A new algorithm for predicting disease risk.

I pass on the text of this piece from Gina Kolata, and then the abstract of the article by Khera et al. she is referencing:

By surveying changes in DNA at 6.6 million places in the human genome, investigators at the Broad Institute and Harvard University were able to identify many more people at risk than do the usual genetic tests, which take into account very few genes.

Of 100 heart attack patients, for example, the standard methods will identify two who have a single genetic mutation that place them at increased risk. But the new tool will find 20 of them...The researchers are now building a website that will allow anyone to upload genetic data from a company like 23andMe or Ancestry.com. Users will receive risk scores for heart disease, breast cancer, Type 2 diabetes, chronic inflammatory bowel disease and atrial fibrillation...People will not be charged for their scores.

The abstract from Nature Genetics:

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

Playing with proteins in virtual reality.

Much of my mental effort while I was doing laboratory research on the mechanisms of visual transduction (changing light into a nerve signal in our retinal rod and cone photoreceptor cells) was devoted to trying to visualize how proteins might interact with each other. I spent many hours using molecular model kits of color-coded plastic atoms one could plug together with flexible joints, like the Tinkertoys of my childhood. If I had only had the system now described by O'Connor et al! Have a look at the video below showing manipulating molecular dynamics in a VR environment,  and here is their abstract:

We describe a framework for interactive molecular dynamics in a multiuser virtual reality (VR) environment, combining rigorous cloud-mounted atomistic physics simulations with commodity VR hardware, which we have made accessible to readers (see isci.itch.io/nsb-imd). It allows users to visualize and sample, with atomic-level precision, the structures and dynamics of complex molecular structures “on the fly” and to interact with other users in the same virtual environment. A series of controlled studies, in which participants were tasked with a range of molecular manipulation goals (threading methane through a nanotube, changing helical screw sense, and tying a protein knot), quantitatively demonstrate that users within the interactive VR environment can complete sophisticated molecular modeling tasks more quickly than they can using conventional interfaces, especially for molecular pathways and structural transitions whose conformational choreographies are intrinsically three-dimensional. This framework should accelerate progress in nanoscale molecular engineering areas including conformational mapping, drug development, synthetic biology, and catalyst design. More broadly, our findings highlight the potential of VR in scientific domains where three-dimensional dynamics matter, spanning research and education.

Sampling molecular conformational dynamics in virtual reality from david glowacki on Vimeo.

The ‘social genomes’ of friends are correlated.

Here is an interesting study from Domingue et al.:

Significance

Our study reported significant findings of a “social genome” that can be quantified and studied to understand human health and behavior. In a national sample of more than 5,000 American adolescents, we found evidence of social forces that act to make friends and schoolmates more genetically similar to one another compared with random pairs of unrelated individuals. This subtle genetic similarity was observed across the entire genome and at sets of genomic locations linked with specific traits—educational attainment and body mass index—a phenomenon we term “social–genetic correlation.” We also find evidence of a “social–genetic effect” such that the genetics of a person’s friends and schoolmates influenced their own education, even after accounting for the person’s own genetics.

Abstract

Humans tend to form social relationships with others who resemble them. Whether this sorting of like with like arises from historical patterns of migration, meso-level social structures in modern society, or individual-level selection of similar peers remains unsettled. Recent research has evaluated the possibility that unobserved genotypes may play an important role in the creation of homophilous relationships. We extend this work by using data from 5,500 adolescents from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine genetic similarities among pairs of friends. Although there is some evidence that friends have correlated genotypes, both at the whole-genome level as well as at trait-associated loci (via polygenic scores), further analysis suggests that meso-level forces, such as school assignment, are a principal source of genetic similarity between friends. We also observe apparent social–genetic effects in which polygenic scores of an individual’s friends and schoolmates predict the individual’s own educational attainment. In contrast, an individual’s height is unassociated with the height genetics of peers.

Trauma is passed over generations.

