-American women without a previous history of heart or diabetes were about four times as likely to have a clot-based stroke,” Mossavar-Rahmani said, but that stroke risk didn’t apply to white women.

“In white women, the risks were different,” she said. “They were 1.3 times as likely to have coronary heart disease.”

The study also looked at various subtypes of ischemic stroke, which doctors use to determine treatment and medication choices. They found that small-artery occlusion, a common type of stroke caused by blockage of the smallest arteries inside the brain, was nearly 2½ times more common in women who had no heart disease or diabetes but were heavy consumers of diet drinks. This result held true regardless of race or weight.

Only an association

This study, as well as other research on the connection between diet beverages and vascular disease, is observational and cannot show cause and effect. That’s a major limitation, researchers say, as it’s impossible to determine whether the association is due to a specific artificial sweetener, a type of beverage or another hidden health issue.

“Postmenopausal women tend to have higher risk for vascular disease because they are lacking the protective effects of natural hormones,” North Carolina cardiologist Dr. Kevin Campbell said, which could contribute to increased risk for heart disease and stroke.

“This association may also be contributed to by rising blood pressure and sugars that were not yet diagnosed as hypertension or diabetes but warranted weight loss,” thus leading the women in the study to take up diet beverages, said Dr. Keri Peterson, medical advisor for the Calorie Control Council, an international association representing the low- and reduced-calorie food and beverage industry.

Critics also point to the possible benefit of artificially sweetened drinks for weight loss, a critical issue considering the epidemic of obesity in the United States and around the world.

For example, two World Health Organization meta-analyses of existing research on non-sugar sweetners called those studies “low-quality and “inconclusive,” said William Dermody Jr., vice president of media and public affairs for the American Beverage Association, a trade organization.

“Low- and no-calorie sweeteners have been deemed safe by regulatory bodies around the world,” Dermody said, “and there is a substantial body of research that shows these sweeteners are a useful tool for helping people reduce sugar consumption.

“We support the WHO’s call for people to reduce sugar in their diets, and we are doing our part by creating innovative beverages with less sugar or zero sugar, clear calorie labeling, responsible marketing practices and smaller package sizes.”

The American Heart Association issued an advisory last year saying that short term use of low-calorie and artificially sweetened drinks to replace sugary ones “may be an effective strategy” to promote weight loss in adults, but not children.

The guidance is aimed at those who “find it difficult to move directly from sugary drinks to water,” said University of Hawaii nutrition professor Rachel Johnson, chairwoman of the writing group for that scientific advisory. “Low-calorie sweetened drinks may be a useful tool to help people make this transition.”

On the whole, Johnson said, “there is solid science that consumption of sugary drinks is associated with adverse health outcomes. Thus, it may be prudent to limit intake until we know more about how they may impact people’s risk of stroke.”

While science continues to explore the connection, Americans are turning more and more to water and other non-calorie beverages, according to the Beverage Marketing Corporation, a data and consulting group. In 2016, bottled water surpassed carbonated soft drinks to become the number-one beverage by volume and has continued to dominate the market in 2017 and 2018.

In 2018, Americans are projected to drink just over 3 billion gallons of diet sodas out of a total of 12.2 billion gallons of carbonated sodas, according to data from the Beverage Marketing Corporation.

“Personally, I’ve stopped drinking artificially sweetened beverages,” Sacco said, adding that he sees the emerging research as “an alert” for hard-core fans of diet drinks and anyone thinking of turning to them for weight loss.

“We should be drinking more water and natural beverages, such as unsweetened herbal teas,” Mossavar-Rahmani said. “We can’t just go on, all day drinking diet soda. Unlimited amounts are not harmless.”

COMMENT: Nancy,

This web site article that you cited is an excellent rebuttal to that poorly-designed study that was inappropriately described by the CNN_News.com journalists, i.e. they have “gone for sensatinalism” and did not try to understand the facts. Which (unfortunately) happens too often these days — when scientific studies are “translated” by journalists into news media reports.

