Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

The theme of these GEITP pages (in a broad sense) is gene-environment interactions, and how they can be understood, and further elucidated, by using genome-wide association studies (GWAS). This article [see attached] reminds me of a story: [The drunk fellow was searching for his car-keys under a street lamp at night, when a passerby asked if he was sure he’d lost his keys there; he said ‘No, but it’s easier to look here, where there’s more light’.] In other words, GWAS are designed to look for single-nucleotide variants (SNVs) throughout the genome that are statistically significantly associated with a phenotype (i.e. a trait such as obesity, type-2 diabetes, response to a drug, response to an environmental toxicant or mixture of toxicants). The (germ line) DNA used in GWAS is typically derived from white blood cells or cells from skin or sputum. In contrast, this study [see attached article] searches for gene expression uniqueness — specifically occurring in adipose tissue. 😊

Excess adipose tissue, especially around the hips and waist, is associated with increased cardiometabolic risk and mortality. This subcutaneous adipose tissue expands to store additional lipids, and serves as a buffering system for lipid energy balance — especially for fatty acids — providing a protective role in metabolic risk. Interestingly, expansion of adipocyte size (i.e. fat cells getting larger), rather than formation of new adipocytes (new fat cells), has also been linked to insulin resistance. Identification of genetic variants associated with gene expression quantitative trait loci (eQTLs) in relevant tissues has proven useful to correlate non-coding GWAS variants (SNVs that do not participate in transcription to RNA or translation into protein) to plausible candidate genes that may influence complex traits. Whereas 94% of eQTLs are shared across at least two tissues, some eQTLs are specific to one tissue (or a subset of tissues) — necessitating scientists to study tissues that potentially contribute to GWAS traits, in order to identify credible candidate genes.

Recently, eQTL studies have begun to identify other eQTL signals through conditional analysis (this is where one adjusts for the original SNV (primary eQTL) in the model; then one tests to see if the association between a 2nd SNV (secondary eQTL) is independent of the primary eQTL, or whether it is just because they are ‘geographically correlated’ via linkage disequilibrium (LD), i.e. the non-random association of alleles at different loci along the same chromosome, which occurs in any given population). In addition, eQTL studies examine the more commonly reported “primary eQTLs”. These other conditionally distinct secondary eQTL signals are widespread, and located more distal than primary signals from the transcription start-sites (TSS) of their associated genes. These other eQTL signals have also been shown to co-localize with GWAS loci, suggesting they can detect additional candidate genes.

Authors [see attached article] used subcutaneous adipose tissue RNA-seq data from 434 Finnish men [I can’t figure out why researchers always tend to ‘pick on Finnish men’ for these studies? ☹] — from the METSIM study to identify 9,687 primary and 2,785 secondary eQTLs (within 1 million base pairs of the transcription start-site, and false discovery rate less than 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start-sites, had smaller effect-sizes, and were less enriched in adipose tissue regulatory elements, compared to primary eQTL signals. Among 2,843 cardiometabolic GWAS signals, 262 co-localized by LD; conditional analysis confirmed 318 eQTL transcripts found as primary eQTLs and conditionally distinct secondary eQTLs.

Among the cardiometabolic traits examined for adipose tissue eQTL co-localizations, waist-hip ratio and circulating lipid levels (two quantitative traits) contained the highest percentage of co-localized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (~53%) were associated with decreased gene expression levels. Mediation analysis (this seeks to identify and explain the mechanism, or process, that underlies an observed relationship between an independent variable and a dependent variable — via inclusion of a third hypothetical variable, known as a ‘mediator variable’) of co-localized genes and cardiometabolic traits within the 434 individuals — provided further evidence that gene expression influences variant-trait associations. In summary, these results have identified hundreds of candidate genes that appear to act in adipose tissue to influence cardiometabolic traits.