Bakalar points to work by Santavirta et al. showing that the daughters of women exposed to childhood trauma are at increased risk for psychiatric disorders. The study compared the health of female offspring of ~47,000 Finnish children who were evacuated to Swedish foster homes during World War II, with offspring of female cousins who had not been evacuated. The study:

...found that female children of mothers who had been evacuated to Sweden were twice as likely to be hospitalized for a psychiatric illness as their female cousins who had not been evacuated, and more than four times as likely to have depression or bipolar disorder...But there was no effect among male children, and no effect among children of either sex born to fathers who had been evacuated.

Sorting out complex thoughts and messy emotions

Here is a nice perky piece from Stephen Matheson, editor of Cell Reports, on the genetics of behavior, which I pass along in its entirety (references are in the link):

Cognition. Intelligence. Emotion. Sexuality. These are not merely complicated traits, invoking awed respect. These are aspects of animal life and human nature that are daunting in their biological complexity and in their existential importance. Curious biologists have been tackling animal behavior for centuries, but some topics and behaviors still remain opaque to biological understanding. While the demystification of human nature might give some unease, more of us are simply skeptical of any attempt to unravel the genetic underpinnings of such things.

For years now, genome-wide association studies (GWAS) have been mining ever-growing genetic datasets for clues to the genetic bases of complex traits and diseases that include behaviors and disabilities in cognition, intelligence, sexuality, social interaction, and emotion. Along with a few breakthroughs, there have been significant disappointments and legitimate questions about the limits of potential success (Visscher et al., 2012).

Some geneticists don’t seem to have gotten the memo.

Discussing the biology of human intelligence is a good way to start a scholarly brawl, and yet this complex trait is strongly heritable. Previous GWAS have found hints and candidates for causative genes, but the results are thought to be statistically underpowered. However, in May an international collaborative group published a large meta-analysis of data combined from these previous GWAS (and with new data), and reported 30 new and very promising candidate genes influencing human intelligence (Sniekers et al., 2017). By increasing the cohort (nearly 80,000 people) and using some new tools (such as MAGMA), the work substantially expanded the list of genetic players. One new candidate is FOXO3, a transcription factor involved in insulin/IGF signaling.

What of love? Shakespeare claimed that the course of true love never did run smooth, but geneticists recently claimed that assortative mating occurs in humans, meaning that humans tend to select mates that resemble themselves to some extent (Robinson et al., 2017). This operates phenotypically, separate from confounding influences (such as socialization), and has implications for human population genetics and evolution. Another recent report found 12 genes associated with human reproductive behavior, specifically age at first birth and number of children (Barban et al., 2016). Romantic.

Not even parenting practices are sacred. Hopi Hoekstra and her group study the evolution and genetics of behavior in closely related species of mice—the mice exhibit significant behavioral differences but can interbreed. This facilitates quantitative genetics and whole-genome analysis of behavioral traits. In a paper in April, the group reports on the genetics of parenting (Bendesky et al., 2017). Their tour de force showed heritability of a suite of parental behaviors (such as nest-making and baby-licking) and then dissected the genetic infrastructure. Even though the behaviors seem very similar in males and females, the underlying genetics can differ significantly. One behavior, nest-building, stands out, both because it seems genetically independent of other parenting tasks and because it has evolved through changes in the expression of vasopressin.

Quantitative genetics is bringing powerful tools to old questions, including some deemed sacred or hopelessly complex. More drama is certain to come. Be sure to get a good seat.

Metabolic and physical decline that occurs during aging promoted by a DNA repair enzyme.

Damage to our DNA accumulates during our aging, and Park et al. show a link between this damage and the loss of metabolic function associated with physical decline and aging-associated diseases. They show that DNA breaks activate the repair promoting enzyme DNA-dependent protein kinase (DNA-PK) in skeletal muscle, but the kinase also suppresses mitochondrial function, energy metabolism, and physical fitness. A small-molecule inhibitor of DNA-PK improves the physical fitness of young obese mice and older mice. Whether there is therapeutic potential in such small inhibitors depends on whether inhibition of DNA repair has deleterious effects, such as increasing the potential for cancer. Here is the abstract:

Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.

