Gene genie

[Jo Bowyer]

Each Cell Has a Clock

http://jonlieffmd.com/blog/neuronal-...f84f7-90589721

For many years there was a consensus that most organisms have a circadian clock. In humans it was considered to be directed centrally by the master clock in the brain region suprachiasmatic nucleus (SCN). This clock appears to be involved in directing essential physiological processes throughout the body including secretion of hormones, metabolism, energy, and of course, sleep and wakefulness. It was not at all clear how this central clock works and how it communicates with so many different cellular physiological functions.

Recently, it was a shock to the scientific community, when it was discovered that every cell has a fully functional clock, including microbes. The question now has become how all these cells interact together—how they coordinate their clocks, their genes, and their activity.

Meal Timing Regulates the Human Circadian System

http://www.cell.com/current-biology/...showall%3Dtrue

Highlights

•A 5-hr delay in meal times changes the phase relationship of human circadian rhythms

• Plasma glucose, but not insulin or triglyceride, rhythms are delayed by late meals

• Adipose PER2 rhythms are delayed by late meals

• Rhythm changes occur without altered subjective or actigraphic sleep markers

Summary

Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants’ circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.

Update 04/06/2017

[marcel]

Where are the genes that are relevant to the brain?

[YT]AzDLkPFjev4[/YT]

Full video Robert Sapolsky: Are Humans Just Another Primate?

The gene "myth" is a "soundbite":" our genes are 98% similar to those of chimps"

[marcel]

You may find this interesting;

Sue Biggins (Fred Hutchinson Cancer Research Center, HHMI) 1: Chromosome Segregation

Proper chromosome segregation during cell division is critical to ensure that daughter cells inherit the correct number of chromosomes.
Microtubules emanating from the spindle poles pull on sister chromatids to move one chromosome to each pole. The kinetochore, a protein complex on the chromosome, is key to regulating chromosome segregation. Kinetochores form attachments to microtubule ends (no easy feat since microtubules are constantly growing and shrinking), they sense tension to ensure that sister chromatids are connected to microtubules from opposite poles, and they signal the cell to stop cell division if attachment is not correct. Biggins gives an excellent overview of kinetochore structure and its critical functions in chromosome segregation.

When Biggins began working on kinetochores, the experiments that she could do were limited by the lack of a method to purify intact kinetochores. In Part 2 of her talk, Biggins explains how her lab purified kinetochores from yeast (for the first time ever!). They showed that the purified protein complex functioned in the same manner in vitro as endogenous kinetochores. Using electron microscopy and other techniques, Biggins and her collaborators were able to visualize the structure of the kinetochore-microtubule attachment and demonstrate, surprisingly, that tension directly stabilizes the attachment.

Speaker Biography:
Dr. Sue Biggins studied biology as an undergraduate at Stanford University and initially thought she would apply to medical school after receiving her degree. However, after a summer working in a research lab, she changed her mind and decided to apply to graduate school. Biggins received her PhD in molecular biology from Princeton and was a post-doctoral fellow with Andrew Murray at the University of California, San Francisco.
Currently, Biggins is a Principal Investigator in the Division of Basic Sciences at the Fred Hutchinson Cancer Research Center and an Investigator of the Howard Hughes Medical Institute. Her lab studies the kinetochore and how it regulates chromosome segregation. Chromosome mis-segregation results in aneuploidy, a common hallmark of cancer as well hereditary birth defects.
Biggins’ groundbreaking research has been recognized with numerous honors. In 2013, Biggins received the National Academy of Sciences Award in Molecular Biology and the Hutchinson Center McDougall Mentoring Award. In 2015, she was awarded the Novitski Prize from the Genetics Society of America, and was elected to the National Academy of Sciences.

(at 02:40 you can see chromosome segregation in real time)


[YT]xtqUu8DGQko[/YT]

You'll find Part 2 here

[Jo Bowyer]

Leukocyte telomere length pattern in a Chuvash population that experienced mass famine in 1922–1923: a retrospective cohort study

http://ajcn.nutrition.org/content/104/5/1410

Abstract

Background: To our knowledge, there are no experimental studies that have addressed the effects of starvation on the maintenance of telomere length. Two epidemiologic studies that have addressed this topic gave controversial results.

Objective: We characterized leukocyte telomere length (LTL) in a Chuvash population that was comprised of survivors of the mass famine of 1922–1923 and in these survivors’ descendants.

Design: The tested cohort consisted of native Chuvash men (n = 687) and women (n = 647) who were born between 1909 and 1980 and who resided in small villages in the Chuvash Republic of the Russian Federation. Data were gathered during 3 expeditions undertaken in 1994, 1999, and 2002. With the use of this method of gathering the study cohort, we were able to treat age and birth year as independent variables (i.e., after adjustment for age, we were able to analyze how LTL correlates with a birth year in the interval between 1909 and 1980). The DNA of peripheral blood leukocytes was used to measure the telomere length with a quantitative polymerase chain reaction technique.