DwN

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Studies of algae — suggest eukaryotes “receive many gifts” of bacterial DNA

Studies of algae — suggest eukaryotes “receive many gifts” of bacterial DNA
Nebert, Daniel (nebertdw)
Thu 2/14, 8:04 PM

Horizontal gene transfer (HGT) is a fascinating topic within the purview of gene-environment interactions (i.e. if an organism picks up a foreign gene, then that organism is likely to have an altered response to environmental signals and adversity). HGT is defined as “the movement of genetic information between organisms”; this process includes the spread of antibiotic resistance genes between bacteria, which obviously promotes evolution of pathogens. Many resistance genes evolved, long ago, in natural environments without anthropogenic influence. Today these genes are rapidly spreading to, and among, human pathogens (i.e. this mechanism is contributing to clinical diseases). This is an evolutionary phenomenon, much like the process of tumorigenesis. Bacterial HGT occurs by three well-understood genetic mechanisms [see figure]:

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Transformation = Bacteria take up DNA from their environment.
Conjugation = Bacteria directly transfer genes to another cell.
Transduction = Bacteriophages (bacterial viruses) move genes from one cell to another [This diagram is taken from Evol Med Public Health 2015; 2015: 193–194.]

Once transferred, the genes (most commonly bacterial, viral and fungal DNA) continue to evolve in their new host — often resulting in organisms with greater survival skills. Antibiotic use, in human medicine and agriculture, continually selects for resistant bacteria (e.g. tetracycline and β-lactams commonly fed to animals provide a selective environment for tetracycline and methicillin resistance). After a strain gains resistance by HGT, the bacteria proliferate and continue to evolve, as they move among patients and hospitals. This process has now occurred in many bacterial lineages, resulting in diverse populations of a variety of strains. Ongoing HGT poses a problem for clinical surveillance and treatment. Bacterial populations evolve rapidly (cell division often occurring in 30 minutes) — resulting in diversity that necessitates individual screening to determine effective treatments and to detect new strains — such as methicillin- and high-level vancomycin-resistant Staph aureus (MRSA and VRSA). Even when new drugs and diagnostic tools become available, the persistence of HGT will require ongoing surveillance for newly resistant pathogens, leaving practitioners and researchers “racing against evolution”.

Authors of the 2-page editorial [see attached] expand this topic to algae (green scum; plants having chromosomal pairs, rather than single chromosomes like bacteria do) — found in thermal springs and other extreme environments. It appears that the trasferred genes might help these algae adapt to hostile environments. Even the human genome had been found to contain some microbial genes (but further work showed that such genes found in vertebrate genomes are often contaminants introduced during the process of sequencing). If bacterial genes were continually moving into eukaryotes and being put to use, some have suggested that a pattern of such gene accumulation should be discernible within the eukaryotic family tree. However, no such pattern has been detectable.

The initial sequencing of genomes from two species of red algae (called Cyanidiophyceae) indicates that as much as 6% of their DNA have a prokaryotic (bacterial) origin. These so-called extremophiles — which live in acidic hot springs and even inside rocks — cannot afford to maintain superfluous DNA (i.e. they appear to contain only genes needed for survival). The 13 red algal genomes they studied contain 96 foreign genes, nearly all of them sandwiched between typical algal genes in the DNA fragment sequenced, which makes it highly unlikely they were accidentally introduced in the lab.

The transferred genes seem to transport or detoxify heavy metals, or they help the algae extract nourishment from the environment, or cope with high temperature and other stressful conditions (e.g. salinity, osmolarity). By acquiring genes from extremophile prokaryotes, these red algae have adapted better to increasingly extreme environments. Of course, what’s happening in red algae might not be happening in animals such as humans; humans and all other multicellular eukaryotes, including plants, have specialized reproductive cells — e.g. sperm or eggs or their stem cells — and it would have to be only these types of cells that had picked up foreign DNA that could be passed on.