A chemical link between early life stress and adult schizophrenia

A massive collaboration finds that schizophrenia-like symptoms induced by early life stress in mice correlates with expression of a DNA altering enzyme. Inhibition of that enzyme (whose levels are also increased in human patients with early life stress) reduces schizophrenia-like symptoms:

Significance

Early life stress (ELS) is an important risk factor for schizophrenia. Our study shows that ELS in mice increases the levels of histone-deacetylase (HDAC) 1 in brain and blood. Although altered Hdac1 expression in response to ELS is widespread, increased Hdac1 levels in the prefrontal cortex are responsible for the development of schizophrenia-like phenotypes. In turn, administration of an HDAC inhibitor ameliorates ELS-induced schizophrenia-like phenotypes. We also show that Hdac1 levels are increased in the brains of patients with schizophrenia and in blood from patients who suffered from ELS, suggesting that the analysis of Hdac1 expression in blood could be used for patient stratification and individualized therapy.

Abstract

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Visual category selectivity is innate.

Interesting work from Hurk et al., who find that the brains of people blind since birth show category specific activity patterns for faces, scenes, body parts, and objects, meaning that this functional brain organization does not depend on visual input during development.

Significance

The brain’s ability to recognize visual categories is guided by category-selective ventral-temporal cortex (VTC). Whether visual experience is required for the functional organization of VTC into distinct functional subregions remains unknown, hampering our understanding of the mechanisms that drive category recognition. Here, we demonstrate that VTC in individuals who were blind since birth shows robust discriminatory responses to natural sounds representing different categories (faces, scenes, body parts, and objects). These activity patterns in the blind also could predict successfully which category was visually perceived by controls. The functional cortical layout in blind individuals showed remarkable similarity to the well-documented layout observed in sighted controls, suggesting that visual functional brain organization does not rely on visual input.

Abstract

To what extent does functional brain organization rely on sensory input? Here, we show that for the penultimate visual-processing region, ventral-temporal cortex (VTC), visual experience is not the origin of its fundamental organizational property, category selectivity. In the fMRI study reported here, we presented 14 congenitally blind participants with face-, body-, scene-, and object-related natural sounds and presented 20 healthy controls with both auditory and visual stimuli from these categories. Using macroanatomical alignment, response mapping, and surface-based multivoxel pattern analysis, we demonstrated that VTC in blind individuals shows robust discriminatory responses elicited by the four categories and that these patterns of activity in blind subjects could successfully predict the visual categories in sighted controls. These findings were confirmed in a subset of blind participants born without eyes and thus deprived from all light perception since conception. The sounds also could be decoded in primary visual and primary auditory cortex, but these regions did not sustain generalization across modalities. Surprisingly, although not as strong as visual responses, selectivity for auditory stimulation in visual cortex was stronger in blind individuals than in controls. The opposite was observed in primary auditory cortex. Overall, we demonstrated a striking similarity in the cortical response layout of VTC in blind individuals and sighted controls, demonstrating that the overall category-selective map in extrastriate cortex develops independently from visual experience.

Genetic variants linked to education predict longevity

I'll follow yesterday's post on genetic variation and societal outcomes by passing on yet another piece, this one from Marioni et al.:

Significance

Individuals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including >130,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents; compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.

Abstract

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members’ polygenic profile score for education to predict their parents’ longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.

Genetic correlates of social deprivation and household income

From Hill et al.:

 Highlights

•Common SNPs (single nucleotide polymorphisms) explain 21% of social deprivation and 11% of household income 

•Two loci attained genome-wide significance for household income 

•Genes in these loci have been linked to synaptic plasticity 

•Genetic correlations were found between both measures of SES and many other traits

Summary

Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age. Explanations for the association between SES and health typically focus on factors that are environmental in origin. However, common SNPs have been found collectively to explain around 18% of the phenotypic variance of an area-based social deprivation measure of SES. Molecular genetic studies have also shown that common physical and psychiatric diseases are partly heritable. It is possible that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using 112,151 participants of UK Biobank. We find that common SNPs explain 21% of the variation in social deprivation and 11% of household income. Two independent loci attained genome-wide significance for household income, with the most significant SNP in each of these loci being rs187848990 on chromosome 2 and rs8100891 on chromosome 19. Genes in the regions of these SNPs have been associated with intellectual disabilities, schizophrenia, and synaptic plasticity. Extensive genetic correlations were found between both measures of SES and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings suggest that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES obviously do not reflect direct causal effects and are probably mediated via other partly heritable variables, including cognitive ability, personality, and health.

