Board Theme Genes
This board is about specific genes and their effects. Any factors at play may also be discussed.
Studies and Research are encouraged. Hard science in general welcome.
For loose and low moderation discussion there is >>>/speciation/
Anything about races or speciation goes. You can discuss culture, behavior/psychology, and race.
For discussion about races there is >>>/genetics/
Here is a high moderation board that includes epigenetics and general biochemistry.
The difference between /genetics/ and /genes/ is that while genes is specific /genetics/ is broad.
Plant gene editing
The CRISPR/Cas9-sgRNA system has been developed to mediate genome editing and become a powerful tool for biological research. Employing the CRISPR/Cas9-sgRNA system for genome editing and manipulation has accelerated research and expanded researchers’ ability to generate genetic models. However, the method evaluating the efficiency of sgRNAs is lacking in plants. Based on the nucleotide compositions and secondary structures of sgRNAs which have been experimentally validated in plants, we instituted criteria to design efficient sgRNAs. To facilitate the assembly of multiple sgRNA cassettes, we also developed a new strategy to rapidly construct CRISPR/Cas9-sgRNA system for multiplex editing in plants. In theory, up to ten single guide RNA (sgRNA) cassettes can be simultaneously assembled into the final binary vectors. As a proof of concept, 21 sgRNAs complying with the criteria were designed and the corresponding Cas9/sgRNAs expression vectors were constructed. Sequencing analysis of transgenic rice plants suggested that 82% of the desired target sites were edited with deletion, insertion, substitution, and inversion, displaying high editing efficiency. This work provides a convenient approach to select efficient sgRNAs for target editing.
The efficient editing of target genes in transgenic plants can provide researcher with desired mutants, which will accelerate the progress of gene function dissection. We confirmed that the sgRNAs complying with the criteria were efficient for target gene editing. Both this work and Ma et al.’s9 confirmed that at least two same snoRNA promoters can be used simultaneously to drive different sgRNAs. Our work also revealed that the number of sgRNA cassettes has no effect on the editing efficiency of sgRNAs. It is noteworthy that up to 84.8% of edited plants contained loss-of-function gene mutations (i.e., biallelic or homozygous mutations) in the T0 transgenic plants and they can be used directly for functional analysis. In our two-sgRNA expression plants, both targets sites can be edited simultaneously, which also caused deletion or inversion of DNA fragment between two target sites. The editing of both target sites will facilitate the gene correction via homologous recombination by providing a mutant plant with wild type DNA fragment donor. Altogether, our toolbox for sgRNA design criteria and assembly of multiplex CRISPR/Cas9-sgRNA system provides researchers with a new approach to efficiently edit one or multiple target sites and perform genetic improvement.
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Nestmate Recognition System of Formica altipetens: Social Parasitism of Polyergus breviceps
The authors found that enslaved Formica colonies were more genetically and chemically diverse than their free-living counterparts. The researchers think these differences are likely caused by seasonal raids to steal pupa from several adjacent host colonies.
"When free-living Formica ants are kidnapped into the Polyergus colony, they enter a society that [comprises] kidnapped ants from many other Formica colonies. Here, we show that this rich social environment alters the behaviors displayed by the enslaved ants," said Neil Tsutsui.
The different social environments of enslaved and free-living Formica also appear to affect their recognition behaviors: enslaved Formica workers were less aggressive towards non-nest mates than were free-living Formica. Future studies are needed to understand the underlying mechanisms, but the authors suggest their findings indicate that parasitism by P. breviceps alters both the chemical and genetic context in which their hosts develop, leading to changes in how they recognize nest mates.
Our study contrasts with other studies that compared the nestmate recognition systems of monogynous (single queen) with those of polygynous colonies (multiple queens). Martin et al. [71] found that Formica execta colonies with higher genetic diversity (polygynous) had reduced nestmate recognition cue diversity compared to those that were less genetically diverse (monogynous).
The Effect of Social Parasitism by Polyergus breviceps on the Nestmate Recognition System of Its Host, Formica altipetens
MIMIVIRE
Didier Raoult of Aix-Marseille University in France and his colleagues discovered a new kind of virus lurking inside single-celled protozoans back in 2003. Like other viruses, it couldn’t grow on its own, lacking the biochemical machinery to build proteins and genes. Instead, it had to infect host cells and use their material to produce new viruses.
But this new virus was enormous, measuring hundreds of times bigger than any previously known virus. What’s more, it was far more complex. Typical viruses may have just a few genes. The new virus had over 900 — more than many species of bacteria.
