Happiness is in your gene?

We know by nature that some people are always happier than others, no matter in what situation, so we say it's his/her nature. But looking around the world, you also see people in some countries feel happier than those in others, such as, Northern latinos and West Africans are happier than others, even they are poor with more diseases and murders. Will you still say it's their nature? 

Some will say, it is probably due to the equatorial weather; whereas others will argue, it is probably due to national wealth; and there are serious scientists working on these hypotheses. A resent study published in the Journal of the happiness studies (they even have a journal!) suggests that there is indeed a genetic basis for happiness, as we all have taken granted for it.

A basic question is what's happiness, and there is no consistent standard; they used a relative stable standard "good mood" or "positive affect" for people from every nation. The data is from "world values survey". With a scale from  "very happy", "rather happy", "not very happy", to "not at all happy", the percentage of  "very happy" is used for the correlation studies.

Another basic question is what are the possible genes for happiness? One of the candidate is serotonin receptor from depression studies; if you are more likely to be depressive than others, you will less likely to be in good mood.  The other candidate is FAAH, a degradation enzyme of an endogenous cannabinoid from pain studies; if you have less pain than others, you will more likely to be in good mood. The beauty of the gene correlation studies is that with only one genetic code difference, you separate people in different groups, just like what the ABO blood system does — here is a difference on serotonin receptor gene or FAAH gene. In another word, Some people have "C" in a location of FAAH gene, whereas others have "A", and the one with "A" is more likely in good mood than the one with "C". This is their hypothesis.

Therefore, the authors collected the survey data and gene data from many countries and tested the correlation of happiness and gene difference. They did find a strong correlation between happiness and FAAH gene with "A" on the location of rs324420. I immediately checked my data from 23&me, and found that what I have is "C" rather than "A", which fall in the 77% Chinese carrying "C" and "16%" Chinese that don't feel "very happy".  While the top happy nation like Mexican has 46% people with "A" and 60% people feel "very happy". 

This is an interesting result, but it may not be the only correlated gene, and may not be the causal gene for happiness. If gene modification is allowed, we may modify our genes to change the natural happiness if we want, but what for?

When do we start to be aware of fairness?

Imagine a day in the African savanna, when you killed a lion, and went back to your tribe; the chief offered to distribute the lion to everyone with equal shares, but you rejected it because you felt it was unfair to you, and no one had his share. In another day, your brother came back with a dead lion, and the chief offered to give you half of the lion even though you did nothing for the hunting, you rejected again because you felt it was unfair to your brother, and no one got his share. We all have the sense of fairness, which is important for human cooperation.

In economics, this phenomenon is called inequity aversion — disadvantageous inequity aversion (DI) for the first case, and advantageous inequity aversion (AI) for the second case. So when do we start to have the sense of fairness as we grow up? Do we share different fairness in different cultures?

A recent paper in Nature reported the investigation of these questions in children of 4-15 years old from seven communities, with two in WIERD (Western, industrialized, educated, rich, and democratic) countries (USA, Canada), and five in non-WIERD countries (India, Mexico, Peru, Senegal, Uganda). 

They hypothesized that DI is more common than AI across cultures; Children in WEIRD communities are more likely to show AI than those in other communities do, given the difference on adhering to norms of equality; and DI appears earlier than AI. 

To test the hypothesis, they used inequity game in 866 pairs of children, with one of them as actor to decide accepting or rejecting the offers from the experimenter. The offers are small food treats distributed at 1-1 (equal), 1-4 (DI), or 4-1 (AI) ratios. 

They did prove their hypothesis though with some exceptions. What does it mean? They explained, DI "may represent an early application of norms of fairness with a focus on unfairness to oneself... or preserve one’s status relative to potential competitors". Whereas AI "express a norm-based sense of fairness with a focus on unfairness to others". Its commonness in WIERD countries may be due to their incline of adhering to norms of equality.

What's next? Like the authors suggested, they will do more experiments with more life span, diverse communities, and affecting factors of AI and DI. 

Although it's interesting, how will this help in economy? It seems you need both DI and AI to keep the society running normally. Isn't it natural for the survival game?

Family tree of neurons in the brain

Darwin built the tree of evolution, where we learn our position in the history of life on Earth. You can build your family tree with your clan pedigree books. A recent paper in Science reports building a linage tree for neurons.

Archeologists use radioactive isotopes to estimate the age of a rock or bone; biologists use DNA labels to trace cell division;  with genome sequencing, geneticists can use gene mutations to trace our ancestors to African apes. In the Science paper, Lodato et al. used whole genome sequencing of single neurons to detect the mutations with which they built a linage tree of neurons for a single person.