The Social Gene

I want to pass on some clips from Joseph's Swift's review of a book, "The Society of Genes" by Yanai and Lercher that updates Richard Dawkins's classic "The Selfish Gene" publised 40 years ago. (Their title reminds me of "Society of Mind," a classic book published in 1986 by Marvin Minsky, who recently died at age 88.)

Genetic research has moved rapidly since the publication of Richard Dawkins's The Selfish Gene 40 years ago. In the intervening years, we have come to realize that many of the most interesting and important phenomena in human biology are not caused by any single gene. Processes like the immune system's ability to recognize infection, or the timing of our sleep-wake cycle, for example, are the product of many genes working together in a highly integrated way. Citing a wealth of recent research that explores the ways genes work together to produce complex biological processes, Itai Yanai and Martin Lercher argue that it is time to embrace a new, more holistic, metaphor in their book, The Society of Genes.

Rather than focus on any one gene, Yanai and Lercher invite the reader to step back and observe how genes assemble together to make a global genetic system, or genome. From here, one can see that the labor within the genome is not divided equally. Whereas many genes encode for proteins that perform a single monotonous task, such as breaking down a certain type of sugar or producing a specific skin pigment, there are others that serve such fundamental roles that their removal would lead to the crumbling of the genomic society altogether. Among the latter group are genes that manage the behavior of a host of other genes.

When genes are mismanaged by their masters, organisms can be transformed in dramatic ways. For example, in humans, when SOX9 fails to direct its wide range of subordinates succinctly, sex reversal and skeletal malformations can occur.

Given that catastrophic things tend to happen when genes don't work together properly, changes to how the genomic society is run are a rare occurrence. When genes with new abilities evolve, Darwinian selection determines whether they will join the ranks as productive members of society. Our ancestors obtained genes that could interpret light as color and a gene for a more efficient oxygen-carrying hemoglobin in this very way.

And then there are the genes that don't contribute to society at all. Instead, they secure their position by hijacking the system. The LINE1 gene, for example, encodes only for its own dispersal, copying and pasting itself throughout our genome while providing the society with no clear benefit. The “bad behavior” of genes amounts to scandal in the genomic society, and learning about their exploits is one of the most enjoyable elements of reading the book.

There are even genes that work to ensure the survival of individual cells within an organism by wreaking havoc on others. In fruit flies, for example, a pair of genes involved in sperm production work in concert to produce both a poison and its antidote. The toxic compound is released from the cell, while the antidote is retained. In this way, surrounding sperm cells without the gene pair are killed. On reading about such systems, one begins to realize that it's not quite right to imagine our genome as some idealized republic. This is a society that is easily compromised from within its own ranks.

In the years since The Selfish Gene was published, the human genome has been sequenced, along with the genomes of many other species. Indeed, probing one's own genes is beginning to become routine. Thus, The Society of Genes represents a timely and welcome handbook for navigating this postgenomic era.

The effects of birth order on personality.

Rohrer et. al. issue a new installment on the perennial question of how our birth order influences us, with a study showing higher intelligence in firstborns,  but no birth-order effects on extraversion, emotional stability, agreeableness, conscientiousness, or imagination.:

Significance

The question of whether a person’s position among siblings has a lasting impact on that person’s life course has fascinated both the scientific community and the general public for >100 years. By combining large datasets from three national panels, we confirmed the effect that firstborns score higher on objectively measured intelligence and additionally found a similar effect on self-reported intellect. However, we found no birth-order effects on extraversion, emotional stability, agreeableness, conscientiousness, or imagination. This finding contradicts lay beliefs and prominent scientific theories alike and indicates that the development of personality is less determined by the role within the family of origin than previously thought. 