Since then, Raoult and his colleagues have found over 150 different kinds of giant viruses all over the world, in oceans, mountains, and the bodies of animals (including our own). One kind of giant virus contains over 2,500 genes.
Exactly what giant viruses do with all those genes has remained mostly a mystery.
But on Monday, Raoult and his colleagues reported in Nature that some of those genes provide giant viruses with something never observed before in a virus: They have an immune system, one that works a lot like the CRISPR system in bacteria that scientists have co-opted as a powerful gene editing tool.
>the potential for such a system to be harnessed for genetic control is intriguing
>Raoult and his colleagues first discovered that giant viruses get infected with viruses of their own back in 2008.
These so-called virophages slip inside the giant viruses and hack their biochemistry, much as the giant viruses do to their own protozoan hosts.
>One of these virophages, called Zamilon, infects a type of giant virus known as a mimivirus. But when Raoult and his colleagues unleashed Zamilon on closely related strains of mimiviruses, they were surprised to find that it couldn’t infect them.
>It appeared as if the giant viruses could defend themselves against their enemies.
Raoult and his colleagues wondered if giant viruses were using a CRISPR-like defense system against Zamilon. To their surprise, they found that resistant giant viruses carried small pieces of the virophage’s DNA in their own genomes. When they searched the DNA that surrounded the Zamilon sequences, they found a gene that unwinds DNA, and another that slices it.
>The scientists hypothesized that giant viruses used these two genes to chop up Zamilon DNA. To test that idea, they silenced each of the genes. Now, the giant viruses became vulnerable, and Zamilon was able to infect them.
>Raoult and his colleagues have dubbed this stretch of giant virus DNA MIMIVIRE, short for “mimivirus virophage-resistance element.” They propose that it serves as an immune system, although they have yet to determine how the giant virus recognizes virophages and directs enzymes to attack it.
“What we know is that it’s critical,” said Raoult. “If you silence the genes, it doesn’t work anymore.”
Raoult said that like CRISPR, MIMIVIRE might be worth investigating as another potential gene editing tool: “It is different, so it may have different applications.”
Even if that search bears no fruit, Raoult thinks that MIMIVIRE is important for what it says about the evolution of giant viruses.
( Study: https://archive.is/VVVdD )
India - When caste lines are drawn literally
Beef is banned. Menstruation is taboo. If you think this is today's news, the same made headlines in 1873. The impact of these exhibits however was not long lasting. Caste is not discussed unless it is a matter of life and death, as proven by Rohith Vemula's suicide on January 17. A startling reminder of how the caste system continues to maim and kill, in modern India.
India's present diverse population arose from five types of ancient populations that freely mixed and interbred for thousands of years before the rigid caste system, with its principle of prohibition of marriage outside the caste, put an end to this mixing. This ancient history hinted at in various linguistic, archeological and genetic studies has been confirmed by a path-breaking genetic study recently published.
Researchers from the National Institute of Biomedical Genomics (NIBMG) at Kalyani, West Bengal, analysed DNA samples of 367 unrelated Indians belonging to 20 population groups. These covered castes from different parts of India, and most large tribal populations from central and Northeastern India. Also included were samples from two Andaman & Nicobar tribes.
"Genetic analysis shows mainland India's present population is a result of the intermixing of four main types of ancestral populations - North Indian, South Indian, Austro Asian and Tibeto-Burman," said Partha Majumder, director of NIBMG who led the study. The Andaman & Nicobar tribals have a completely different fifth ancestral origin that originated in Pacific Ocean populations.
The study compared genetic sequences from Indian samples with those from Central Asia, West Asia, China and adjacent regions to trace how humans first arrived in India.
What the study also unearthed was the deep imprint of a significant social cultural process in Indian society . It found that interbreeding between communities `abruptly' ended around 70 generations ago, which translates to about 1,575 years ago, sometime in the 6th century .
"To understand this, we looked at the history of the time. It coincided with the period when the Gupta Empire ruled India," Majumder told TOI. This period had seen the consolidation and supremacy of the caste system, entrenched through the sanction of scriptures as well as enforcing mechanisms of the rulers.
"The genetic revelations corroborate India's history.The genetic mixing was contained by the prescription of a social construct," says Majumder.
David Reich of the Harvard Medical School, known for his extensive genetic analysis from samples of two main ancestral populations of India - North Indians and South Indians told TOI that the new study goes beyond his work by including smaller populations of Autro-Asians, Tibeto-Burmans and Andamanese and Nicobarese.
