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Gene Which Decreases Risk Of Social Network-related Stress, Increases Finance-related Stress Risk

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Researchers have discovered that the same gene which increases your risk of depression following financial stress as you grow older also reduces your chance of depression associated with friendship and relationships stresses when young- your social network.

This may have implications for treatment, but also offers a possible answer to a question which has puzzled scientists: why has depression survived through evolution? This work is presented at the ECNP Congress in Barcelona.

5-HTTLPR, which is found on chromosome 17, is a form (a variant) of the gene which carries the instructions for producing the serotonin transporter protein, which is central to the pharmacology of depression: antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs, e.g. Prozac, Paxil, Zoloft, and others) are the mainstay of drug treatment for depression. One of the two variants of 5-HTTLPR, the short (s) variant is generally thought to promote a tendency to depression, although as depression is associated with many genes, there is no single genetic cause of depression.

For an inherited trait to survive over time, there normally needs to be some advantage to it being passed on, but with depression there is no obvious reason why evolution should allow a tendency to depression to survive.

Now scientists have found that the s variant (5-HTTLPRs) of this gene may help protect against the depression associated with stressors and life events deriving from the social network in younger people. In previous work, the same scientists had found that the 5-HTTLPRs variant does not increase the depression risk following exposure to most types of stressors as had been believed, but in fact may actually only increases the risk of depression following financial stress in older males.

Researcher Dr Xenia Gonda said:

“What we see is the same gene having opposite effects following different types of environmental events and even at different points throughout one’s life. For people under around the age of 30, their social network of friends and acquaintances is vitally important. This is the period when they are looking to form attachments. In this younger age, we found that the 5-HTTLPR s variant protects people against depression when exposed to social network stress. However, our previous work showed us that the same gene variant tends to make people more susceptible to depression if they experience financial stress when they get older.

With the older group, we found that if we looked at the two genders separately, this effect was observable only in men, whose traditional gender role is that of the provider for the family so that’s perhaps why financial problems may be more stressful for them.”

For the latest work, the team had enrolled a sample of 1081 volunteers from Budapest and Manchester, all under the age of 30, and questioned them about 4 different types of stress experience including relationship problems, illness or injury, financial difficulties, and stresses related to the social network such as friends and acquaintances. They found that the short variant of 5-HTTLPR, which is present in around 37-40% of the Caucasian population, conferred a statistically significant protection against depression risk following social network problems, but not against the other stressors in the study.

Dr Gonda continued,

“Depression is not a single disease, and depression related to different types of genes and different stresses may respond to different types of pharmacological and psychotherapeutic treatment. What our study shows that genes involved in depression may actually have positive effects which can also be exploited for therapy. For example those with higher social sensitivity conferred by the s allele may respond better to psychotherapy than those who do not carry this variant, however, further studies would be needed to confirm this.

It’s a subtle distinction, but we believe depending on the environmental context, 5-HTTLPR may have both negative and positive effects; so sometimes it may promote depression, but in certain circumstances, like when exposed to life events and stressors affecting the social network, it protects. We should always consider the possible ancestral context when looking at the adaptive or risk side of genes, and it appears that the adaptive role of 5-HTTLPR was to increase sensitivity to social influences and events with positive outcomes, and its negative effect like increasing depression risk appear only in case of a few types of stress. And this is probably why these genes have been preserved in evolution. But we need to remember that there are multiple genes involved in depression which interact with one another and with the environment, so it’s not as simple as saying ‘this gene causes depression’.

The take-home message from this work is that “depressogenic” genes (genes which are associated with more depression) are not always depressogenic, it depends on their environmental context, your gender, your age, and what type of stress you are under.”

She added:

“We have surveyed more than 1000 people in this research, but this is a fairly modest sample in terms of population genetics, so we are continuing the research to allow us to confirm the findings.”

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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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