We know during early development, all cells divide and the mutations at that stage will be carried to the descending cells; and after the body mature, most cells stop dividing and keep the mutations from their ancestors. But new mutations will continue to appear in the after dividing cells, which could be the cause of diseases. Every neuron in the brain is different, single mutation in one neuron may becomes the seed for Alzheimer disease,  Parkinson disease, Huntington disease, and CJD......For this reason, Lodato et al. wanted to investigate the mutation pattern in single somatic neurons.

They did whole genome sequencing of 36 neurons from 3 normal adult brains, and analyzed the data on single nucleotide variants. By comparing with reference data, they found ~1500 mutations for each neuron, which are more associated with transcription regulating neuronal functions than DNA replication in cell division as in cancer cells. By comparing the mutations in each neuron, they found the neurons could be arranged into four clades clusters, each originating from the same ancestors during fetal development. The result is a beautiful tree of neurons, though the neurons are taken from a brain tissue within millimeters.

This study makes use of the new techniques to prove a concept that somatic mutations can be used to construct the linage tree of neurons, which is important to understand neurodevelopment. It also indicates somatic mutations may have more weight than germ line mutations for the neurological disorders. This method could be extended to patients' brain to search for the most possible culprit of neurological diseases. However, non-localized somatic mutation, like cancer mutation, is hard to be targeted by gene therapy.

A new therapy for memory loss?

Deep brain stimulation has been used in the treatment of several neurological diseases, such as essential tremor, Parkinson disease, dystonia, and oppressive compulsive disorder. But the exact mechanisms are unknown. A recent paper in Nature add a new disease to the catalogue.

Hao et al. reported that forniceal deep brain stimulation rescued hippocampal memory in Rett syndrome mice. Rett syndrome is a genetic disorder caused by MECP2 gene mutation, leading to a series of abnormalities including apraxia, seizure and intellectual disability. The authors studied the hippocampus-dependent memory in the mouse model of Rett syndrome, because memory deficits is the most reproducible measures in this model. One of the reasons that they use forniceal deep brain stimulation, though not mentioned in the beginning of the paper, might be that forniceal stimulation can enhance hippocampal memory in rodents. Thus their hypothesis is that forniceal stimulation can rescue the memory deficits in Rett syndrome mice.

The animals were divided into 4 groups: wild type sham, wild type stimulation, Rett syndrome sham, and Rett syndrome stimulation. They implanted the stimulation electrodes into the fibria-fornix, and recording electrodes into the dentate gyrus of the brain. Then mice in deep brain stimulation groups were treated with 130 Hz, 60 microsecond pulse for 1 hour a day for 14 days, and the mice in sham group were treated without pulsation. After 3 weeks, they performed the functional tests on these mice. They observed the changes of the fear memory, spatial learning and memory, long term potentiation, and neurogenesis. All these phenotypes were improved in stimulation group compared with sham group, not only for Rett syndrome mice but also for wild type mice. The results indicate that hippocampal neurogenesis are increased by foniceal deep brain stimulation, and thus the hippocampus-dependent memory is improved. More neurogenesis, better memory, like the treadmill experiments in mice once encourage people to run, is not new. And in this report, they may need to increase neurogenesis by another way to see if the memory tests in Rett syndrome brain are improved.

Although it's quite an interesting paper with some promise for neurological disorders that affect learning and memory, I am surprised that Nature accepted this paper.

Visible inequality causes less cooperation and wealth?

In a social network like Linkedin, would you more likely to connect with people with higher social status than you or those with lower ones than you? If you are told your coworkers earned much less than you, would you like to collaborate with them for a project? A recent paper published in Nature provides a laboratory model for questions like these.

Economic inequality exist in most human societies, whereas human have strong preference for equalities. Nishi et al. asked what may determine the inequality and what is the consequence of inequality on wealth. They displayed a networked public goods game—

1. 1462 subjects were placed in groups with a average size of 17.21.

2. Each subject was connected to an average of 5.33 neighbors.

3. The subjects were initially assigned wealth (units) to be rich, poor, or non-rich-non-poor.

4. The subjects played a cooperation game lasting 10 rounds.

5. In each round, the subjects chose to cooperate or defect with each neighbor—cooperate by reducing 50 units from their own wealth to increase their neighbors' by 100 units each; defect by doing nothing to cause no cost and benefit.

6. After the choosing cooperation or defect, the subjects were informed their neighbors' choices, they can then decide to keep or break the connection with their neighbors.

7. Some of the groups were informed the wealth situations (rich, poor, non-rich-non-poor) before the game started.

What they found—

1. Visible wealth, relative to invisible wealth, increases the inequality when the subjects knows they are unequal in the beginning.

