Parasites practicing mind control.

Zimmer points to a further installment in the fascinating story of Toxoplasma gondii parasites, who can infect any mammal or bird, but can reproduce only inside of a cat whose feces then contain cysts that infect new hosts. Infected rats and mice become unafraid of feline odor, and thus become easier prey. It turns out the parasites use a very elegant technique to alter their host's behavior: they use an enzyme to remove inhibiting methyl groups from the arginine vasopressin gene, and the resulting increase in arginine vasopressin makes rats become more fearless. The abstract:

Male rats (Rattus novergicus) infected with protozoan Toxoplasma gondii relinquish their innate aversion to the cat odors. This behavioral change is postulated to increase transmission of the parasite to its definitive felid hosts. Here, we show that the Toxoplasma gondii infection institutes an epigenetic change in the DNA methylation of the arginine vasopressin promoter in the medial amygdala of male rats. Infected animals exhibit hypomethylation of arginine vasopressin promoter, leading to greater expression of this nonapeptide. The infection also results in the greater activation of the vasopressinergic neurons after exposure to the cat odor. Furthermore, we show that loss of fear in the infected animals can be rescued by the systemic hypermethylation, and recapitulated by directed hypomethylation in the medial amygdala. These results demonstrate an epigenetic proximate mechanism underlying the extended phenotype in the Rattus novergicus – Toxoplasma gondii association.

Study on relationship between genomics and well being receives a critical trashing.

I recently did a post passing on (as usual, uncritically) what looked like a neat correlation between genomics and human well-being. Brown et al. now issue a foot stomping refutation of that work:

Fredrickson et al. [Fredrickson BL, et al. (2013) Proc Natl Acad Sci USA 110(33):13684–13689] claimed to have observed significant differences in gene expression related to hedonic and eudaimonic dimensions of well-being. Having closely examined both their claims and their data, we draw substantially different conclusions. After identifying some important conceptual and methodological flaws in their argument, we report the results of a series of reanalyses of their dataset. We first applied a variety of exploratory and confirmatory factor analysis techniques to their self-reported well-being data. A number of plausible factor solutions emerged, but none of these corresponded to Fredrickson et al.’s claimed hedonic and eudaimonic dimensions. We next examined the regression analyses that purportedly yielded distinct differential profiles of gene expression associated with the two well-being dimensions. Using the best-fitting two-factor solution that we identified, we obtained effects almost twice as large as those found by Fredrickson et al. using their questionable hedonic and eudaimonic factors. Next, we conducted regression analyses for all possible two-factor solutions of the psychometric data; we found that 69.2% of these gave statistically significant results for both factors, whereas only 0.25% would be expected to do so if the regression process was really able to identify independent differential gene expression effects. Finally, we replaced Fredrickson et al.’s psychometric data with random numbers and continued to find very large numbers of apparently statistically significant effects. We conclude that Fredrickson et al.’s widely publicized claims about the effects of different dimensions of well-being on health-related gene expression are merely artifacts of dubious analyses and erroneous methodology.

Genetic influence on our valuation of free choice

Cockburn et al. find an interesting correlation: A polymorphism in DARPP-32, a gene linked to dopaminergic striatal plasticity and individual differences in reinforcement learning, predicts how strongly people exhibit preference for options they have freely chosen over equally valued options they have not. Here is their abstract, along with a statement of highlights:

 Highlights

Participants exhibit a biased preference for freely chosen rewarding options

DARPP-32 genotype predicts choice bias as a function of expected value

Bias is mirrored by a model that amplifies positive free-choice learning signals

Choice bias is the byproduct of a mechanism that refines learning signal fidelity

Summary

Humans exhibit a preference for options they have freely chosen over equally valued options they have not; however, the neural mechanism that drives this bias and its functional significance have yet to be identified. Here, we propose a model in which choice biases arise due to amplified positive reward prediction errors associated with free choice. Using a novel variant of a probabilistic learning task, we show that choice biases are selective to options that are predominantly associated with positive outcomes. A polymorphism in DARPP-32, a gene linked to dopaminergic striatal plasticity and individual differences in reinforcement learning, was found to predict the effect of choice as a function of value. We propose that these choice biases are the behavioral byproduct of a credit assignment mechanism responsible for ensuring the effective delivery of dopaminergic reinforcement learning signals broadcast to the striatum.

Early life anxiety in monkeys and humans correlates with connectivity between prefrontal cortex and amygdala.