He cautioned, however, that Majumder and his team's calculation could have erred as they used certain statistical methods software, and also considered 22.5 years as the span of one generation. "Standard citation in genetics literature is 29 years based on studies in many diverse societies around the world. We usually use 29 years and that would give substantially older calendar dates than the authors cite," he told TOI.
Majumder explains his data saying these are estimates. There is scope for correction. "The caste system originated in Vedic times, perhaps 1500 BCE or earlier. It must have slowly spread and got entrenched over centuries. Its impact on genetic material becomes evident around 1600 years ago," he explained.
The new study also found some strange goings on even within the rigidity of endogamy . Ancient North Indian males appeared to continue interbreeding with other population groups but the converse process was not happening, probably due to "elite dominance and patriarchy" the study says.
Genetic analysis also revealed that in many parts interbreeding across caste rigidities continued for some time, as in Bengal and Maharashtra. The establishment of endogamy among tribal populations was less uniform.
The study called "Genomic reconstruction of the history of extant populations of India reveals five distinct ancestral components and a complex structure" has been authored by Analabha Basua, Neeta Sarkar-Roy, and Partha P. Majumder.
Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse
The Y chromosome is thought to be important for male reproduction. We have previously shown that with the use of assisted reproduction, live offspring can be obtained from mice lacking the entire Y chromosome long arm. Here, we demonstrated that live mouse progeny can also be generated using germ cells from males with the Y chromosome contribution limited to only two genes, the testis determinant factor Sry and the spermatogonial proliferation factor Eif2s3y. Sry is believed to function primarily in sex determination during fetal life. Eif2s3y may be the only Y chromosome gene required to drive mouse spermatogenesis allowing formation of haploid germ cells that are functional in assisted reproduction. Our findings are relevant but not directly translatable to human male infertility cases.
At present, our findings in mice do not translate directly to humans. ROSI is still considered experimental in human ART due to concerns regarding the safety of injecting immature germ cells and technical difficulties (23). In spite of this, some children have already been born (24, 25) and those were healthy. As we learn more about the effects and improve technical aspects of ROSI, this method may become more acceptable. Indeed, studies on ROSI effects in mice have been encouraging (26). Thus our study may bear importance for clinicians working in ART clinics supporting the possibility that ROSI may be a viable option for overcoming infertility in men with non-obstructive azoospermia.
Considering that we have obtained live offspring using germ cells from males with only two Y chromosome genes one could question the importance of Y chromosome in male reproduction. We believe that the answer lies in defining the need. Human Y chromosome is not on the way to oblivion, as it has been implied in the past (27), and its genetic information is undoubtedly important for many aspects of reproduction involving the development of mature sperm and its function in normal fertilization (28). Most of the mouse Y chromosome genes are involved in spermiogenesis and sperm function and as such are necessary for normal fertilization (29, 30). However, when it comes to assisted reproduction, our mouse study proves that the Y chromosome contribution can be brought to a bare minimum consisting of Sry and Eif2s3y. Indeed, it may well be possible to eliminate mouse Y chromosome altogether if appropriate replacements are made for those two genes.
Neurogenesis in the Mammalian Brain
Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer’s patients, showed evidence of adult neurogenesis. Gage’s collaborators in Sweden were getting the same results. Wanting to be absolutely positive, Gage even sent slides to other labs to analyze. In November 1998, the group published its findings, which were featured on the cover of Nature Medicine.1
“When it came out, it caught the fancy of the public as well as the scientific community,” Gage says. “It had a big impact, because it really confirmed [neurogenesis occurs] in humans.”
Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus—and this time learned that neurogenesis may continue for most of one’s life.2 Neuroscientist Jonas Frisén of the Karolinksa Institute in Stockholm and his colleagues took advantage of the aboveground nuclear bomb tests carried out by US, UK, and Soviet forces during the Cold War. Atmospheric levels of 14C have been declining at a known rate since such testing was banned in 1963, and Frisén’s group was able to date the birth of neurons in the brains of deceased patients by measuring the amount of 14C in the cells’ DNA.
“What we found was that there was surprisingly much neurogenesis in adult humans,” Frisén says—a level comparable to that of a middle-aged mouse, the species in which the vast majority of adult neurogenesis research is done. “There is hippocampal neurogenesis throughout life in humans.”