DwN

Am J Hum Genet Oct 2019; 105: 773-787

Posted in Center for Environmental Genetics | Comments Off on Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

Ultrarare variants drive substantial cis heritability of human gene expressio

These GEITP pages have often described genome-wide association studies (GWAS), because they provide information about what genes are correlated with any multifactorial trait (phenotype) — these can include complex diseases (e.g. obesity, type-2 diabetes, coronary arter disease), quantitative traits (e.g. height, serum cholesterol levels, blood pressure), and responses to drugs as well as environmental toxicants. And it is well known that hundreds or thousands of “small-effect” genes often contribute to these multifactorial traits. The topic today [see attached article] concerns single-nucleotide variants (SNVs) having minor allele frequencies (MAFs) of less than 1% (recall that each gene has two alleles, one on each of a chromosome pair, and one derived from each parent). “Common variants” in any population might exhibit a frequency of 10% or 70%, compared with “rare variants” with frequencies of less than 1% or “ultra-rare variants” (singletons) found in only one individual in a large population study. Whereas many rare variants and ultra-rare variants underlying Mendelian diseases (e.g. phenylketonuria, sickle cell disease, cystic fibrosis), have been found, their role in complex disease is unknown.

Recent methodological breakthroughs have enabled researchers to estimate the independent contributions of low- versus high-frequency alleles to multifactorial traits — often demonstrating a large-effect contribution by a rare variant, probably driven by

natural selection [process whereby any organism that adapts better to its environment — will improve its survival (find food, avoid predators, and produce more offspring)]. However, these studies excluded the rarest variants; this is a problematic limitation — given that some plausible evolutionary models predict that the largest contributions to phenotypic variance could come from the rarest variants. Directly querying the role of all variants with large-scale sequencing and sensitive statistical tests — has the potential to reveal important sources of missing heritability, inform strategies to increase the success rate of association studies, and clarify how natural selection has shaped human phenotypes.

Authors [see attached article] developed, validated, and applied an approach for inferring the relative phenotypic contributions of all variants — from the ultra-rare to the high-frequency variants. Authors focused on the narrow-sense heritability (h2) of gene expression (because a growing body of literature suggests that genetic variants primarily affect disease by modifying gene regulatory programs, and recent examinations have identified significant rare-variant effects on transcription). To characterize genetic architecture (i.e. underlying genetic basis of a phenotypic trait and its properties of variability) of gene expression, authors analyzed 360 unrelated individuals of European ancestry with paired whole-genome DNA and RNA-sequencing (RNA-seq) of immortal lymphoblastoid cell lines.

Authors conservatively estimate that singletons (i.e. rare variants often seen only once, within a large human population study) contribute ~25% of cis heritability across genes — which dwarfs the contributions of other allele frequencies). [Cis-regulatory elements (CREs) are regions of non-coding DNA that regulate transcription of nearby gene(s).] The majority (~76%) of singleton heritability is derived from ultra-rare variants — that are almost always absent from thousands of additional samples..!! Authors developed an inference procedure to demonstrate that their results are consistent with pervasive purifying selection which shapes the regulatory architecture of most human genes. These findings have enormous implications to gene-environment interactions in molecular and environmental genetic toxicology. 😊

DwN

·

· Nature Genetics Sept 2019; 51: 1349–1355

Posted in Center for Environmental Genetics | Comments Off on Ultrarare variants drive substantial cis heritability of human gene expressio

A reference genome for the pea plant provides insight into legume genome evolution

The basic principles of genetics (inheritance and independent segregation) were first discovered and detailed by Gregor Mendel’s meticulous studes of the pea plant in the 1850s and 1860s. Generations of students have learned about dominant and recessive traits — through examples of pea plant height, and pea pod or seed color and shape. The simple laws elucidated by Mendel are experimentally analyzed in classrooms worldwide, and “Mendelian inheritance” is a very common, fundamental term. Although genetic analysis has become orders of magnitude more sophisticated today, Mendel and his pea plant experiments are a great guide and entry point into the study of inheritance.

Most genetics students became familiar with traits of the pea — including green versus yellow and wrinkled versus smooth, often placed within the ordered Punnett square — as their first foray in any course of genetics. Today, a basic understanding of what a genome is, and how it operates, along with a sense of the complexity and sheer amount of information that genomes hold, is important to teach to students — as early in school as possible. When public policy is being shaped around the privacy of individuals’ genetic data, regulation of gene-edited or genetically modified agricultural products, and guidelines for gene-based therapies to treat diseases — it is important for the public to have a basic working knowledge of genetics and genomics.