A group of collaborators, mainly at the University of Wisconsin, including Ned Kalin and Richard Davidson, provide new information about the evolutionarily conserved brain network underlying extreme early-life anxiety:

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

Homologous dorsolateral prefrontal cortex (dlPFC) subdivisions show decreased intrinsic connectivity with the central (Ce) nucleus in anxious children and monkeys. (a) Children with anxiety disorders at rest. Bottom-left panel shows the Ce nucleus seed (cyan in red ring). Upper-left panel depicts a coronal slice through the human dlPFC cluster (dark orange; corrected for the combined volume of the mPFC and right dlPFC; n.s. when corrected for the volume of the whole brain). The intermediate frontal sulcus (IFS) is shown in dark red. Upper-right panel shows the IFS with the location of the coronal slice indicated by the blue vertical line. Bottom-right panel shows the location of the dlPFC cluster relative to the architectonic subdivisions of the human dlPFC. (b) Young monkeys with high levels of anxious temperament (AT) under anesthesia. Conventions are similar to a; dark red indicates the location of the sulcus principalis. The bottom-right panels of this figure were adapted with permission from Badre and D'Esposito.74 L, left hemisphere; R, right hemisphere.

Origins of good and evil in human babies.

Felix Warneken does a review in TICS (Trends in Cognitive Sciences) of Paul Bloom new book "Just Babies: The Origins of Good and Evil," which argues that humans, already in the first year of life, have a basic moral sense that is shaped by innate evolved processes.

Bloom...reviews studies in which babies can choose to touch one of two geometrically shaped agents with googly eyes – and they prefer to touch one who helps a struggling fellow up a hill rather than one who pushes that fellow down. This indicates that babies like helping and despise harming others, even if they are only a third party who observes how other people treat each other. Beyond their judgments of the actions of others, young children also display helpful tendencies in their own behavior. Bloom reviews the extensive work on toddlers as young as 18 months of age who display a tendency to comfort others who are in distress, and spontaneously help clumsy people by picking up dropped objects and holding doors open. Last but not least, preschool children seem to have a sense of fairness when faced with the task of divvying up desirable resources, with equality already serving as a guiding principle.

...although our basic, parochially bound moral sentiments come naturally to us without much effort, applying these principles to strangers takes some mental effort. It requires that we employ perspective-taking in our interactions with others...Expanding our moral circle to include strangers thus depends on socialization and abilities that develop only in late childhood...our evolutionarily evolved morality is prepared for kin and friends, but not for strangers. This can be seen in young children's ingroup biases and toddlers’ stranger anxiety.

Still,

...human children depend more on interactions beyond the immediate family than do our closest evolutionary relatives... Infants thus have to tolerate being handed around and interact with many unfamiliar people from early on. We might therefore expect infants to be open-minded and vigilant at the same time, creating their social circles in a more sophisticated manner than ducklings who follow either white feathers or men with white beards, whichever they see first. And it seems as if they do so, not in a naïve fashion, but in a sophisticated way that balances risk and opportunity.

How much do our genes influence our political beliefs?

One of MindBlog’s subject threads has been noting articles that examine the correlation between our genetic constitution and our political behaviors. Thus I point to a recent article by Thomas Edsall that notes work in this controversial field by Ludeke et al. who:

...write that “authoritarianism, religiousness and conservatism,” which they call the “traditional moral values triad,” are “substantially influenced by genetic factors.” — all three traits are reflections of “a single, underlying tendency,” previously described in one word by Bouchard in a 2006 paper as “traditionalism.” Traditionalists in this sense are defined as “having strict moral standards and child-rearing practices, valuing conventional propriety and reputation, opposing rebelliousness and selfish disregard of others, and valuing religious institutions and practices.”

From this perspective, the Democratic Party — supportive of abortion rights, same-sex marriage and the primacy of self-expressive individualism over obligation to family — is irreconcilably alien to a segment of the electorate. And the same is true from the opposite viewpoint: a Republican Party committed to right-to-life policies, to a belief that marriage must be between a man and a woman, and to family obligation over self-actualization, is profoundly unacceptable to many on the left.

Ludeke et al. studied a sample of identical (monozygotic) and fraternal (dizygotic) twins who were separated from each other early in life. They assessed their adult social, political, and social attitudes, finding that they represented a single construct that was heritable and similar to a traditionalism measure. Their abstract:

Social attitudes, political attitudes and religiousness are highly inter-correlated. Furthermore, each is substantially influenced by genetic factors. Koenig and Bouchard (2006) hypothesized that these three areas (which they termed the Traditional Moral Values Triad) each derive from an underlying latent trait concerning the tendency to obey traditional authorities. We tested this hypothesis with data from a sample of twins raised in different homes. We assessed social attitudes with Altemeyer’s (1988) Right-Wing Authoritarianism scale, political attitudes with Wilson and Patterson’s (1968) Conservatism scale, and religiousness with Wiggins’ (1966) Religious Fundamentalism scale. The best-fitting model identified the three TMVT domains as different manifestations of a single latent and significantly heritable factor. Further, the genetic and environmental bases for this factor overlapped heavily with those for the Multidimensional Personality Questionnaire Traditionalism scale, supporting the conception of traditionalism as the latent factor represented by the three scales in contemporary Western societies.