DwN

Science 1 Feb 2o19; 363: 439–440

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Insights from genomes into the evolutionary importance and prevalence of hybridization in nature

Hybridization [interbreeding between two animals or plants of different groups (of one or more populations of an organism or organisms determined by taxonomists to form a unit] between species, subspecies, or lineages within species — has long been viewed as a powerful tool for understanding evolutionary biology. The study of hybridization has had two primary foci over the past century: one, concerned with understanding species barriers; two, concerned with the role of hybridization in generating novel gene combinations that selection can then act upon. The usefulness of using hybrid zones to understand the process of speciation (i.e. to identify regions of the genome that likely are involved in maintenance of reproductive isolation) is clear, and this has been the focus during hundreds of studies. The crossing-experiments that occur in natural hybrid zones would often be impossible to replicate in the lab, and the importance of studying hybridization in nature is hard to overstate.

The importance of hybridization in the processes of adaptation and speciation has, however, been rigorously debated in the literature, and a consensus that hybridization can, and often does, play a creative role in evolution has recently been forming. Importantly, the role that hybridization plays in the evolutionary history of different taxa is variable (i.e. there may be periods of introgression, hybrid speciation, and/or adaptive introgression), and the emphasis on certain outcomes of hybridization (e.g. hybrid speciation) appear to be skewed in the literature.

Historically, botanists and zoologists have approached this problem with different perspectives. The importance of hybridization in the evolution and diversification of plants is well-documented, and a creative role for hybridization in the evolution of plants has long been accepted. Zoologists, on the other hand, have generally viewed hybridization as a useful tool for studying species barriers and reproductive isolation, but not as a source of genetic novelty that selection can act upon. There has been a significant shift in this view since the mid-1900s, and many now see hybridization as a potentially creative force in evolution and adaptation for both plants and animals.

It is becoming increasingly evident that hybridization, whether intermittent or ongoing, has played a major role in the evolutionary history of many taxa, including hominins (hominids include orangutans, gorillas, chimpanzees, and modern humans). For a long time, however, it has been difficult to fully understand the extent to which hybridization between closely related taxa has influenced their evolutionary histories. This is, in part, because (in the recent past) researchers lacked the tools to dissect genomes at high resolution. Over the past decade, this landscape has rapidly changed, and whole genomes from most non-model taxa can now be sequenced at a relatively low cost. Studies that leverage genome-spanning data in their analyses are uncovering signatures of hybridization in taxa that were never really expected to have a history of hybridization. These studies confirm previous hypotheses about the role of hybridization in diversification. In the era of high-throughput sequencing, scientists are better equipped than ever before to determine the extent to which hybridization has played a role in the evolution of life on Earth.

Authors [see attached review] describe analyses of whole genomes that are providing further insight into this evolutionary problem. Recent studies have documented ancient hybridization in a diverse array of taxa — including mammals, birds, fish, fungi, and insects. Evidence for adaptive introgression (i.e. management and genetic conservation when exposed to a changing environment) is being documented in an increasing number of systems, though demonstrating the adaptive function of introgressed genomic regions remains difficult. And finally, several new homoploid hybrid speciation events have been reported. Authors review herein the current state of the field and specifically evaluate the additional insights gained from having access to whole-genome data. Authors also review challenges that remain, with respect to understanding the evolutionary relevance and frequency of ancient hybridization, adaptive introgression, and hybrid speciation in nature.

DwN

Nature Ecol Evol 2019; 3, 170–177

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Problems with plagiarism at the sixth World Conference on Research Integrity, to be held in Hong Kong, China, in June 2019

Problems with plagiarism at the sixth World Conference on Research Integrity, to be held in Hong Kong, China, in June 2019
Nebert, Daniel (nebertdw)
Mon 2/11, 9:17 PM

This ironic news item was just a small paragraph in a recent issue of Science magazine, but the story underscores where science is — and has been going — for some years now. There was a time when virtually all scientists were ethical, trustworthy, and above reproach. However, this news item was pubished by the planning committee of the sixth World Conference on Research Integrity (which is scheduled to be held in Hong Kong, China, in June 2019). Members of the committee were surprised to receive an abstract that was obviously not an honest article, but rather full of apparent plagiarism. This surprise induced them to explore further.

After closely examining all 430 abstract submissions, the members determined 11 additional cases of “suspected plagiarism”. When they contacted the authors of each of these 11 abstracts — two of which, ironically, were about plagiarism — authors of six of those abstracts did not respond, one withdrew their submission, one blamed the staff (i.e. ‘it wasn’t the coauthors of the abstract who had done the plagiarizing), and two replied by claiming they “had permission to use other people’s work.” Only two gave “acceptable” explanations.