Furthermore, with increasing interest in the direct-to-consumer genetic testing now used by individuals to find out more about their ancestry — people should understand what those tests are reporting and, more importantly, what their limitations are. This understanding would often require a deeper knowledge of population genetics; however, basic principles, from Mendel to genome sequencing, would aid in interpretation of these genetic testing kits. For example, knowing about the laws of segregation and independent assortment would help people put into context the understanding of family disease risk variants (i.e. how your DNA relates to that of your parents or siblings). Being familiar with concepts of recombination and inheritance would enrich understanding and interpretation of ancestry information. This understanding would also help reduce hype and avoid over-interpretation of genetics findings.

Authors [see attached article & editorial] report the first annotated chromosome-level reference genome assembly for the pea plant.

Phylogenetics (the scientific study of phylogeny, which pertains to the evolutionary history of the relationships of an organism to other organisms according to similarities and differences) and paleogenomics (reconstruction and analysis of genomic information in extinct species, including comparisons of ancient ancestors against modern-day humans) show genomic rearrangements across legumes (e.g. peas, beans, alfalfa, clover, chickpeas, lentils, soybeans, and peanuts) and suggest a major role for repetitive elements in pea genome evolution. Compared to other sequenced Leguminosae genomes, the pea genome shows intense gene dynamics, most likely associated with genome size expansion when the Fabaceae (genus, or tribe, included in the family Leguminosae.) diverged from its sister tribes. During Pisum (genus of the pea) evolution, translocations and transpositions differentially occurred across lineages. This reference sequence will also accelerate our understanding of the molecular basis of agronomically important traits and support crop improvement.

DwN

· Nat Genet Sept 2019; 51: 1411–1422 & editorial p. 1297

Posted in Center for Environmental Genetics | Comments Off on A reference genome for the pea plant provides insight into legume genome evolution

The importance of “indifference” in scientific research

This is a follow-up editorial by the same author; there are some further pearls of wisdom in this article. Scientific research is not always “a process of rolling, powerfully and inevitably forward”, but rather “oddly fragile”. Once we have a reasonably accurate picture of how things work — the testing and validation can proceed in a well-organized, efficient manner. But, in the early stages, when we really don’t understand the system and possibilities seem endless, it is easy to go astray. “Is that 1.5-fold change meaningful? Maybe if conditions are optimized — it will become a 5-fold change. Or maybe it’s just a blip and doesn’t mean a thing.” The question often becomes how much effort should we expend on working out the bugs and obtaining a robust result.

The author describes being fooled by a nice result that “happened twice, but then stopped; only after spending a long time trying to repeat it, and then exploring the system, using other approaches, did I realize that it was not correct.” Alternatively, “we can get results that looked nice once or twice, then stopped working, but then, after extensive optimization — turned out to be correct and important.” The author says he also has had a weak, hard-to-reproduce result that he abandoned — only to see it published a few years later in a very nice paper by another lab. In short, one must continuously be on guard for false positives and false negatives.

Nor does statistical analysis solve the essential problem. No result is statistically significant at the start. Statistical analysis comes later — only after the system has been optimized and the experiment repeated a number of times. In the early stages of a project when the picture is just emerging, it’s hard to know. At the early stage in any project, intuition is a major factor. When you really know your system, sometimes a preliminary result just feels right. Or being right makes so much sense that you are willing to follow a feeble lead. However, a major confounding variable in this process is the human tendency to want our hypotheses to be correct. [‘If my hypothesis is correct — it means I’m smart, I’m close to writing the paper, and then I have a good shot at landing the job or getting tenure.’] Our desire to be correct makes it harder actually to be correct.

There is a state of mind that facilitates clear thinking; in the title, the author jokingly called it “disinterest” (perhaps a better term is ‘open-mindedness’ or “not being judgmentally/opinionated’). To be more accurate, the author says he might have called it “passionate disinterest”. Buddhists call it non-attachment. We all have hopes, desires and ambitions; non-attachment means acknowledging them, accepting them, but then not inserting them into a process that, at some level, has nothing to do with you.

Molecular biology and genetics science occupies a middle ground between two opposite forms of exploration. The arts explore, in free-form manner, every aspect of individual, subjective human experience. At the opposite pole, mathematics elucidates a kind of universal language that is true for all time in all places, independent of its creators. Molecular biology and genetics science lies in between — scientists aim to discover universal laws, yet we do so through subjective experiences that we call “experiments”. Making non-attachment a central part of science education would be far more important than ethics classes, and discussing regulations about the “use of Photoshop in preparing figures”. 😊

DwN
J Cell Sci Aug 2015; 128: 2745-2746
This (intriguing) 1-page editorial is not directly “gene-environment interactions-related”, but has to do with teaching graduate students in the fields of science. It was offered to me recently by a colleague and GEITP-reader. The author of the article is still at the University of Virginia Charlottesville College of Medicine. Basically, he suggests that “Ph.D. programs often do students a disservice — in two ways.”