Dopamine receptor genes and independent versus interdependent social orientation.

Kitayama et al. make yet another stab at finding correlates of the often cited distinction of European American (more independent) and Asians (more interdependent). Their suggested genetic correlate can be compared with the environmental correlate I just noted in a recent post. Here, with the usual 'correlations are not causes' disclaimer, is their abstract:

Prior research suggests that cultural groups vary on an overarching dimension of independent versus interdependent social orientation, with European Americans being more independent, or less interdependent, than Asians. Drawing on recent evidence suggesting that the dopamine D4 receptor gene (DRD4) plays a role in modulating cultural learning, we predicted that carriers of DRD4 polymorphisms linked to increased dopamine signaling (7- or 2-repeat alleles) would show higher levels of culturally dominant social orientations, compared with noncarriers. European Americans and Asian-born Asians (total N = 398) reported their social orientation on multiple scales. They were also genotyped for DRD4. As in earlier work, European Americans were more independent, and Asian-born Asians more interdependent. This cultural difference was significantly more pronounced for carriers of the 7- or 2-repeat alleles than for noncarriers. Indeed, no cultural difference was apparent among the noncarriers. Implications for potential coevolution of genes and culture are discussed.

Given that the independent/interdependent ratio is a consequence of gene-cultural environment interaction, it is possible that some cultural effects might be moderated by specific dopamine receptor genetic variants. (Other work has suggested different alleles of the serotonin transporter gene correlate with susceptibility to stress and depression, and that serotonin 1A receptor gene polymorphism correlates with cultural difference in holistic attention.)

Rapidity of human brain and muscle evolution - the downside of smarts?

Roberts does a summary of fascinating work by Bozak et al. He sets the context: 

Somewhat narcissistically, one of the spectacular changes in phenotype that we tend to be most interested in is the enhancement in our own brain power which has occurred over the 6 million years that separate us from our last shared ancestor with chimpanzees. The chimp genome is famously very similar to our own, but the technological, linguistic, and cultural phenotype is clearly profoundly different. Several studies have asked open-ended questions as to what happens between the genotype and phenotype to make us so different from our cousins, finding differences in levels, splicing, and editing of gene transcripts, for example. Now a paper just published in PLOS Biology by Katarzyna Bozek, Philipp Khaitovich, and colleagues looks at another intermediate phenotype—the metabolome—with some intriguing and unexpected answers...The metabolome is the set of small molecules (metabolites) that are found in a given tissue; by “small” we mean those with a molecular weight of less than 1,500 Daltons, which includes fats, amino acids, sugars, nucleotides, and vitamins (vitamin B12, for example, is near the top end of this range).  

...the metabolomes of human prefrontal cortex (and of combined brain regions) have changed four times as rapidly in the last 6 million years as those of chimps. While gratifying, this largely confirms for metabolites what was already known for transcripts. 

...brain is not the most spectacular outlier here. The real surprise is that the human muscle metabolome has experienced more than eight times as much change as its chimp counterpart. Indeed, metabolomically speaking, human muscle has changed more in the last 6 million years than mouse muscle has since we parted company from mice back in the Early Cretaceous.  

...the authors compared the performance of humans, chimps, and macaques in a strength test that involved pulling a handle to raise a weight. Human strength, as measured by this test, was barely half that of the non-human primates. Amazingly, untrained chimps and macaques raised in captivity easily outperformed university-level basketball players and professional mountain climbers. The authors speculate that the fates of human brain and muscle may be inextricably entwined, and that weak muscle may be the price we pay for the metabolic demands of our amazing cognitive powers.

Language universals at birth.

Fascinating observations from Gómez et al. showing that human babies are born with linguistic biases concerning syllable structure:

The evolution of human languages is driven both by primitive biases present in the human sensorimotor systems and by cultural transmission among speakers. However, whether the design of the language faculty is further shaped by linguistic biological biases remains controversial. To address this question, we used near-infrared spectroscopy to examine whether the brain activity of neonates is sensitive to a putatively universal phonological constraint. Across languages, syllables like blif are preferred to both lbif and bdif. Newborn infants (2–5 d old) listening to these three types of syllables displayed distinct hemodynamic responses in temporal-perisylvian areas of their left hemisphere. Moreover, the oxyhemoglobin concentration changes elicited by a syllable type mirrored both the degree of its preference across languages and behavioral linguistic preferences documented experimentally in adulthood. These findings suggest that humans possess early, experience-independent, linguistic biases concerning syllable structure that shape language perception and acquisition.

Passing ADHD from one generation to the next.