The organizing committee of the 6th World Conference reported this sad, pathetic news last week on the Retraction Watch blog. 🙁

DwN

Science 18 Jan 2o19; 363: 209

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First born, only child, middle child? What birth order reveals about you

This is a fun read. And the author’s generalizations perhaps have some truth to his theory.

First born, only child, middle child? What birth order reveals about you

Dr. Kevin Leman
Which description is most like you?

1: A natural leader and perfectionist, you are logical, technical, well-organized, conscientious, a good reader, and a list-maker. You take life seriously and don’t like surprises.

2: Self-motivated, a voracious reader, and high achiever, you think in black and white and use always and never a lot. You complete every project thoroughly, expect a lot out of yourself and can’t stand the idea of failure.

3: Independent, sometimes secretive, and a diplomatic mediator, you go out of your way to avoid conflicts and often compromise to keep the waters of life smooth. At home, you never got much attention, so you developed a loyal friendship network.

4: Affectionate, charismatic, and a people person, you enjoy the limelight and surprises. You engage easily with strangers. Growing up, you were “cute” so you got away with everything.

If you picked 1, you’re either the first child born in your family or the first child of your gender born in your family.

If you picked 2, you’re an only child.

If you picked 3, you’re a middle child.

If you picked 4, you’re the baby of the family.

How can I be so confident? After studying birth order for years, I’ve seen these descriptions play out over and over. Birth order isn’t an exact science, because not all characteristics fit every person in that birth order. Variables such as the number of years between kids, gender, physical, emotional, or mental differences, adoption, death, blended families and a critical-eyed parent can change that birth order (for more, see “The Birth Order Book”).

Why should you care about birth order? Because the role you played in your family has everything to do with how you perceive “reality.” It’s why a brother and sister can view the same growing-up years differently. And that perceived reality affects how you feel about yourself and relate to others.

If you’re a firstborn.

You had an incredible advantage and disadvantage no other child in your family had – your parent(s) all to yourself for a while. You were the guinea pig for their parental experiments. Everything you did right or wrong was heightened. When you reached for a forbidden item, you were told, “Don’t touch that!” in an excited tone. By the time your second brother was born, your parents barely noticed he had his finger in the electrical outlet.

You walked and talked earlier than your siblings, had a large vocabulary, and acted like an adult because you always interacted with adults. Your parents made a big deal out of everything you did, so you became a perfectionist with only one “right way” to do things. Anything else is “wrong.” That’s why it drives you crazy when others – partners, kids, or coworkers – don’t do tasks the same way you’d do them, don’t pursue goals with the same excellence you do, or don’t take life as seriously. That’s why you assume leadership of a project or take it on as a solo act. You expect a lot out of yourself and others because you’ve been groomed to be highly achievement oriented.

If you’re an only child.

You have firstborn traits times three. You act mature beyond your years – you were a little adult by age 7 or 8. Books were not only your best friends growing up but also siblings and companions. You’re used to working independently, so that’s most comfortable for you. After all, no one can jump the high bar of your expectations. Problem is, you’re even tougher on yourself than you are on others.

If you’re a middleborn.

Since you’re not the superhuman, driven-to-excellence firstborn and you’re not the cute baby of the family, you grew up in the hazy, anonymous “middle” where you weren’t often noticed. In fact, you were the one least likely to be missed if you went AWOL at the dinner table. You could get away with being lazy sometimes because your parents didn’t expect you to accomplish as much as your firstborn sibling. In fact, whatever he or she was like, you went the opposite way. After all, why try to compete with the best?

Because you were stuck between the hard-driving firstborn and the baby, who couldn’t seem to get anything done without help, you frequently played “peacemaker” at home. You carried that role into your loyal friend network too. But wanting everyone to get along so the waters of life stay smooth opens the door for others to easily take advantage of you.

If you’re a lastborn.