First, students are not made to understand how hard it is to do research — and how very, very hard it is to do creative research. “It’s a lot harder than taking very demanding courses.” What makes it difficult is that research represents immersion in the unknown. We simply do not know what we’re doing. We cannot be sure whether we’re asking the right question, or doing the right experiment — until we get the answer or the result. [Admittedly, science is made harder by competition for grants and space in top journals. But, apart from all that, doing significant research is intrinsically hard — and changing departmental, institutional, or national policies will not succeed in lessening its intrinsic difficulty.]

Second, mentors don’t do a sufficient job of teaching grad students how to be “productively stupid” (i.e. ‘if we don’t feel stupid, then it means we’re not really trying’). The author is not talking about “relative stupidity, in which the other students in the class actually read the material, think about it, and ace the exam, whereas you don’t.” And he is not talking talking about bright people who might be working in dull research areas that don’t match their talents. Science involves confronting our “absolute stupidity” — “that kind of stupidity is an existential fact, inherent in our efforts to push our way into the unknown.” [Perhaps ‘humility’ and ‘endless curiosity’ might be more appropriate terms than ‘stupidity’?]

Preliminary exams and thesis exams have the right idea — when the faculty committee pushes until the student starts getting the answers wrong, or gives up and says, “I don’t know”. [The point of that exam is not to see if the student gets all the answers right. If they do, it’s the faculty who failed the exam.] The point is to identify the student’s weaknesses — partly to see where they need to invest some effort, and partly to see whether the student’s knowledge fails at a sufficiently high level “that they are now ready to take on a creative research project.”

Productive stupidity (or ‘humility’, or ‘endless curiosity’?) means being ignorant by choice. Focusing on important questions puts us in the awkward position of being ignorant. One of the beautiful things about science is that it allows us to bumble along, getting it wrong time after time, and feel perfectly fine — as long as we learn something each time. No doubt, this can be difficult for students who are accustomed to getting all the answers right. [No doubt, reasonable levels of confidence and emotional resilience help.] However, the author thinks that scientific education might do more to ease what is a very big transition: from learning what other people once discovered — to making your own discoveries. “The more comfortable we become with being stupid, the deeper we will wade into the unknown.” And the more likely we are to make important (i.e. creative) discoveries. In fact, most likely, there is a genetic component to this trait, as well. 😊

DwN

J Cell Sci 2008 Jun; 121: 1771

COMMENT: Here are two quick responses by molecular toxicologists — both of whom have spent many decades in the trenches doing laboratory research. Dave, I agree that “ignorance” would have been a much more appropriate, and less provocative, word to use — instead of “stupidity”. And both of you point out the urgent need for students to re-learn the null hypothesis and remember The Scientific Method (1=Make an observation. 2=Ask a question. 3=Form an hypothesis, or testable explanation. 4=Make a prediction based on the hypothesis. 5=Test the prediction (proving the null hypothesis is not the correct one). And 6=Repeat several times — before using the solid data to make new hypotheses or predictions.) 😊

Posted in Center for Environmental Genetics | Comments Off on The importance of “indifference” in scientific research

A global overview of pleiotropy and genetic architecture in complex traits

From the time of the first genome-wide association study (GWAS) on macular degeneration (form of blindness that can occur with increasing age) in 2005, there have now been more than 3,000 GWAS studies published, selecting more than 1,000 traits, and reporting on tens of thousands of “genetic risk variants”. These results have increased our understanding of the genetic architecture (please recall that this means ‘the underlying genetic basis of a phenotypic trait and its properties of variability’) of traits. Occasionally, GWAS results have led to further insight into disease mechanisms — such as autophagy (destruction of damaged cellular components occurring in vacuoles within the cell) for Crohn disease, immunodeficiency for rheumatoid arthritis, and transcriptome regulation, via FOXA2, in pancreas and liver for type-2 diabetes.