But many details remain unclear. How do newly generated neurons in adults influence brain function? Do disruptions to hippocampal neurogenesis play roles in cognitive dysfunction, mood disorders, or even psychosis? Are there ways to increase levels of neurogenesis in humans, and might doing so be therapeutic? Researchers are now seeking to answer these and other questions, while documenting the extent and function of adult neurogenesis in mammals.
Researchers have also demonstrated that neurogenesis occurs in the adult human brain, though the locations and degree of cell proliferation appear to differ somewhat from rodents. Strong evidence now exists that new neurons are born in the dentate gyrus of the hippocampus, where they integrate into existing circuits. But so far, there is no definitive support for the migration of new neurons migrating from the subventricular zone (SVZ) of the lateral ventricle to the olfactory bulb, which is atrophied relative to the olfactory bulb of rodents and other mammals that rely more heavily on smell. However, one study did report signs of neurogenesis in an area next to the SVZ, the striatum, which is important for cognitive function and motor control.
C. Elegans 2 New Neurons "MCMs"
New Neurons Discovered in C. Elegans
Caenorhabditis elegans worms have two sexes: hermaphrodite and male. Hermaphrodites, the best studied, have just 302 neurons, but males have more — the MCMs raise their total to 385 neurons1.
NHGRIIn a species whose neural circuits have been comprehensively mapped, researchers at University College London and their colleagues have identified a new type of neuron. These glia-derived neurons, which researchers dubbed “mystery cells of the male,” or MCMs, are tied to sex-specific learning in the roundworm Caenorhabditis elegans. Researchers reported their finding in Nature last week (October 14).
Finding a new set of neurons in a well-studied system “is a bit of a shock,” study coauthor Richard Poole of University College London told Nature News, which noted that the team next plans to explore MCMs’ roles in brain sex differences and in learning. (See “Sex Differences in the Brain,” The Scientist, October 2015.)
Sex differences in behaviour extend to cognitive-like processes such as learning, but the underlying dimorphisms in neural circuit development and organization that generate these behavioural differences are largely unknown. Here we define at the single-cell level—from development, through neural circuit connectivity, to function—the neural basis of a sex-specific learning in the nematode Caenorhabditis elegans.
We show that sexual conditioning, a form of associative learning, requires a pair of male-specific interneurons whose progenitors are fully differentiated glia.
These neurons are generated during sexual maturation and incorporated into pre-exisiting sex-shared circuits to couple chemotactic responses to reproductive priorities.
Our findings reveal a general role for glia as neural progenitors across metazoan taxa and demonstrate that the addition of sex-specific neuron types to brain circuits during sexual maturation is an important mechanism for the generation of sexually dimorphic plasticity in learning.
Neurons from Glia In Vivo
Scientists present new recipes for directly converting glial cells to neurons in mouse brains.
Adult human brains have a very limited ability to produce new neurons, so scientists have been pursuing ways to convert other types of brain cells into these coveted cell types. Several presentations at this week’s Society for Neuroscience (SfN) meeting held in Chicago demonstrated that it’s possible to reprogram glia—non-neuronal cells known for supporting their neuron neighbors—into neurons within the brains of mice.
Sophie Peron of Johannes Gutenberg University in Germany took the genes for two transcription factors, Sox 2 and Ascl1, and overexpressed them in the cortices of mice. She found that 15 percent of the mouse glia cells turned into neurons.
The features of these new neurons are still to be worked out, Peron said. “That’s the next step. Now that we have a system to get these cells converted we are currently studying their connectivity, functionality, and precise characteristics,” she told The Scientist.
Peron said any potential therapy using reprogrammed cells would have to be able to produce specific neural subtypes, which may require additional steps to guide the cells in the right direction.
Other groups are working to convert reactive astrocytes—a form of glial cells that come to the aid of neurons after an injury, such as stroke—into neurons. Although these cells protect neurons from dying, they can crowd the area to create a sort of scar that impedes a full recovery.
Chun-Li Zhang of the University of Texas Southwestern Medical Center described a method to convert reactive astrocytes to neurons via Sox 2. “Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs,” Zhang wrote in his SfN abstract.
In another presentation, Penn State University’s Gong Chen and Yuchen Chen described administering a gene for the transcription factor NeuroD1 into the cortices of mice that had experienced strokes. Following the treatment, the researchers found that glial scar and atrophy in the cortex were reduced. “These findings suggest that direct reprogramming of glial cells into functional neurons may provide a completely new approach for brain repair after stroke,” Yuchen Chen said in a press release. “Our next step is to analyze whether the glia-neuron conversion technology can facilitate functional recovery in stroke animals.”