Prenatal and early postnatal exposure of the developing brain to nicotine (PNE) is a major risk factor for inducing attention deficit hyperactivity disorder (ADHD). Children born to mothers who smoke cigarettes before, during, or immediately after pregnancy have a twofold higher risk of developing ADHD. Zhu et al. show that hyperactivity and attention deficits induced by putting nicotine in the drinking water of pregnant mice is transmitted from one generation to the next via the maternal but not the paternal line of descent. The authors note:

A plausible mechanism for the transgenerational transmission of the PNE-induced brain and behavioral changes is heritable epigenetic modifications of the germ cell genome. Nicotine is known to produce DNA methylation in a number of genes, including the gene coding for monoamine oxidase, a key enzyme in the metabolism of dopamine and other monoamines.

Genetic predisposition of our behavioral responses.

Gregory sets the context for a recent article by Skuze et al. on how genes for our oxytocin receptors can influence our social recognition skills:

...the notion that the evolution of our behavioral response is solely shaped by the events themselves is challenged by studies that highlight how interindividual differences in social perception and response to social cues may be determined by underlying genetic predisposition. These studies are establishing that our DNA contains heritable variants that contribute to subtle differences in social cognition. These sequence variants are contained within genes that not only play a role in the relationship that parents may have with their offspring but also how we recognize or react to one another. In PNAS, Skuse et al.investigate the signaling pathways of neuropeptides oxytocin (OT) and arginine-vasopressin (AVP) to identify DNA polymorphisms that might explain interindividual differences in response to social cues. The authors genotyped a series of SNPs from the OT and AVP receptor regions to identify SNPs that account for variation in response to tests of social cognition in autism spectrum disorder (ASD) families.

Here is the Skuze et al. abstract:

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7–60 y) and sex. A common SNP (single nucleotide polymorphism) in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range −0.6 to −1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

The social life of our genes - the devastating effects of social isolation

David Dobbs has done a broad and accessible review of how completely the expression of the genes regulating behavior are controlled by the social milieu, giving examples for bees, birds, fish, primates, and humans. Social conditions can change our gene expression with a rapidity, breadth, and depth previously overlooked. Humans, and other animals, most likely have this evolved capability because an organism that responds quickly to fast-changing social environments will more likely survive them. Dobbs points in particular to work by work by Steve Cole on social regulation of gene expression. Cole analyzed the relationship between social factors and human gene expression by surveying transcriptional profiles in white blood cells (leukocytes) from healthy older adults who differed in the extent to which they felt socially connected to others.

Among the 22,283 genes assayed, 209 showed systematically different levels of expression in people who reported feeling lonely and distant from others consistently over the course of 4 years (see Figure). These effects did not involve a random smattering of all human genes, but focally affected three specific groups of genes. Genes supporting the early “accelerator” phase of the immune response—inflammation—were selectively up-regulated; and two groups of genes involved in the subsequent “steering” of immune responses—genes involved in responses to viral infections (particularly Type I interferons), and genes involved in the production of antibodies by B lymphocytes—were down-regulated. These results provided a molecular framework for understanding why socially isolated individuals show heightened vulnerability to inflammation-driven cardiovascular diseases (i.e., excessive nonspecific immune activity) and impaired responses to viral infections and vaccines (i.e., insufficient immune responses to specific pathogens). A major clue about the psychological pathways mediating these effects came from the observation that differential gene-expression profiles were most strongly linked to a person's subjective sense of isolation rather than to their objective number of social contacts.

Figure: Gene expression in human immune cells in lonely and socially integrated people. Expression of 22,283 human gene transcripts was assayed in 10 million blood leukocytes sampled from each of 14 older adults who showed consistent differences over 4 years in their level of subjective social isolation. Two hundred nine gene transcripts showed at least 30% difference in average expression level between six people experiencing chronic social isolation and eight experiencing consistent social integration. In the heat-plot above, each row represents data from one of the 14 study participants, each column contains expression values for one of the 209 differentially active genes, and the coloring of each cell represents the relative level of that gene's expression in a given participant's leukocyte sample: Red = high expression, Black = intermediate expression, Green = low expression.

Social Darwinism isn't dead - the rich really do think they are different...

An engaging piece by Matthew Hutson in Slate points to work by Kraus and Keltner. Some clips:

...In 2012 the top 0.01 percent of households earned an average of $10.25 million, while the mean household income for the country overall was $51,000. Are top earners 200 times as smart as the rest of the field? Doubtful. Do they have the capacity to work 200 times more hours in the week? Even more doubtful.

..say you’re in that top 0.01 percent—or even the top 50 percent. Would you want to admit happenstance as a benefactor? Wouldn’t you rather believe that you earned your wealth, that you truly deserve it? Wouldn’t you like to think that any resources you inherited are rightfully yours, as the descendant of fundamentally exceptional people? .. you might even adjust your ideas about the power of genes. The lower classes are not merely unfortunate, according to the upper classes; they are genetically inferior.