After 14 years of GWAS, we now know that the majority of studied traits represent contribution of countless genes (i.e. highly polygenic) and influenced by many genetic small-effect single-nucleotide variants (SNVs) — with unequal genetic architectures across the various traits. However, fundamental questions remain unanswered: [a] whether all genetic variants or genes in the human genome are associated with at least one, many, or even all, traits; and [b] whether polygenic effects for specific traits are functionally clustered, or randomly scattered across, the genome. Such knowledge would greatly enhance our understanding of how genetic variation leads to trait variation and trait correlations. Whereas GWAS primarily aim to discover SNVs associated with specific traits, current availability of vast amounts of GWAS results allow investigation of these general questions.

With this in mind, authors [see attached article] compiled a catalog of 4,155 GWAS results across 2,965 unique traits from 295 studies (https://atlas.ctglab.nl) — including publicly available GWAS and new results for 600 traits from the UK Biobank. These GWAS results were used in the current study to: [a] chart the extent of pleiotropy (a single gene’s contribution to two or more apparently unrelated traits) at the trait-associated locus, gene, SNV, and gene-set levels, [b] characterize the nature of trait-associated variants (i.e. distribution of effect-size, minor allele frequency (MAF) and biological functionality of trait-associated or credible SNVs); and [c] investigate genetic architecture across a variety of traits and domains in terms of SNP heritability and trait polygenicity.

Authors show that trait-associated loci cover more than half the genome, and 90% of these overlap with loci from multiple traits (i.e. they are pleiotropic). Authors found that potential causal SNVs are enriched in coding and flanking regions, as well as in regulatory elements, and show variation in polygenicity and discoverability of traits. These data provide insights into how genetic variation contributes to variation of any complex disease (e.g. schizophrenia, obesity, type-2 diabetes, response to drugs, environmental toxicants) or quantitative trait (e.g. height, blood pressure, body mass index).

DwN

Nat Genet Sept 2019; 51: 1339–1348

Posted in Center for Environmental Genetics | Comments Off on A global overview of pleiotropy and genetic architecture in complex traits

The microbiome and age-related disease

These GEITP pages have discussed numerous publications on the importance of the microbiome — which we believe is (in every animal) an excellent example of gene-environment interactions. It is now well accepted that the microbiota has essential metabolic and immunological functions that are evolutionarily conserved from worms to humans. In mammals (e.g. mouse, human), the gut microbiota is involved in food processing, activation of satiety (i.e. relief from hunger) pathways, protection against pathogens, and production of metabolites — including vitamins, short-chain fatty acids, and secondary bile acids.

The gut microbiota also signals to distant organs (including liver but especially the brain), contributing to maintenance of host physiology. Alterations in the intestinal microbiota are associated with major disorders (e.g. obesity, type-2 diabetes, cardiovascular disease, nonalcoholic fatty acid liver disease, cancer, response to anti-cancer drugs). Although some research studies have explored the microbiome profile (metabolome) of long-lived humans, no studies have been described in accelerated-aging syndromes. Authors [see attached article] studied the gut microbiome of two mouse models — Hutchinson–Gilford progeria syndrome (HGPS), human HGPS patients, and Nestor–Guillermo progeria syndrome (NGPS) — as well as human centenarians and their controls (the mouse and human progeria syndromes show rapid aging with shortened longevity, whereas 100(+)-year-old humans exhibit long lives).

Authors found these two different mouse models of progeria are characterized by intestinal dysbiosis (i.e. microbial imbalance or maladaptation in the gut) — with changes that include an increased abundance of Proteobacteria and Cyanobacteria, and a decrease in abundance of Verrucomicrobia. Consistent with these findings, authors discovered that human progeria patients also display intestinal dysbiosis and that long-lived human centenarians exhibit a substantial increase in Verrucomicrobia and decreases in Proteobacteria. Fecal microbiota transplantation from wild-type mice improved healthspan and lifespan in both progeria mouse models; transplantation with verrucomicrobia (Akkermansia muciniphila) was also sufficient to exert beneficial effects.