Life to you is a thrill ride from one adventure to another. You’re highly social, spontaneous, thrive on being entertainment central, and easily make people laugh. People swarm to you like ants to honey. Growing up, you were the manipulative charmer who could get your siblings or parents to do anything for you – even things you should have been doing for yourself. Your siblings often sent you as the sacrificial lamb to ask a favor of mom or dad, since you were the one least likely to be punished for asking.

When others don’t smooth your path in life and do things for you now, you are easily irritated and hurt. When you aren’t in the limelight, you don’t feel appreciated.

When you understand your branch of the family tree, you’ll know why you are the way you are – your personality, how you problem-solve, and how you relate to friends, coworkers, and loved ones.

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Single-cell and single-molecule epigenomics uncovers genome regulation at unprecedented resolution

As these GEITP pages have often discussed, any trait (phenotype; e.g. height, eye color, diseases such as schizophrenia and obesity, drug efficacy, or toxicity to an environmental toxicant) reflects contributions of one or many genes (genotype; DNA sequence) and epigenetic effects (DNA-methylation, RNA-interference, histone modifications, chromatin remodeling) plus environmental effects and endogenous influences, and perhaps the gut microbiome. Among the 50-75 trillion cells in the human body, there are ∼210 distinct human cell-types (including those that appear and disappear during development). Contrary to the germline DNA sequence, which is identical in all cells of the body (excluding mutations in specific cells later during life), the human body thus has ∼210 “epigenomes.” And, for the most part, these are DYNAMIC, i.e. changing from minute-to-minute, or from day-to-day.

Large-scale consortia [e.g. Encyclopedia of DNA Elements (ENCODE), National Institutes of Health (NIH) Roadmap Epigenomics Project, & International Human Epigenome Consortium] have applied DNase-I hypersensitivity, chromatin immunoprecipitation (ChIP), and bisulfite sequencing (among others) to characterize chromatin structure, transcription-factor (TF) occupancy, and DNA-methylation — in many cell types and tissues. These genome-wide assays have identified a large diversity of functional regulatory elements and a plethora of chromatin factors that bind these elements. However, these aggregate maps represent averaged signals over populations of cells and thus mask individual-cellular and

-regulatory heterogeneity.

There is now increasing recognition of the importance of cell-to-cell variation within tissues and also measurements of the physical co-occurrence between different chromatin modifications or chromatin regulators at individual loci. Methods for single-cell and single-molecule epigenomic analysis are therefore required to dissect out the mechanisms of gene regulation across the diverse cellular landscape in development and disease.

Advances in molecular biology, microfluidics, and imaging technologies have catalyzed a boom in the number of epigenomic modalities that can be measured at single-cell and single-molecule resolution. Recent reports have described high-throughput single-cell chromatin and DNA-methylation analyses powering epigenomic studies in tens of thousands of cells. Moreover, the surge of technological innovations for single-cell transcriptomics promises to further accelerate the development of single-cell epigenomic technologies. These assays can be used

to characterize cell-types in complex tissues; however, because single-cell transcriptomics is also a widely accessible and robust technology for de novo discovery of cell states, why, then, are single-cell epigenomic studies a worthwhile endeavor?

In the attached article, Authors focus on the unique biology that may be uncovered by single-cell analysis of “the epigenome” in that specific cell. They present a number of motivating concepts unique to single-cell epigenomic analysis (e.g. the unbiased discovery of cis- and trans-regulators and their activity profiles across cell states within complex tissues). Authors also explore how these technologies can be used to answer long-standing questions in cell biology — such as “How do cells choose lineage fates?” and “Is lineage choice first encoded in the epigenome, or in gene expression?”

In addition, authors investigate the biology underlying epigenomic analysis at the single-molecule scale. Lastly, they describe what may be the next generation of single-cell and single-molecule epigenomic tools to advance further our understanding of gene regulation. This Perspective offers a very solid overview of this topic. 🙂

DwN

Nat Genet Jan 2019; 51: 19–25

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Here is a new opinion as to how life on our planet might have emerged

For those GEITP-ers interested further in this topic of “the Origin of Life,” D.Lancet et al. [see attached] are advocating a systems protobiology view, whereby the first replicators are proposed to be assemblies of spontaneously accreting, heterogeneous and mostly non-canonical (unrelated, not conforming) amphiphiles [molecules that are both water-loving (hydrophilic, polar) and fat-loving (lipophilic)]. This approach is supported by rigorous chemical kinetics simulations of the Graded Autocatalysis Replication Domain (GARD) model — based on the reasonable notion that replication or reproduction of compositional information predated that of sequence information.