Abstract

This study examined the long-standing question of whether a person’s position among siblings has a lasting impact on that person’s life course. Empirical research on the relation between birth order and intelligence has convincingly documented that performances on psychometric intelligence tests decline slightly from firstborns to later-borns. By contrast, the search for birth-order effects on personality has not yet resulted in conclusive findings. We used data from three large national panels from the United States (n = 5,240), Great Britain (n = 4,489), and Germany (n = 10,457) to resolve this open research question. This database allowed us to identify even very small effects of birth order on personality with sufficiently high statistical power and to investigate whether effects emerge across different samples. We furthermore used two different analytical strategies by comparing siblings with different birth-order positions (i) within the same family (within-family design) and (ii) between different families (between-family design). In our analyses, we confirmed the expected birth-order effect on intelligence. We also observed a significant decline of a 10th of a SD in self-reported intellect with increasing birth-order position, and this effect persisted after controlling for objectively measured intelligence. Most important, however, we consistently found no birth-order effects on extraversion, emotional stability, agreeableness, conscientiousness, or imagination. On the basis of the high statistical power and the consistent results across samples and analytical designs, we must conclude that birth order does not have a lasting effect on broad personality traits outside of the intellectual domain.

Can epigenetics explain homosexuality?

Michael Balter notes work presented by Vilain's UCLA laboratory at this year's American Society of Human Genetics meeting. His abstract, followed by some clips of his text:

(added note: an alert reader, see comment below, just added this critique of the following work from The Atlantic)

A new study suggests that epigenetic effects—chemical modifications of the human genome that alter gene activity without changing the DNA sequence—may sometimes influence sexual orientation. Researchers studied methylation, the attachment of a methyl group to specific regions of DNA, in 37 pairs of male identical twins who were discordant—meaning that one was gay and the other straight—and 10 pairs who were both gay. Their search yielded five genome regions where the methylation pattern appears very closely linked to sexual orientation. A model that predicted sexual orientation based on these patterns was almost 70% accurate within this group—although that predictive ability does not necessarily apply to the general population.

Researchers thought they were hot on the trail of “gay genes” in 1993, when a team led by geneticist Dean Hamer of the National Cancer Institute reported that one or more genes for homosexuality had to reside on Xq28, a large region on the X chromosome...but some teams were unable to replicate the findings and the actual genes have not been found...Twin studies suggested, moreover, that gene sequences can't be the full explanation. For example, the identical twin of a gay man, despite having the same genome, only has a 20% to 50% chance of being gay himself.

That's why some have suggested that epigenetics—instead of or in addition to traditional genetics—might be involved. During development, chromosomes are subject to chemical changes that don't affect the nucleotide sequence but can turn genes on or off; the best known example is methylation, in which a methyl group is attached to specific DNA regions. Such “epi-marks” can remain in place for a lifetime, but most are erased when eggs and sperm are produced, so that a fetus starts with a blank slate. Recent studies, however, have shown that some marks are passed on to the next generation.

In a 2012 paper, Rice and his colleagues suggested that such unerased epi-marks might cause homosexuality when they are passed on from father to daughter or from mother to son...Such ideas inspired Tuck Ngun, a postdoc in Vilain's lab, to study the methylation patterns at 140,000 regions in the DNA of 37 pairs of male identical twins who were discordant—meaning that one was gay and the other straight—and 10 pairs who were both gay...the team identified five regions in the genome where the methylation pattern appears very closely linked to sexual orientation...Just why identical twins sometimes end up with different methylation patterns isn't clear. If Rice's hypothesis is right, their mothers' epi-marks might have been erased in one son, but not the other; or perhaps neither inherited any marks but one of them picked them up in the womb...In an earlier review, Ngun and Vilain cited evidence that methylation may be determined by subtle differences in the environment each fetus experiences during gestation, such as their exact locations within the womb and how much of the maternal blood supply each receives.

Genetic risk factors for bipolar disorder and schizophrenia predict creativity.

As a follow up to my June 30 post on creativity and neurosis, I wanted to point to the following account by Power et al. (Numerous epidemiological studies have demonstrated overlap between psychiatric disorders and creativity, suggesting that creative genius and insanity are characterized by similar unleashing of thoughts and emotions.)

We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10⁻⁶ and 3.8 × 10⁻⁶ for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.