Results: The main observations were as follows: 1) there were shorter leukocyte telomeres in men born after 1923 (i.e., after the mass famine) than in men born before 1922 (i.e., before the mass famine); 2) there was a stable inheritance of shorter telomeres by men of ensuing generations; and 3) there was an absence of a correlation between LTL and birth year in women.

Conclusions: Our study does not provide direct evidence for leukocyte telomere shortening in famine survivors. However, the comparative analysis of LTL in the survivors and their descendants suggests that such an effect did take place. The study also implies that mass famine may be associated with telomere shortening in male descendants of famine survivors. This observation is in agreement with the “thrifty telomere hypothesis” predicting that longer telomeres are disadvantageous in nutritionally marginal environments.

Keywords:
cohort study famine heritability starvation telomeres

[Jo Bowyer]

Worm Offers New Hope For Human Limb Regeneration

http://neurosciencenews.com/acorn-wo...neration-5619/

A study led by the University of Washington and published in the December issue of the journal Developmental Dynamics has shown that acorn worms can regrow every major body part — including the head, nervous system and internal organs — from nothing after being sliced in half. If scientists can unlock the genetic network responsible for this feat, they might be able to regrow limbs in humans through manipulating our own similar genetic heritage.

“We share thousands of genes with these animals, and we have many, if not all, of the same genes they are using to regenerate their body structures,” said lead author Shawn Luttrell, a UW biology doctoral student based at Friday Harbor Laboratories. “This could have implications for central nervous system regeneration in humans if we can figure out the mechanism the worms use to regenerate.”

[Jo Bowyer]

Die another day: How the immune system keeps 'traitor cells' in lockdown

https://www.sciencedaily.com/release...1110085931.htm

Our immune system is charged with the crucial task of keeping us safe from overwhelming infection. Time and again, our immune cells must decide very quickly whether they are looking at an invading microbe, which poses a threat, or a part of the body, which should be protected. Getting it wrong -- and attacking 'self' -- can lead to devastating autoimmune disorders such as rheumatoid arthritis or lupus.

The researchers have shown how the immune system can stop 'traitor' cells -- which could otherwise make damaging antibodies against the body's own tissues (auto-antibodies) -- in their tracks.

They show that a type of antibody called Immunoglobulin D or 'IgD'- which sits on the surface of immune cells termed B cells -- is responsible for stopping the 'traitor' cells from producing auto-antibodies. IgD keeps the cells in 'lockdown' -- unresponsive to the body's tissues, yet still capable of producing antibodies against invaders.

The findings solve a longstanding mystery surrounding the function of IgD, whose role in the immune system has been unclear since it was first observed 50 years ago.

Professor Christopher Goodnow, Deputy Director of Garvan and Head of the Immunogenomics laboratory, co-led the research with Dr Anselm Enders (who leads John Curtin's Immunisation Genomics group) and Dr Joanne Reed (Garvan).

Prof Goodnow says, "We have known for some time that more than half of the immune system's B cells are capable of producing damaging antibodies against the body's own tissues -- yet they don't do this.

"What we haven't understood before is why and how the immune system keeps these potential 'traitor cells' alive, instead of getting rid of them completely.

"Our new research shows that the antibody IgD is the key player in locking down the traitor cells, so that the immune system can hedge its bets between discarding these cells and drawing upon them to fight an infection. By placing the cells that bear autoantibodies in lockdown, IgD dials down their capacity to produce antibodies against the body's own tissues -- but keeps them alive in case they are needed to fight invasion by a microbe."

The researchers carried out a detailed study of gene expression across the whole genome in locked down (or anergic) B cells from mice, comparing mice with or without functional IgD. The studies revealed a core set of over 200 genes, one third of which are controlled by IgD, that together keep the cells unresponsive to the body's own tissues.

Importantly, however, the cells in lockdown are not removed from the immune system. On the contrary, the researchers found that IgD supports the cells to accumulate in the spleen and lymph nodes (just as other B cells do) and, if necessary, to take part in "target training" to make antibodies against invaders.

"Our experiments have shown that, although IgD places the B cells that can produce autoantibodies in lockdown, it still promotes the formation of germinal centres of those muted cells, which is like a military special operations camp of B cells that begin sharpening their ability to target an invader when they 'see' one," Dr Reed says.

The presence of germinal centres is an indication that, under the right circumstances, the cells are still capable of mounting an attack against an invader.

"We think that the large-scale lockdown of B cells is the immune system's way of avoiding 'holes' in its defensive line, so that it is ready to respond to any conceivable invasion," Prof Goodnow says.

"If every B cell capable of producing autoantibodies was removed, rather than kept in lockdown, we would severely limit the number of foreign invaders that our immune system could recognise.