Kraus and Keltner's work explores "social class essentialism" - the belief that surface differences can be explained by differences in fundamental identities. Studies have shown that

...people hold essentialist beliefs about generally biological categories such as gender, race, and sexuality, as well as about more cultural ones such as nationality, religion, and political orientation. Essentialism leads to stereotyping, prejudice, and a disinclination to mingle with outsiders.

Kraus and Keltner wanted to know if we see social class as an essential category. They found:

...that higher social class was associated with greater social class essentialism. This pattern remained even after controlling for political orientation as well as objective measures of a participant’s income and education level, indicating that it’s one’s sense of being above or below others, not one’s actual resources, that drives the result...the higher people perceived their social class to be, the more strongly they endorsed just-world beliefs (i.e. that the world is a fair place), and that this difference explained their increased social class essentialism: Apparently if you feel that you’re doing well, you want to believe success comes to those who deserve it, and therefore those of lower status must not deserve it.

There is a grain to truth to social class essentialism; the few studies on the subject estimate that income, educational attainment, and occupational status are perhaps at least 10 percent genetic (and maybe much more). ..But that’s a far cry from saying “It is possible to determine one’s social class by examining his or her genes.” Such a statement ignores the role of wealth inheritance, the social connections one shares with one’s parents, or the educational opportunities family money can buy—not to mention strokes of good or bad luck (that are not tied to karma).

Social class essentialism is basically inciting social Darwinism. This distortion of Darwin’s theory of evolution, in one interpretation, is the belief that only the fit survive and thrive—and, further, that this process should be accepted or even accelerated by public policy...It might also entail belief in survival of the fittest as a desired end, given the results linking it to reduced support for restorative interventions... It’s an example of the logical fallacy known as the “appeal to nature”—what is natural is good. (If that were true, technology and medicine would be moral abominations.)

Your brain has many genomes.

Life used to be simple. We had one set of genes, found in all cells of the body. Skin cells, liver cells, and brain cells were different only because different subsets of those genes were expressed appropriate to each organ. Now, it is turning out that one organ, like the heart, may be governed by one set of genes (genome) while the brain may be run by a mosaic of other genomes generated by somatic mutations, (as opposed to germline mutations that are inherited and found in every body cell.) Psychiatric genetic studies generally have assumed mutations in red blood cells would also appear in the brain, but mutations unique to brain genomes have now been found.

Thomas Insel, who is head of the National Institute of Mental Health, has written a paper on this situation titled “The dark matter of psychiatric genetics.” Here is his abstract:

Although inherited DNA sequences have a well-demonstrated role in psychiatric disease risk, for even the most heritable mental disorders, monozygotic twins are discordant at a significant rate. The genetic variation associated with mental disorders has heretofore been based on the search for rare or common variation in blood cells. This search is based on the premise that every somatic cell shares an identical DNA sequence, so that variation found in lymphocytes should reflect variation present in brain cells. Evidence from the study of cancer cells, stem cells and now neurons demonstrate that this premise is false. Somatic mutation is common in human cells and has been implicated in a range of diseases beyond cancer. The exuberant proliferation of cortical precursors during fetal development provides a likely environment for somatic mutation in neuronal and glial lineages. Studies of rare neurodevelopmental disorders, such as hemimegencephaly, demonstrate somatic mutations in affected cortical cells that cannot be detected in unaffected parts of the brain or in peripheral cells. This perspective argues for the need to investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins, a proximate cause of mental disorders in individuals with inherited risk, and a potential guide to novel treatment targets.

Sequence your microbiome!

Some months ago I paid 23andMe about a $100 to analyze a mouth swab of epithelial cell and report back information on my genetic makeup, ancestry, health risks, etc. I was particularly interested in the SNPs (single nucleotide polymorphisms) that correlate with more or less risk for things like heart disease, alzheimer’s, etc. (The FDA has recently shut down their releasing that information to new subscribers because they have decided it is an untested medical diagnostic procedure.)

I want now to mention another neat test you can purchase for ~$100, where you send in a swab of your poop, mouth , and skin and are sent back information on your microbiome, the genes of hundreds of microbial species (microbiota) that share your body with you. Michael Pollan, the guy who has written best selling food books (Omnivore’s Dilemma, etc.) has done an engaging piece on this. Some clips:

To the extent that we are bearers of genetic information, more than 99 percent of it is microbial. And it appears increasingly likely that this “second genome,” as it is sometimes called, exerts an influence on our health as great and possibly even greater than the genes we inherit from our parents. But while your inherited genes are more or less fixed, it may be possible to reshape, even cultivate, your second genome.