From the review by Keller and Visscher:

They used a large discovery sample of 86,292 adults from Iceland and four replication samples totaling over 27,000 adults from Sweden and the Netherlands. All had genome-wide SNP genotyping and their professions were known. None of them knowingly suffered from a psychiatric illness. About 1% of them were artists, including actors, dancers, musicians and writers. The authors piggy-backed on recent large genome-wide association studies (GWASs) conducted on SCZ (Schizophrenia) and BD (bipolar disorder) patients and controls, and used the estimated effect on risk of SCZ and BD from thousands of SNP variants that were associated with either SCZ or BD. They then used the observed genotypes in the healthy people from Iceland, Sweden and the Netherlands and predicted a genetic risk score—the sum of associated risk alleles weighted by their estimated effect sizes. Power et al. found that people at higher genetic risk for SCZ or BD had a higher probability of being employed as an artist or belonging to an artists' union.

Evolving ourselves

I pass on a few clips from Xue’s review of “Evolving Ourselves: How Unnatural Selection and Nonrandom Mutation Are Changing Life on Earth” by  J. Enriquez and S. Gullans:

Welcome to the post-genomic age. The idea of the human genome is obsolete…It’s fashionable now to speak of multiple genomes in a single individual, generated by mutations that occur as the body’s cells grow and divide. And genomes aren’t enough: everything has an “-ome” these days. The epigenome, proteome, microbiome, metabolome, connectome, interactome—each vies to be the next new scientific thing to set the public imagination on fire.  

If genes seem to lose their luster, there is no shortage of biological paradigms looking to take their place. The authors describe the epigenome—chemical modifications to DNA that affect when genes are expressed—as each person’s “second genome,” one subject to heritable change due to environmental effects. As it happens, “Second Genome” is also the name of a company that aims to develop therapeutic interventions for the microbiome, which has been increasingly linked to physical health as well as moods and mental disease. “My microbiome made me do it,” one T-shirt proclaims.

It’s no surprise that scientists and the media alike embrace these totalizing languages. They have a seductive simplicity. Genomes first or second are reified into biology itself; scientific progress morphs into promises of technologically designed utopia. “Forever Young, Beautiful, and Fearless?” asks one chapter. “The Robot-Computer-Human Interface,” posits another. It is enough, I hope, to give one pause. Genetic (epigenetic, microbial) engineering could be used for disastrous ends, with or without intent. At the grand-historical scale of the authors’ imaginings, technologies alone cleave a Gordian knot, leaving convoluted personal, political, and societal consequences in their wake.

We may submit to these totalizing scientific vocabularies to pursue fantasies of total biological control, but the bargain is Faustian. When scientific concepts become all that is worth knowing, humanity shrinks to fit what can be known. When all aspects of the human experience are fully and scientifically understood—when DNA becomes the language of personality, and hormones, microbes, and electric pulses the substance of emotion—when genes, memories, and thoughts can be generated and manipulated at will—then, will mankind have ascended at last?   

Altering the oxytocin receptor gene enhances perception of anger and fear.

Puglia et al. find that the epigenetic modification of methylating the DNA of the oxytocin receptor gene (OXTR) decreases the control of amygdala fear responses by brain regions involved in affect appraisal and emotion regulation. Thus individuals with higher levels of OXTR methylation are more reactive to negative emotional facial cues. Clips from their introduction:

A peripheral hormone and central neuromodulator, oxytocin influences a variety of social and affective processes including affiliative behaviors, care-giving, and stress reactivity. Intranasally administered, oxytocin has also been implicated in specialized components of social cognition, such as trust, envy, and mentalizing...One way oxytocin may influence behavior is through anxiety reduction; intranasal oxytocin has been shown to have anxiolytic effects on brain systems supporting affective responses to negatively arousing stimuli. These findings support oxytocin’s role in anxiety reduction and make it an attractive candidate in neurobiological models of psychiatric disorders...Methylation of 5′-Cytosine-phosphate-Guanine-3′ (CpG) dinucleotide pairs in DNA is a highly investigated epigenetic modification that may influence behavioral phenotypes. DNA methylation within the promoter region of OXTR is variable within the population, and methylation of specific OXTR CpG sites reduces transcription of the gene. High levels of OXTR methylation at these same sites have been associated with autism, callous unemotional traits, and anorexia nervosa, suggesting the utility of OXTR methylation as a biomarker of phenotypic variability.