Even more exciting, metabolomic analysis of ileal (distal small intestine) contents suggested that restoration of secondary bile acids is a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. These data demonstrate that correction of accelerated aging-associated intestinal dysbiosis is beneficial — suggesting the existence of a link between aging and the gut microbiota. These findings provide a rationale for microbiome-based interventions against age-related diseases (i.e. should everyone eat more of the ‘right kind’ of fecal material, in order to live longer?). 😉

DwN

·

· Nat Med Aug 2019; 25: 1234-1242

Posted in Center for Environmental Genetics | Comments Off on The microbiome and age-related disease

Comprehensive single-cell transcriptome lineages of a proto-vertebrate (the sea squirt)

These GEITP pages, from time to time, highlight a particularly exciting breakthrough in developmental biology [see attached article and editorial]. Single-cell RNA-sequencing methods are revolutionizing our understanding of how cells are specified to become definitive tissues during development. Such studies allow elucidation of virtual lineages for select tissues, and provide detailed expression profiles for cell-types (e.g. pluripotent progenitor cells, which are capable of differentiating into any cell-type). However, a major limitation of previous studies has been the incomplete coverage of vertebrate embryos — owing to the large numbers of cells present in these embryos.

As one of the closest living relatives of vertebrates (animals having spines), the ascidian Ciona intestinalis (sea squirt) serves a critical role in understanding developmental and physiological processes that are comparable to — but far less complex than — those of vertebrates. In comparison to vertebrate embryos, sea squirt embryos are simple: gastrulating embryos (see Figure 1 of attached article, showing gastrula as the original ball of cells) are composed of only 100–200 cells, and swimming tadpoles contain ~2,500 cells.

Owing to these small numbers of cells, it is possible to obtain comprehensive coverage of every cell-type during development, including rare neuronal subtypes. Authors [see attached] extended insights into the regulatory ‘blueprint’ that spans the early phases of embryogenesis, by profiling the transcriptomes (i.e. ‘active gene’ transcripts that are transcribed into messenger RNA) of individual cells in sequentially staged Ciona embryos, from gastrulation at the 110-cell stage to the neurula and larval stages.

Authors determined single-cell transcriptomes for more than 90,000 cells that span the entirety of development — from the onset of gastrulation to swimming tadpoles — in the sea squirt. Authors used single-cell transcriptome trajectories to construct virtual cell-lineage maps and provisional gene networks for 41 neuronal subtypes that comprise the larval nervous system. Authors summarized several applications of these datasets, including annotating the synaptome of swimming tadpoles and tracing the evolutionary origin of cell types such as the vertebrate telencephalon (the most highly developed, and frontal, part of the forebrain, consisting chiefly of the cerebral hemispheres in vertebrates).

Nature 18 July 2019; 571: 349-354 & pp 333-334 (editorial)

Posted in Center for Environmental Genetics | Comments Off on Comprehensive single-cell transcriptome lineages of a proto-vertebrate (the sea squirt)

microRNA regulation of adult neural stem cells

One constant theme of these GEITP pages is the contribution — of genetics, epigenetic factors, environmental effects, endogenous influences, and the microbiome — to any multifactorial trait (phenotype). Multifactorial traits include complex diseases (e.g. schizophrenia, obesity), quantitative traits (e.g. height, body mass index), and responses to drugs as well as to various environmental toxicants. Epigenetic factors include DNA methylation, RNA interference (microRNA regulation), histone modifications, and chromatin remodeling. The former two categories are quite well understood and assays are available, whereas the latter two currently remain poorly understood and are under intensive study.

Adult neural stem cells (NSCs) are located in few specific and restricted niches of the mammalian brain, and they generate neurons throughout the life of the animal. Lifelong neurogenesis (ability to generate new nerve cells) in the adult brain relies on a population of quiescent NSCs (qNSCs), set apart during development. Upon “activation” within the adult brain, the vast majority of these once quiescent cells will produce only a few cohorts of neurons before being depleted, or returning to quiescence. Therefore, an important cornerstone in understanding the regulation of neurogenesis within the adult brain — including its age-related decline — is to decipher mechanisms controlling the balance between qNSC maintenance and activation.

Authors [see attached article] identified a post-transcriptional control mechanism (recall that DNA is transcribed into RNA; RNA is then translated into protein), centered around microRNA 204 (miR-204). As one category of epigenetic factors, microRNAs represent a form of RNA-interference (RNAi) that ties up messenger RNAs (mRNAs) from specific sets of genes, thereby controlling gene expression post-transcriptionally. miR-204 is known to regulate a spectrum of transcripts involved in cell-cycle regulation, nerve-cell migration, and differentiation in qNSCs; miR-204 was found specifically to govern, or maintain, levels of qNSCs. When miR-204 was inhibited, the number of qNSCs in a particular region of the brain [the subependymal zone (SEZ)] was decreased — by inducing premature activation and differentiation of NSCs.