Disorders in our internal ecosystem — a loss of diversity, say, or a proliferation of the “wrong” kind of microbes — may predispose us to obesity and a whole range of chronic diseases, as well as some infections. “Fecal transplants,” which involve installing a healthy person’s microbiota into a sick person’s gut, have been shown to effectively treat an antibiotic-resistant intestinal pathogen named C. difficile, which kills 14,000 Americans each year....[there is concern] about the damage that antibiotics, even in tiny doses, are doing to the microbiome — and particularly to our immune system and weight. “Farmers have been performing a great experiment for more than 60 years...by giving subtherapeutic doses of antibiotics to their animals to make them gain weight...the “Westernized microbiome” most of us now carry around is in fact an artifact of civilization”

...a pristine microbiome — of people who have had little or no contact with Westerners — features much greater biodiversity, including a number of species never before sequenced, and ... much higher levels of prevotella than is typically found in the Western gut....these vibrant, diverse and antibiotic-naïve microbiomes may play a role in Amerindians’ markedly lower rates of allergies, asthma, atopic disease and chronic conditions like Type 2 diabetes and cardiovascular disease.

The successful gardener has always known you don’t need to master the science of the soil, which is yet another hotbed of microbial fermentation, in order to nourish and nurture it. You just need to know what it likes to eat — basically, organic matter — and how, in a general way, to align your interests with the interests of the microbes and the plants. The gardener also discovers that, when pathogens or pests appear, chemical interventions “work,” that is, solve the immediate problem, but at a cost to the long-term health of the soil and the whole garden. The drive for absolute control leads to unanticipated forms of disorder.

This, it seems to me, is pretty much where we stand today with respect to our microbiomes — our teeming, quasi-wilderness. We don’t know a lot, but we probably know enough to begin taking better care of it. We have a pretty good idea of what it likes to eat, and what strong chemicals do to it. We know all we need to know, in other words, to begin, with modesty, to tend the unruly garden within.

A genetic predisposition to note the negative.

Another interesting example of viewing the world through gene-colored glasses...Todd et al. note an interesting behavioral correlation involving a gene variant, carried by ~50% of Caucasians, of subtype B of the α2-adrenergic receptor: people with the variant are more likely to take note of negative events. They use the "attentional blink" paradigm to reach this conclusion:

The attentional blink...is a phenomenon in which participants are typically unable to identify a target stimulus when it is presented less than approximately 500 ms after a previous target in a rapid stream of stimuli. One interpretation of this blink is that it reflects a failure of attentional filters to consolidate the second target into working memory when it appears too quickly after the first, which results in impaired perceptual awareness. When the second target has emotional significance, there is a reduced attentional blink, or an emotional sparing. This emotional sparing, or reduction of the attentional blink for emotional stimuli relative to neutral stimuli, can be seen as the relative tuning of selective attention to affective stimuli.

Here is their abstract (which contains the fairly common error of using "are responsible for" instead of the more correct "correlate with"):

Emotionally enhanced memory and susceptibility to intrusive memories after trauma have been linked to a deletion variant (i.e., a form of a gene in which certain amino acids are missing) of ADRA2B, the gene encoding subtype B of the α2-adrenergic receptor, which influences norepinephrine activity. We examined in 207 participants whether variations in this gene are responsible for individual differences in affective influences on initial encoding that alter perceptual awareness. We examined the attentional blink, an attentional impairment during rapid serial visual presentation, for negatively arousing, positively arousing, and neutral target words. Overall, the attentional blink was reduced for emotional targets for ADRA2B-deletion carriers and noncarriers alike, which reveals emotional sparing (i.e., reduction of the attentional impairment for words that are emotionally significant). However, deletion carriers demonstrated a further, more pronounced emotional sparing for negative targets. This finding demonstrates a contribution of genetics to individual differences in the emotional subjectivity of perception, which in turn may be linked to biases in later memory.

How environments talk to genes.

The January issue of Nature Neuroscience has some fascinating articles on gene-environment interactions. Vassoler et al. report that in rats paternal cocaine use causes a heritable increase in cortical brain-derived neurotrophic factor (Bdnf) gene expression, which then confers a cocaine-resistant phenotype in male, but not female, progeny (The sins of the father are forgiven!):

We delineated a heritable phenotype resulting from the self-administration of cocaine in rats. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (Bdnf) mRNA and BDNF protein were increased in the medial prefrontal cortex (mPFC), and there was an increased association of acetylated histone H3 with Bdnf promoters in only the male offspring of cocaine-experienced sires. Administration of a BDNF receptor antagonist (the TrkB receptor antagonist ANA-12) reversed the diminished cocaine self-administration in male cocaine-sired rats. In addition, the association of acetylated histone H3 with Bdnf promoters was increased in the sperm of sires that self-administered cocaine. Collectively, these findings indicate that voluntary paternal ingestion of cocaine results in epigenetic reprogramming of the germline, having profound effects on mPFC gene expression and resistance to cocaine reinforcement in male offspring.