Their abstract:

In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease.

Individuals with increased methylation of OXTR display elevated amygdala response to angry and fearful faces. Mean Z statistic values are plotted against percent OXTR methylation for each participant (n = 98). Gray shading indicates 95% confidence interval around the best-fit line. (Inset) Z statistic map of voxels shows significant main effect of OXTR methylation depicted in MNI space (y = 0), FDR corrected at q less than 0.05. Region of interest is depicted in blue.

Expert listening to music alters gene transcription...So?

I can't resist comment on a piece generated by PsyBlog, "Classical Music's Surprising Effect on Genes Vital to Memory and Learning." ..."How 20 minutes of Mozart affects the expression of genes vital to learning, memory and more…" that points to work of Järvelä​ and collaborators, whose abstract states:

To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experienced participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons...

Apart from issues of control and sample sizes, there is the problem that almost distinctive behavior (athletic engagement, meditation, whatever, can be shown to alter genes transcription. Presenting a trained (versus a naive) person with stimuli in the trained area of expertise would be expected to alter the “transcriptome” to support the brain processing required for that expertise, regardless of what the area is (music, visual art, literature, athletics). We're a long way from being able to make much sense of or interpret the statements that conclude the abstract:

...the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase-coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants.

To be sure, primitive first steps such as these are useful, but it is unfortunate when their popularization by blogs vying for attention proceeds to overinterpretation and hyperbole.

An informative genetic grammatical impairment - the biological basis of language

A fascinating article from van der Lely and Pinker:

•Specific language impairment is a heterogeneous family of genetic developmental disorders that affects the acquisition of language in 7% of children. 

•We have identified a subtype, Grammatical-SLI, which affects the children's syntax, morphology, and phonology in similar ways. 

•Grammatical abilities are not impaired across the board: the children handle forms that are local, linear, semantic, and holistic, while stumbling on those that are nonlocal, hierarchical, abstract, and composed. 

•The mosaic of impaired and spared abilities is consistent with new models of the neural bases of syntax, morphology, and phonology which distinguish several dorsal and ventral language pathways in the brain. 

•We foresee substantial progress in the biology of language – evolution, genetics, neurobiology, computation, behavior – if language and language impairments are differentiated into underlying pathways and components.

Specific language impairment (SLI), a genetic developmental disorder, offers insights into the neurobiological and computational organization of language. A subtype, Grammatical-SLI (G-SLI), involves greater impairments in ‘extended’ grammatical representations, which are nonlocal, hierarchical, abstract, and composed, than in ‘basic’ ones, which are local, linear, semantic, and holistic. This distinction is seen in syntax, morphology, and phonology, and may be tied to abnormalities in the left hemisphere and basal ganglia, consistent with new models of the neurobiology of language which distinguish dorsal and ventral processing streams. Delineating neurolinguistic phenotypes promises a better understanding of the effects of genes on the brain circuitry underlying normal and impaired language abilities.

The article contains some very useful summary graphics describing language areas and their interactions (click to enlarge):

Legend - Neural correlates of Extended and Basic syntax. Syntactic processing in the brain is implemented in distinct dorsal and ventral circuits which may correspond to Extended and Basic syntax. The dorsal route (unbroken red arrow) links Brodmann Area 44 (BA44, a part of Broca's area) via the arcuate fasciculus to the posterior superior temporal gyrus (STG, a part of Wernicke's area); this pathway has been implicated in complex syntactic processing, including hierarchical phrase structure and movement, that is, Extended syntax. The caudate nucleus of the basal ganglia (not shown), a subcortical structure, is interconnected with frontal cortex, and it has also been found to affect Extended syntax. The first of the two ventral circuits (blue arrow) links the frontal operculum (FO, the cortex inferior and medial to BA 44 and 45, mostly hidden) via the uncinate fasciculus to the anterior STG; it supports local phrase structure. The second (purple arrow) links Brodmann Areas 45 (BA45, another part of Broca's Area) and 47 via the extreme capsule fiber system to the middle portion of the superior and middle temporal lobe; it supports retrieval of stored words and associated semantic processing. The two ventral pathways, therefore, may correspond to Basic syntactic processing. Abbreviations: MTG, middle temporal gyrus; ITG, inferior temporal gyrus.