Authors identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 — which is then released into the cerebrospinal fluid to control the number of NSCs within the SEZ. Thus, these data describe a novel mechanism for maintaining adult somatic stem cells — by a “niche-specific” miRNA that is involved in repressing activation and differentiation of stem cells. 😊

DwN

·

· The EMBO J 2019; 38: e100481

Posted in Center for Environmental Genetics | Comments Off on microRNA regulation of adult neural stem cells

There is no climate emergency

This is a letter from Professor Guus Berkhout, representing 500 scientists, to two top officials at the United Nations — telling them there is no climate emergency — contrary to what that 14-year-old Swedish child, Greta Thunberg, was hysterical about in her recent speech to the U.N. [Because this was the career field of research of my late son, I am personally in email contact with a number of these 500 climatology scientists who have signed this letter.] 😊
DwN

Brief CLINTEL aan VN-baas Guterres

Professor Guus Berkhout
The Hague
guus.berkhout@clintel.org

23 September 2019

Sr. António Guterres, Secretary-General, United Nations,
United Nations Headquarters,
New York, NY 10017, United States of America.

Ms. Patricia Espinosa Cantellano, Executive Secretary,
United Nations Framework Convention on Climate Change,
UNFCCC Secretariat, UN Campus, Platz der Vereinten Nationen 1,
53113 Bonn, Germany

Your Excellencies,

There is no climate emergency.

A global network of more than 500 knowledgeable and experienced scientists and professionals in climate and related fields have the honor to address to Your Excellencies the attached European Climate Declaration, for which the signatories to this letter are the national ambassadors.

The general-circulation models of climate on which international policy is at present founded are unfit for their purpose. Therefore, it is cruel as well as imprudent to advocate the squandering of trillions on the basis of results from such immature models. Current climate policies pointlessly, grievously undermine the economic system, putting lives at risk in countries denied access to affordable, continuous electrical power.

We urge you to follow a climate policy based on sound science, realistic economics and genuine concern for those harmed by costly but unnecessary attempts at mitigation. We ask you to place the Declaration on the agenda of your imminent New York session.

We also invite you to organize with us a constructive high-level meeting between world-class scientists on both sides of the climate debate early in 2020. The meeting will give effect to the sound and ancient principle no less of sound science than of natural justice that both sides should be fully and fairly heard. Audiatur et altera pars! [Let the other side also be able to speak!]

Please let us know your thoughts about such a joint meeting.

Yours sincerely, ambassadors of the European Climate Declaration,

Professor Guus Berkhout – The Netherlands
Professor Richard Lindzen – USA
Professor Reynald Du Berger – French Canada
Professor Ingemar Nordin – Sweden
Terry Dunleavy – New Zealand
Jim O’Brien – Rep. of Ireland
Viv Forbes – Australia
Professor Alberto Prestininzi – Italy
Professor Jeffrey Foss – English Canada
Professor Benoît Rittaud – France
Morten Jødal – Norway
Professor Fritz Vahrenholt – Germany
Rob Lemeire – Belgium
The Viscount Monckton of Brenchley – UK

There is no climate emergency

A global network of 500 scientists and professionals has prepared this urgent message. Climate science should be less political, while climate policies should be more scientific. Scientists should openly address the uncertainties and exaggerations in their predictions of global warming, while politicians should dispassionately count the real benefits as well as the imagined costs of adaptation to global warming, and the real costs as well as the imagined benefits of mitigation.

Natural as well as anthropogenic factors cause warming

The geological archive reveals that Earth’s climate has varied for as long as the planet has existed, with natural cold and warm phases. The Little Ice Age ended as recently as 1850. Therefore, it is no surprise that we now are experiencing a period of warming.

Warming is far slower than predicted

The world has warmed at less than half the originally-predicted rate, and at less than half the rate to be expected on the basis of net anthropogenic forcing and radiative imbalance. It tells us that we are far from understanding climate change.