And, Klengel et al. find a molecular mechanism in the case of post-traumatic stress disorder: demethylation of a glucocorticoid response element in the stress response regulator FKBP5 that depends on both the risk allele and childhood trauma. Here is the jargon:

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

Resilience to stress replacing happiness as fashionable research topic

Nature has published a special supplement on Stress and Relilience, a topic also of major emphasis in Richard Davidson's new book. I thought the article by Nestler on epigenetic regulation of resilience to stress was particularly interesting, especially following on this past Monday's post (look there for reminder of definitions of epigenetic changes, etc.) His research is on epigenetic differences between mice that are resilient versus susceptible to stress:

We can make susceptible mice resilient by blocking or inducing epigenetic modifications to certain genes or by altering the expression patterns of those genes to mimic the epigenetic tweaks. Likewise, epigenetic modifications and gene expression can be altered in resilient mice to make them more susceptible.

Other groups have found similar epigenetic alterations that last a lifetime. For instance, rat pups that are rarely licked and groomed by their mothers are more susceptible to stress later in life than are pups with more diligent carers. They are less adventurous than better-cared-for offspring and put up less of a fight in unpleasant situations (such as being placed in a beaker of water). Moreover, the females are less nurturing towards their own offspring. Epigenetic modifications seem to occur at several genes in the hippocampus in response to how much grooming young rats receive, and these alterations persist into adulthood.

These findings are likely to hold up in humans. For example, researchers have found that the genes identified in the rat-grooming studies were more methylated in the hippocampi of suicide victims who had experienced trauma as children than in the those of people who had died from suicide or natural causes and whose childhoods were normal. Likewise, our findings in mice given cocaine mirror epidemiological studies from the past few decades that have linked drug abuse, obesity and conditions such as multiple sclerosis, diabetes and heart disease to increased susceptibility to stress in humans.

More controversial is whether animals inherit epigenetic vulnerability to stress. According to this notion, epigenetic modifications in sperm or eggs drive aberrant patterns of gene expression in the next generation. Several groups have reported that male mice exposed to stress — by being removed from their mothers as pups or exposed to more aggressive mice as adults, for example — produce offspring that are more vulnerable to stress.

A mechanism is still elusive. Exposure to stress could somehow corrupt the male mouse's behaviour or affect some signalling molecule in his semen such that his partner alters her care for their young. Another possibility is that stress-linked epigenetic 'marks' in the sperm affect the development of offspring. No causal evidence yet links epigenetic changes in sperm to altered behaviour in offspring.

A revolution in understanding our genetics, personality, and disease.

A revolution is taking place. It challenges the basic genetic orthodoxy of the past century, changing what all of us thought we knew. This is dense material, but very important, and I would urge general readers to try to have a go at it. (Few MindBlog readers would be up for taking on the Wonkish details of Nelson et al.'s paper on 'epigenetic effects of…cytidine deaminase deficiency…etc.' - so I want to pass on edited and rearranged clips from a commentary by Mattick that shows (still Wonkish, but less so) the context and importance of this and similar studies):

Nelson et al. present intriguing evidence that challenges the fundamental tenets of genetics. It has long been assumed that the inherited contribution to phenotype is embedded in DNA sequence variations in, and interactions between, the genes endogenous to the organism, i.e., alleles derived from parents with some degree of de novo variation. This assumption underlies most genetic analysis, including the fleet of genome-wide association studies launched in recent years to identify genomic loci that influence complex human traits and diseases....the perplexing and much debated surprise has been that most genome-wide association studies have superficially failed to locate more than a small percentage of the inherited component of complex traits. This may be a result of a number of possibilities...including... intergenerational epigenetic inheritance, which is not polled by DNA sequence. However, the latter has not thus far been paid much attention or given much credence as a major factor.

Now Nelson et al. provide data suggesting that epigenetic inheritance may be far more important and pervasive than expected. (Mechanistically, epigenetic memory is embedded in DNA methylation and/or histone modifications, which are thought to be erased in germ cells, but may not be, at least completely, as some chromatin structure appears to be preserved. Some information may also be cotransmitted by RNA.) Their findings add to a growing list of studies indicating that genetic influence of ancestral variants can commonly reach through multiple generations and rival conventional inheritance in strength. These include the demonstrations, with considerable molecular and genetic detail, of epigenetic inheritance (i.e., “paramutation”) in plants, and, although still somewhat controversial, in animals.

Although the genetics are complex, Nelson et al.show in an elegant and comprehensive series of analyses that grand-maternal (but not grand-paternal) heterozygosis for a null allele of the Apobec1 cytidine deaminase gene modulates testicular germ cell tumor susceptibility and embryonic viability in male (mouse) descendants that do not carry the null allele, an effect that persists for at least three generations.

...here is now good evidence that epigenetic inheritance is RNA-mediated...as it is becoming clear that a major function of the large numbers of noncoding RNAs that are differentially expressed from the genome is to direct chromatin-modifying complexes to their sites of action. This conclusion is consistent with the recent findings of the ENCODE project, suggesting that much if not most of the human genome may be functional, and explains the informational basis of the extraordinary precision and complexity of the epigenetic superstructure of the genome in different cells required to specify developmental architecture.