Legend - Neural correlates of Extended and Basic morphology. Regular inflectional forms (walked, played) are computed by Extended processes that closely overlap with those underlying Extended syntax, namely BA 45 extending into BA 44 and BA47, the arcuate fasciculus, and the superior and middle temporal cortex. The frontal regions are part of a circuit that also includes the caudate nucleus (not shown). In contrast, the storage and retrieval of irregular forms (‘brought’, ‘went’) appears to be mediated bilaterally (blue outline) in a more diffuse set of posterior and middle temporal lobe structures. Derived morphological forms, both regular (‘bravely’) and irregular (‘archer’), activate a third, bilateral network, which we tentatively associate with the ventral pathway, specifically, BA47 extending into BA45, and the anterior superior temporal gyrus (STG) and middle temporal gyrus (MTG) (purple lines). This network may support a network of related but whole word forms. Individuals with G-SLI are impaired in productive regular inflection, an Extended process that engages the dorsal route, but their performance is less impaired with the retrieval of irregular and derived forms, a Basic process which is more tried to lexical memory, and which engages bilateral ventral and posterior routes.

Legend - Neural correlates of Extended and Basic phonology. Phonological processing begins with spectrotemporal and segmental processing in bilateral auditory cortex (superior temporal gyrus, STG, and superior temporal sulcus, STS; right hemisphere not shown). From there it splits into two streams. A left-hemisphere dorsal stream runs to a sensorimotor integration area in the Sylvian portion of the parietal–temporal junction (SPT), and from there further bifurcates into a pathway along the superior longitudinal fasciculus to premotor areas (PM; pink arrow) and a pathway along the arcuate fasciculus to Broca's area (BA44; red arrow). These pathways connect acoustic speech representations to articulatory ones, the former perhaps to basic articulatory phonetic skills, the latter to complex syllables and words, self-monitoring speech, and verbal working memory. A bilateral ventral stream (right hemisphere portion not shown) runs from auditory cortex to the middle and inferior temporal gyri (MTG and ITG), and from there to the anterior temporal lobe, and also to a conceptual network widely distributed through the temporal and other lobes. This pathway connects the sounds of words to their meanings. We suggest that the Extended phonology which challenges G-SLI is associated with the part of the dorsal pathway that runs to Broca's area (red), but perhaps not the part that runs to premotor areas (pink), as articulation in the syndrome is relatively unimpaired. Basic phonology is associated with acoustic and phonological analysis in auditory cortex and with the ventral pathway.

Exercise changes our muscle DNA

Following yesterday's post on changing gene expression with brain waves, I'll point to another bit of work on gene changing. Chemical changes to DNA, mainly methylation, can alter gene expression in response a number of environmental changes such as stress, diet, and pollutants. Reynolds points to work by Lindholm et al. now showing that exercise activates health enhancing genes by this epigenetic mechanism. They use the simple trick of measuring and comparing methylation of DNA in exercised and unexercised legs of single individuals (twentythree young subjects bicycled using only one leg, leaving the other unexercised, for three months. The pedaling was at a moderate pace for 45 min, four times per week for three months.) Not surprisingly, the exercised leg was more powerful, but in addition more than 5,000 sites on the genome of muscle cells from the exercised leg now featured new methylation patterns.

This work makes me wish I had a home kit for detecting methylation change in the DNA of my thumb muscles, which show dramatic changes in strength and size depending on how often and energetically I practice the piano.

Genes that turned wildcats into kitty cats.

Reaction of my Abyssinian cat, Melvin, to finding that his genome had been sequenced.

David Grimm summarizes work by Montague et al., who sequenced the genome of a female Abyssinian cat, a domestic breed, and compared it with genome assemblies of six other domestic breeds, two wild cat species, and four other mammals to find genomic differences that might underlie cat biology and domestication. The authors found that, compared with wild cat genomes, domestic cat genomes displayed evidence of natural selection in genes linked to memory, fear-conditioning behavior, and stimulus-reward learning, suggesting that the genetic changes may underlie the evolution of tameness.