Climate policy relies on inadequate models

Climate models have many shortcomings and are not remotely plausible as policy tools. Moreover, they most likely exaggerate the effect of greenhouse gases, such as CO2. In addition, they ignore the fact that enriching the atmosphere with CO2 is beneficial.

CO2 is plant food, the basis of all life on Earth

CO2 is not a pollutant. It is essential to all life on Earth. Photosynthesis is a blessing. More CO2 is beneficial for nature, greening the Earth: additional CO2 in the air has promoted growth in global plant biomass. It is also good for agriculture, increasing the yields of crop worldwide.

Global warming has not increased natural disasters

There is no statistical evidence that global warming is intensifying hurricanes, floods, droughts and suchlike natural disasters, or making them more frequent. However, CO2-mitigation measures are as damaging as they are costly. For instance, wind turbines kill birds and bats, and palm-oil plantations destroy the biodiversity of the rainforests.

Policy must respect scientific and economic realities

There is no climate emergency. Therefore, there is no cause for panic and alarm. We strongly oppose the harmful and unrealistic net-zero CO2 policy proposed for 2050. If better approaches emerge, and they certainly will, we have ample time to reflect and adapt. The aim of international policy should be to provide reliable and affordable energy at all times, and throughout the world.

Posted in Center for Environmental Genetics | Comments Off on There is no climate emergency

Maternal microbiota in pregnancy and early life

These GEITP pages have often discussed the microbiome, because of its direct relationship to our gene-environment interactions theme. Molded by both host biology and the physical relationship between mother and child, an important microbial connection is formed at the earliest moments of life when the newborn’s skin and mucosal surfaces are seeded with microorganisms derived from the mother’s body — referred to as the maternal microbiota. This initial microbial exposure establishes an early-life microbiota that reflects a mutualistic relationship with the host, and leaves a lasting impression on childhood development that can control the balance between health and disease. As described in the attached 2-page editorial ‘perspectives’, the quest to understand this microbial bond has uncovered exciting new discoveries about host–microbial mutualism and immune development in early life, while simultaneously revolutionizing our understanding of how certain traits and diseases are passed down through generations.

In humans and other mammals, the first microbes encountered in early life are those from the maternal microbiota. Despite the foundational nature of this event in human development, uncertainty persists about the precise timing of this first contact. The dogmatic belief — that fetal development occurs within a sterile intrauterine environment — has been challenged by evidence of bacterial genomic DNA within placental and chorioamniotic tissues and culturable microbes in newborn meconium (i.e. the first feces passed after birth), raising the controversial possibility that microbial colonization may begin in utero. However, these observations stop short of providing definitive evidence of colonization during fetal development with a bona fide microbiota (i.e. a live, persistent, and functional community of microorganisms); therefore, the concept of a fetal microbiota remains the subject of debate. In support of this, a recent study (on 11 Sept 2019, these GEITP pages reported this) found that the human placenta was devoid of a microbiome — although it was found to contain potential pathogens in a small proportion of samples.

On the contrary, a wealth of evidence demonstrates that the early-life microbiota is seeded at the time of delivery through contact with maternal commensal (i.e. natural, nonpathogenic) bacteria that inhabit the birth canal. The microbial inoculum of vaginally-delivered neonates is dominated by maternal cervicovaginal and fecal microbes, whereas delivery by caesarian section imparts distinct microbial consortia that are often dominated by skin microorganisms. These findings — together with observational studies suggesting an association between caesarian delivery and increased risk of adverse childhood health outcomes (e.g. obesity, asthma, and others), have led some to hypothesize that the distinctive early-life microbiota associated with caesarian delivery may have lasting effects on childhood health.

Although this does not constitute a causal relationship, this provocative association has contributed to the increasingly popular practice of “vaginal seeding” of infants born by caesarian section (i.e. exposing neonates to maternal vaginal content in the first minutes of life) — in an attempt to recapitulate the microbial exposure of a vaginal delivery. However, observational studies of maternal–infant pairs have challenged the lasting impact of delivery route on the early-life microbiota — with data showing evolution of microbial communities over the first 6 weeks of life that culminates in a diversified microbiota, regardless of the original route of delivery. Hmm. Some interesting concepts to ponder… See the attached 2-page perspectives article for more. 😊

DwN

·

· Science 6 Sept 2019; 365: 984-985

Posted in Center for Environmental Genetics | Comments Off on Maternal microbiota in pregnancy and early life