2. Invisible wealth causes more average-wealth increase than visible wealth does.

3. Visible wealth, relative to invisible wealth, lowers overall cooperation with neighbors.

4. If the wealth are visible, the new rich in the initial equal condition are more likely to cooperate, whereas the current rich in the initial unequal condition are more likely to defect.

5. The rich keeps rich, and the poor keeps poor.

What does it mean? It means concealing wealth may increase the cooperation and reduce the inequality in the society. And initial equality, relative to initial inequality, causes more wealth increase. Are these true in the real world? It may support some phenomenons like the one mentioned in the beginning, but the real world is complicated, and there are many other factors that may affect the results. At least, it's more difficult to conceal your wealth, and go back to the initial equality now than the hunter-gather time.

The brain structure that makes mothers special

We know intuitively that women are more likely than men to pursue child care. This social task division is attributed to sexual dimorphism in the brain. The hormone difference between women and men not only forges different sexual organs, but also shapes different brain. Due to the difficulties to study human behaviors, our knowledge of sexual dimorphism is mainly based on animal experiments. In a recent Nature paper, the investigators discovered a new neural circuit that control the maternal care in mice.

Dopamine is a neurotransmitter playing essential roles in controlling voluntary movements in midbrain, short of which cause Parkinson disease; it also contributes to many behavioral processes, including mother-pup interaction. In an anatomical structure called anteroventral periventricular nucleus (AVPV) in the hypothalamus, a brain area critical in coordinating sexual dimorphism, we know that there are more dopaminergic neurons in females than males. Thus the investigators of the paper raised their hypothesis — the difference of dopaminergic neurons in AVPV of males and females may cause the sex differences in parental care.

First, they confirmed the double numbers difference of dopaminergic neurons in AVPV between male and female mice, also with more AVPV dopaminergic neurons in parental females than virgin females. Then they pharmacologically destroyed these neurons or genetically overexpressed dopamine in these neurons, or selectively activated these neurons, after which they recorded the parental behavior changes of these mice, including latency to retrieve pups and parental duration in both male and female mice, also aggressive behaviors in male mice. As expected, the ablation of AVPV dopaminergic neurons increased the pup-retrieval latency, and decreased the maternal duration, while overexpressing dopamine or activating these neurons did the opposite in female but not male mice. Unexpectedly, they found the ablation of AVPV dopaminergic neurons can increase male aggressiveness to pups, while overexpressing dopamine or activating these neurons can reduce the aggressiveness.

Next, to connect the dopaminergic neuron difference with more direct functional difference in parental behavior, they tested several possible hormones involved, including oestradiol, corticosterone, prolactin, and oxytocin. Oxytocin is the only hormone that was reduced after AVPV dopaminergic neuron ablation, which let the investigators to make their second hypothesis that AVPV dopaminergic neurons control oxytocin secretion in oxytocin-secreting neurons in paraventricular nucleus (PVN) or supraoptic nucleus (SON). By using chemical tracer and electrophysiological recording, they proved that AVPV dopaminergic neurons projected to PVN oxytocin-secreting neurons, which completes the circuit for maternal care.

These experiments used classical strategy to study anatomical and functional neural circuits, with modern molecular techniques. It could be furthered if the investigators can clarify the dopaminergic control of aggressiveness in male mice during parenting, maybe through another nucleus in amygdala.

ALDH1 and ALDH2, two faces of alcohol tolerance?

Alcoholic is a social problem in western countries but not in East Asian countries probably due to an enzyme difference for alcohol metabolism among the people. Aldehyde dehydrogenase (ALDH) is one of the key enzymes that degrade alcohol to acetic acid in the liver. There are two major isoenzymes of ALDH: ALDH1 and ALDH2. ALDH1 locates in cytosol and ALDH2 locates in mitochondria. Most Caucasians have both isoenzymes, but ~50% East Asians have normal ALDH1 and inactive ALDH2. Interestingly, low ALDH2 activity is associated with alcohol intolerance, whereas low ALDH1 activity is associated with alcoholic.  A recent paper in Science (Kim et al. (2015)) provides a possible explanation for this phenomena.

In the Science paper, the investigators elucidate an alternative pathway for GABA synthesis in midbrain dopaminergic neurons. The neurotransmission in midbrain dopaminergic neurons is essential to understand the mechanisms of Parkinson disease, a neurodegenerative disorder affecting many people. The investigators are interested in a puzzle that GABA and dopamine are co-released from dopaminergic neurons, but very few dopaminergic neurons express the classic GABA synthesis enzymes—glutamate decarboxylases (GAD65 and GAD67). Learning from another enzyme, ALDH, used by plant, frog, and glia cells to synthesize GABA, they had a hypothesis that ALDH is the enzyme for GABA synthesis in midbrain dopaminergic neurons.