Authors [attached pdf at right] show a preliminary new version of their model, metabolic GARD (M-GARD), in which lipid covalent modifications are carried out by non-enzymatic lipid catalysts — themselves compositionally reproduced. M-GARD fills the gap of the lack of true metabolism in basic GARD, and is reinforced by a published experimental instance of a lipid-based mutually catalytic network. GARD analysis in a whole-planet context offers the potential for estimating probability of life’s emergence. The concepts presented in this review enhance the validity of autocatalytic sets as a bona fide early-evolution scenario.

DwN

Sent: Tuesday, February 05, 2019 4:03 PM

Dear Dan,

I am glad to see this Origin of Life item among your emails. I am not sure I ever told you that in the last 20-some years I have worked quite extensively on this topic. Just to share with you this relatively rcent interst, I am attaching the 2018 reprint, our latest on the topic. I would be delighted to share with you in more detail my rather unorthodox model of how life arose.

Warm regards, xx

Dept. Molecular Genetics
Weizmann Institute of Science
Herzl 234, Rehovot 7610010, Israel

From: Nebert, Daniel (nebertdw)
Sent: Tuesday, February 05, 2019 3:33 PM
Subject: Here is a new opinion as to how life on our planet might have emerged

As these GEITP pages have previously detailed, Earth formed ~4.53 billion years ago (approximately one-third of the 13.8-billion-year age of the universe); this happened by accretion (gravitational attraction of gaseous particles) of material from solar nebula (Solar System cloud). Volcanic eruptions, followed by contributions from oceans, most likely created the primordial atmosphere — which contained barely any diatomic O2. Early in Earth’s existence, a major collision ~4.51 billion years ago (with a planet-sized body named Theia) is believed to have formed the moon. The Hadean eon represents the era before reliable (fossil) evidence of life (i.e. beginning with Earth’s formation and ending ~4.0 billion years ago).

A new scenario [see attached editorial] suggests that ~4.47 billion years ago — a moon-size object might have sideswiped Earth and exploded into an orbiting cloud of molten iron and other metals; dense elements (e.g. iron, gold, platinum, and palladium), should have sunk to the planet’s core, whereas silicon and other light elements would have floated nearer the surface. Yet, those metals remain plentiful near the planet’s

surface — at levels thousands of times more abundant than they should be.

The metallic hailstorm likely continued for centuries, ripping oxygen atoms from water molecules and binding to iron atoms, creating vast rust-colored deposits of iron oxide across Earth’s surface. After things cooled down, simple organic molecules began to form under the blanket of hydrogen as a catalyst. Those molecules are proposed to have linked up eventually, to form RNA starting ~4.35 billion years ago, the molecular player long credited as essential for the beginning of life and existing before DNA. In other words, the stage for life’s emergence was set, almost as soon as our planet was born. Because of altered ratios of carbon isotopes in zircon, ~4.1 billion years ago, these data suggest hints of the earliest of life forms [see Figure in attached editorial].

This scenario fascinated participants at an October 2018 Origins of Life Workshop in Atlanta — where geologists, planetary scientists, chemists, and biologists compared notes on the latest thinking as to how life might have started on Earth. No rocks or other direct evidence remain from the hypothetical cataclysm; however, its starring role is inferred, because “it would solve a bevy of mysteries.” The metal-laden rain would account for the distribution of metals across our planet’s surface today. The hydrogen atmosphere would have favored emergence of the simple organic molecules, which later formed more complex molecules such as RNA. And the planetary collision would move back the likely birthdate for RNA, and possibly life’s emergence, by hundreds of millions of years.

This hypothesis aligns itself better with recent geological evidence, suggesting an early emergence of life. Many in the “origins-of-life” field now see a consistent narrative beginning to take shape — as far as describing how and when life began on Earth.

DwN

Science 11 Jan 2019; 363: 116–119 [Opinion]

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