The available evidence not only suggests an intimate interplay between genetic and epigenetic inheritance, but also that this interplay may involve communication between the soma and the germline. This idea contravenes the so-called Weismann barrier, sometimes referred to as Biology’s Second Law, which is based on flimsy evidence and a desire to distance Darwinian evolution from Lamarckian inheritance at the time of the Modern Evolutionary Synthesis. However, the belief that the soma and germline do not communicate is patently incorrect—as demonstrated by the multigenerational inheritance of RNAi-mediated phenotypes delivered to somatic cells in Caenorhabditis elegans.

Thus, if RNA editing can alter hardwired genetic information in a context-dependent manner, and thereby alter epigenetic memory, it is feasible that not only allelic but also environmental history may shape phenotype, and provide a far more plastic and dynamic inheritance platform than envisaged by the genetic orthodoxy of the past century. Morever...RNA, more than DNA, may be the computational engine of the evolution and ontogeny of developmentally complex and cognitively advanced organisms

The unimaginable complexity of our evolved human systems.

In the face of all the current hubris about redesigning and engineering humans using modern genetic and biochemical tools, trying to reverse engineer brain systems that were never engineered in the first place, Randolph Nesse offers a very therapeutic essay. Here is a slightly edited version:

The products of natural selection are … not merely complicated in the way that machines are complicated, they are organically complex in ways that are fundamentally different from any product of design. This makes them difficult for human minds to fully describe or comprehend. So, we use that grand human gambit for understanding, a metaphor, in this case, the body as machine…it easy to portray the systems that mediate cell division, immune responses, glucose regulation, and all the rest, using boxes for the parts, and arrows to indicate causes what. Such diagrams summarize important information in ways we can grasp. .. But, they fundamentally misrepresent the nature of organic complexity.

Thinking about the body as a machine was a grand advance in the 16th century, when it offered an alternative to vitalism and vague notions of the life force. Now it is outmoded. It distorts our view of biological systems by fostering thinking about them as simpler and more sensibly "designed" than they are. Experts know better. They recognize that the mechanisms that regulate blood clotting are represented only crudely by the neat diagrams medical students memorize; most molecules in the clotting system interact with many others. Experts on the amygdala know that it does not have one or two functions, it has many, and they are mediated by scores of pathways to other brain loci. Serotonin exists not mainly to regulate mood and anxiety, it is essential to vascular tone, intestinal motility, and bone deposition. Leptin is not mainly a fat hormone, it has many functions, serving different ones at different time, even in the same cell. The reality of organic systems is vastly untidy. If only their parts were all distinct, with specific functions for each! Alas, they are not like machines. Our human minds have as little intuitive feeling for organic complexity as they do for quantum physics.

Recent progress in genetics confronts the problem. Naming genes according to postulated functions is as natural as defining chairs and boats by their functions. If each gene were a box on a blueprint labeled with its specific function, biology would be so much more tractable! However, it is increasingly clear that most traits are influenced by many genes, and most genes influence many traits. For instance, about 80% of the variation in human height is accounted for by genetic variation. It would seem straightforward to find the responsible genes. But looking for them has revealed that the 180 loci with the largest effects together account for only about 10% of the phenotypic variation. Recent findings in medical genetics are more discouraging. Just a decade ago, hope was high that we would soon find the variations that account for highly heritable diseases, such as schizophrenia and autism. But scanning the entire genome has revealed that there are no common alleles with large effects on these diseases. Some say we should have known. Natural selection would, after all, tend to eliminate alleles that cause disease. But, thinking about the body as a machine aroused unrealistic hopes.

The grand vision for some neuroscientists is to trace every molecule and pathway to characterize all circuits in order to understand how the brain works. Molecules, loci, and pathways do serve differentiated functions, this is real knowledge with great importance for human health. But, understanding how the brain works by drawing a diagram that describes all the components and their connections and functions is a dream that may be unfulfillable. The problem is not merely fitting a million items on a page, the problem is that no such diagram can adequately describe the structure of organic systems. They are products of miniscule changes, from diverse mutations, migration, drift, and selection, which develop into systems with incompletely differentiated parts and incomprehensible interconnections, that, nonetheless, work very well indeed. Trying to reverse engineer brain systems focuses important attention on functional significance, but it inherently limited, because brain systems were never engineered in the first place.

If bodies are not like machines, what are they like? They are more like Darwin's "tangled bank" with its "elaborately constructed forms, so different from each other, and dependent upon each other in so complex a manner." Lovely. But, can an ecological metaphor replace the metaphor of body as machine? Not likely. Perhaps someday understanding how natural selection shapes organic complexity will be so widely and deeply understood that scientists will be able to say "A body is like…a living body," and everyone will know exactly what that means.