"By locking down B cells, and keeping them alive, IgD strikes a delicate balance between protection from invaders and avoiding an immune attack on the body's own tissues."

How our bodies can create billions of defences against disease with just 20,000 genes

https://aeon.co/videos/how-our-bodie...50a68-69418129

How is the human body able to produce antibodies to mount a defence against any attacking microorganism – even those it’s never encountered before? After all, our mere 20,000 genes seem woefully inadequate to produce the billions of different antibodies necessary to fight every possible disease. The problem stumped researchers for decades until the Japanese scientist Susumu Tonegawa discovered the key to our incredible adaptive capacity for fighting contagions – an accomplishment that earned him the Nobel Prize in Physiology or Medicine in 1987. The answer, explored in this brief animation from Nature, lies in recombination-activating genes (RAGs) – DNA-‘shuffling’ enzymes that can create proteins capable of fighting any foreign invader.

Nice video! Have a look, its fascinating.

Update 17/04/2017

[Jo Bowyer]

Do you think gene therapy could be a leading pain treatment in the far future?

At gene level, Yes. To a certain extent genetic modification (in the lab) and modification of gene expression is already with us. But pain perception/tolerance varies greatly with the individual neuroendocrine system and person, I have lost count of the number of times I have been told "Well, I wouldn't call it pain as such." in situations where some of the outward signs (pallor, sweating, groaning are present).

It looks as if this could develop into an interesting discussion on a day when I will have very little access to a computer.

I am not counting the days though, there is a huge amount we can do already.

[WildBear]

Do you think gene therapy could be a leading pain treatment in the far future?

[Jo Bowyer]

Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants

http://onlinelibrary.wiley.com/doi/1.../brb3.528/full

Abstract

Introduction

The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear.
Methods

C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography.
Results

Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed.
Conclusions

Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.

[Jo Bowyer]

How farming changed the dog

http://www.sciencemag.org/news/2016/...&et_cid=978678

Farming didn’t just revolutionize human society—it transformed the genome of our oldest friend, the dog. A new study reveals that by 7000 years ago, our canine companions were eating so much wheat and millet they made extra copies of starch-digesting genes to help them cope. And this adaptation is what allowed them to stay by our sides, even as our world changed.

[Jo Bowyer]

Mammalian Bone Gene May Be Repurposed to Fuel Cognition in Humans

http://neurosciencenews.com/bone-gene-cognition-5466/

A gene that regulates bone growth and muscle metabolism in mammals may take on an additional role as a promoter of brain maturation, cognition and learning in human and nonhuman prim ates, according to a new study led by neurobiologists at Harvard Medical School.

Describing their findings in the Nov. 10 issue of Nature, researchers say their work provides a dramatic illustration of evolutionary economizing and creative gene retooling–mechanisms that contribute to the vast variability across species that share nearly identical set of genes yet differ profoundly in their physiology.

The research reveals that osteocrin–a gene found in the skeletal muscles of all mammals and well-known for its role in bone growth and muscle function–is completely turned off in rodent brains yet highly active in the brains of nonhuman primates and humans.

Notably, osteocrin was found predominantly in cells of the neocortex–the most evolved part of the primate brain, which regulates sensory perception, spatial reasoning and higher-level thinking and language in humans.

[Jo Bowyer]

The Strength of Selection against Neanderthal Introgression

http://journals.plos.org/plosgenetic...l.pgen.1006340

Abstract

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral—and segregating at high frequency—in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human–Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.

Author Summary

A small percentage of Neanderthal DNA is present in the genomes of many contemporary human populations due to hybridization tens of thousands of years ago. Much of this Neanderthal DNA appears to be deleterious in humans, and natural selection is acting to remove it. One hypothesis is that the underlying alleles were not deleterious in Neanderthals, but rather represent genetic incompatibilities that became deleterious only once they were introduced to the human population. If so, reproductive barriers must have evolved rapidly between Neanderthals and humans after their split. Here, we show that observed patterns of Neanderthal ancestry in modern humans can be explained simply as a consequence of the difference in effective population size between Neanderthals and humans. Specifically, we find that on average, selection against individual Neanderthal alleles is very weak. This is consistent with the idea that Neanderthals over time accumulated many weakly deleterious alleles that in their small population were effectively neutral. However, after introgressing into larger human populations, those alleles became exposed to purifying selection. Thus, rather than being the result of hybrid incompatibilities, differences between human and Neanderthal effective population sizes appear to have played a key role in shaping our present-day shared ancestry.