First, they recorded the alterations in inhibitory postsynaptic currents (IPSC) in spiny projection neurons in the striatum of mice, which receive input signal (GABA) from midbrain dopaminergic neurons. By using GAD inhibitor or GAD knockout, they confirmed that the IPSC in spiny projection neurons are independent of GAD activity. In addition, they excluded the possibility that dopamine may activate GABA receptors on spiny projection neurons.

Next, based on previous knowledge that one isoenzyme of ALDH, ALDH1,  is cytosolic and highly expressed in the brain, they checked Aldh1a1 expression in midbrain and found it highly abundant in the terminals of midbrain dopaminergic neurons. Then they found the IPSC in spiny projection neurons were reduced with ALDH inhibitors or Aldh1a1 knockout, which supports the hypothesis that ALDH1 mediates the GABA synthesis in midbrain dopaminergic neurons.

At last, due to the association of Aldh1a1 with alcoholic and the involvement of dopaminergic system in alcoholic addiction, they continued to test the connection in a alcohol binge model in mice. They found binge drinking can reduce IPSC in spiny projection neurons, and Aldh1a1 knockout mice consume more alcohol than normal mice. It indicates that alcohol can inhibit GABA synthesis in midbrain dopaminergic neurons, and in people with ALDH1A1 variants, the GABA inhibition is abolished, which causes alcoholic behavior. 

Although both ALDH1 and ALDH2 are involved in alcoholic metabolism, ALDH1 is responsible for GABA synthesis in dopaminergic neurons, whereas ALDH2 is responsible for alcohol clearance. without ALDH1, you are more likely to be alcoholic; without ALDH2, you are more likely to be intolerable of alcohol. That said, ALDH2 is also highly expressed in the brain. Will ALDH2 variants affect the GABA synthesis and alcohol addiction? This is the limit of this paper.

A hope for Down syndrome patient

Recently, a research paper published in Nature sheds some light on the treatment of Down syndrome, a genetic disorder due to an extra copy of chromosome 21 in human cells. A group in University of Massachusetts developed a strategy to silence the extra copy of chromosome 21 and restore the genes in Down syndrome cells to normal in the culture dish.

Down syndrome is a genetic disorder that affects one in 691 live births in US; it causes mental retardation, seizure, early onset of Alzheimer disease, heart disease, diabetes, cancer, and many others.  The British physician John Langdon Down first described the syndrome in 1866, and the French physician Jerome Lejeune first identified the cause of Down syndrome as the presence of an extra copy of chromosome 21 in cells of patients. In the past 147 years, generations of scientists have extensively studied this disorder, and gained much knowledge on the genetics, pathology, diagnosis, and management of Down syndrome. However, due to the complexity of multiple genes over-expressed from the extra copy of chromosome 21 (more than 500 genes have been identified on chromosome 21), there is no cure for this syndrome yet.

Nature is always our best teacher: we learned to use sonar navigation from bats and lighten up cells with green fluorescence protein from jelly fish. Women have two copies of X chromosomes in their cells, but only one copy is activated, with the other copy shutting down during early fetal development. This is caused by a gene on X chromosome, named X-inactive specific transcript (XIST). In 1990s, scientists have discovered that XIST gene translocated to the other chromosomes can silence all the gene expression from that chromosome. But it is not until this year that scientists in University of Massachusetts use this strategy to shut down the genes on chromosome 21 in cells from Down syndrome.

The XIST gene was inserted into one selected location on chromosome 21 in induced pluripotent stem cells (iPS cells) from Down syndrome patients by using a Zinc Finger protein targeting technique. The iPS cells were made from skin cells of a Down syndrome patient; with the characteristics of embryonic stem cells, the iPS cells have the potential to develop into all types of tissues and organs. Because XIST functions in early embryonic development, they used iPS cells for XIST silencing. After the gene insertion by homologous recombination (a natural DNA replication and repair during cell division), they initiated the XIST gene expression by turning on a drug-controlled switch. They then analyzed the gene profiles including mRNA expression and DNA methylation level and found the cellular activities restored to the normal two-copy chromosome level.

The limits of this technique include very low efficiency of inserting XIST gene into chromosome 21, and use of stem cells for the gene integration. However, with the first working proof, the improvement and alternative approaches will grow, and this strategy may provide a real cure for Down syndrome in the future.

References:

Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM, Carone DM, Carone BR, Shivak DA, Guschin DY, Pearl JR, Rebar EJ, Byron M, Gregory PD, Brown CJ, Urnov FD, Hall LL, Lawrence JB.  Translating dosage compensation to trisomy 21. Nature. 2013 Aug 15;500(7462):296-300.  (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12394.html)