[Jo Bowyer]

The Impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts

http://journals.plos.org/plosgenetic...l.pgen.1006294

Abstract

Regularly performed endurance training has many beneficial effects on health and skeletal muscle function, and can be used to prevent and treat common diseases e.g. cardiovascular disease, type II diabetes and obesity. The molecular adaptation mechanisms regulating these effects are incompletely understood. To date, global transcriptome changes in skeletal muscles have been studied at the gene level only. Therefore, global isoform expression changes following exercise training in humans are unknown. Also, the effects of repeated interventions on transcriptional memory or training response have not been studied before. In this study, 23 individuals trained one leg for three months. Nine months later, 12 of the same subjects trained both legs in a second training period. Skeletal muscle biopsies were obtained from both legs before and after both training periods. RNA sequencing analysis of all 119 skeletal muscle biopsies showed that training altered the expression of 3,404 gene isoforms, mainly associated with oxidative ATP production. Fifty-four genes had isoforms that changed in opposite directions. Training altered expression of 34 novel transcripts, all with protein-coding potential. After nine months of detraining, no training-induced transcriptome differences were detected between the previously trained and untrained legs. Although there were several differences in the physiological and transcriptional responses to repeated training, no coherent evidence of an endurance training induced transcriptional skeletal muscle memory was found. This human lifestyle intervention induced differential expression of thousands of isoforms and several transcripts from unannotated regions of the genome. It is likely that the observed isoform expression changes reflect adaptational mechanisms and processes that provide the functional and health benefits of regular physical activity.

Author Summary

Skeletal muscle is the most abundant tissue of the healthy human body. It is also highly adaptable to different environmental stimuli, e.g. regular exercise. Exercise training improves overall health and muscle function, and can be used to prevent and treat several common diseases e.g. cardiovascular disease and type II diabetes. Therefore, it is of great importance to understand the molecular mechanisms behind adaptation processes in human skeletal muscle. In this study, we show that different expression variants from the same gene can be regulated in different directions with training, implicating alternative protein functions from one single gene. Such findings are emblematic of the complex mechanisms regulating the effects of training. We also find that training changes the activity of functionally unknown parts of the genome, with the potential for new proteins involved in the health-enhancing effects of exercise. Additionally, our results challenge the belief of a skeletal muscle memory, where previous training can affect the response to a subsequent training period. Overall, we provide understanding of the skeletal muscle biology and novel insights into the mechanisms behind the massive benefits of regular exercise on the human skeletal muscle transcriptome, inspiring further studies for deeper investigation.

[Jo Bowyer]

Evolution of spit

Looking to saliva to gain insight on evolution
https://www.sciencedaily.com/release...0825113228.htm

There's no need to reinvent the genetic wheel. That's one lesson of a new study that looks to the saliva of humans, gorillas, orangutans, macaques and African green monkeys for insights into evolution. The work shows that adaptation isn't just about creating new tools for survival -- it's also about tweaking the ones we have

Recent evolution of the salivary mucin MUC7
http://www.nature.com/articles/srep31791

Duplications, deletions, inversions and translocations of genetic segments, collectively called genomic structural variants, constitute an evolutionarily important form of genetic variants1. When two genomes from the same primate species are compared with each other, structural variants constitute 2 to 7 times more base pair differences than single nucleotide variants2. A functionally relevant, but understudied subset of structural variants, is copy number variation of tandem repeats within individual coding exons (subexonic repeat variation)3. A recent study has shown that, despite the high intrinsic mutability of subexonic repeats, the vast majority of thousands of subexonic repeats remain strongly conserved among mammals4. However, there is no study to our knowledge that specifically investigated the evolution of copy number variable subexonic repeats from their initial emergence as functional units to the adaptive constraints and mutational properties that contributed to their extant variation in primates.

[Jo Bowyer]

Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis

http://journals.plos.org/plosmedicin...l.pmed.1002090

Abstract

Background

Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.

Methods and Findings

Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum β = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 5.68 x 10−2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum β = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.

Conclusions

Genetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.

Author Summary

Why Was This Study Done?

Genetic factors and the environment you share with your nuclear family, siblings, or spouse may determine your risk of chronic pain.
Depression is also associated with chronic pain, but whether this relationship is explained by shared genetic factors, environment, or both is not known.
We sought to investigate these issues using genetic data and family environmental information from Generation Scotland: Scottish Family Health Study and UK Biobank.

What Did the Researchers Do and Find?

Using data from the family-based Generation Scotland study, we found that genetic factors and the environment you share with your partner/spouse are important risk factors for the development of chronic pain.
Shared genetic and environmental factors also partly explained the association between chronic pain and depression.
Finally, we found evidence showing that the genetic contribution to chronic pain arises through the combined effect of many different genetic risk factors and that the cumulative effects of genetic risk factors for depression increased an individual’s chance of having chronic pain.

What Do These Findings Mean?

Both genetic factors and chronic pain in a partner or spouse contribute to the risk of chronic pain for an individual.
Chronic pain is caused by an accumulation of many small genetic effects and is associated with some of the same genetic and environmental risk factors that confer risk of depression.