Updates - Genetic Engineering - News Megathread
Genetic Engineering & NanoBioTechnology
We are rapidly approaching an era when it may not only be possible but also insuppressible that people will be able to modify their genes at low cost.
In decades to come, however much the well meaning worry about the nefarious applications of gene editing, the needs of the sick will continue to drive science and medicine forward - as they should.
Researchers are beginning to understanding how the animals maintain their hundreds of teeth throughout their adult lives. By studying how structures in embryonic fish differentiate into either teeth or taste buds, the researchers hope to one day be able to turn on the tooth regeneration mechanism in humans - which, like other mammals, get only two sets of teeth to last a lifetime.
Still, today, there are those who fear genetic engineering.
"Genetic alteration is never predictable and can result in oversized embryos, resulting in painful births. It can leave the animals severely affected in a way which is impractical for life. The process also very wasteful."
In reference to the dog study, Hawkins said, "The genetic alteration of animals simply to make them stronger, or to have greater running ability, is completely unacceptable.
Viruses are a more nuanced scalpel – they have an evolutionarily vetted mode of entry and expression. To avoid the unsavory bursting cell scenario, “replication-deficient” viruses have been engineered. Given these strategic advantages, and spurred on by the enhanced editing capabilities enabled by CRISPR-based nucleases, Xiaoyu Chen and Manuel Goncalves at Leiden University Medical Center recently published a review of viral vectors as gene editing tools in Molecular Therapy. They highlight three types of viruses that can do the trick, each with its own strengths and weaknesses.
Lentiviruses have the unique ability to infect non-dividing cells, an important consideration for hosts that aren’t actively growing. Most engineered lentivirus vectors are based on HIV-1 – whose wild type variant is responsible for the global AIDS pandemic – because they can stably insert imported genes into the host’s genome. But that’s not necessarily a good thing for a CRISPR-mediated gene replacement, where a separate DNA strand (one not integrated into the genome) can be used to bridge the CRISPR-Cas-damaged site. With this consideration in mind, an engineered “integrase-deficient” lentivirus that ditches the DNA insertion step is many gene editors’ vector of choice.
Adeno-associated and adenoviral vectors are the other promising options; the former is a minuscule 20 nm across, while the latter can pack particularly large cargos. All three types of viruses can be developed to spec, loaded with a researcher’s specific gene or protein sequences, within a few weeks. Viral delivery of gene editing proteins is actively being investigated for clinical use. After all, nuclease-modified cells are already showing promising results: in one clinical study, immune cells modified in a lab by removing the CCR5 gene (a critical receptor for HIV) were infused into HIV-positive patients. The edited cells outlasted the native cells. If this modification could be made in the body, an effective gene therapy could be within reach.
Remember the plans to eliminate malaria by using gene alterations and killing the primary hosts?
We can also eliminate pests by gene altered releases of males whose female children die rather than reproducing.
“The goal of this research, and the overall goal of my program, is to try and manage insects more effectively with less environmental impact,” says Shelton. ;;;Without a single pesticide or toxin, the GM moths nearly took out the pest population in as few as two generations.;;; “The Oxitec moths are an improvement on the traditional sterile insect technology, and I think it’s pretty exciting improvement.”
This promising study comes on the heels of another Oxitec success story, a similarly-modified mosquito, which was recently found to reduce populations of dengue-carrying Aedes aegypti in Brazil by 95%. The company is awaiting word from the FDA for trials of GM mosquitos in Florida, but in the meantime, scientists can’t seem to praise their technologies enough. According to Shelton, the GM moths have no downsides. “From an environmental standpoint, we only see benefits.
Optogenetics Advances in Monkeys
Researchers have selectively activated a specific neural pathway to manipulate a primate’s behavior
WIKIMEDIA, J.M. GARGScientists have used optogenetics to target a specific neural pathway in the brain of a macaque monkey and alter the animal’s behavior. As the authors reported in Nature Communications last month, such a feat had been accomplished only in rodents before.
Optogenetics relies on the insertion of a gene for a light-sensitive ion channel. When present in neurons, the channel can turn on or off the activity of a neuron, depending on the flavor of the channel. Previous attempts to use optogenetics in nonhuman primates affected brain regions more generally, rather than particular neural circuits. In this case, Masayuki Matsumoto of Kyoto University and colleagues delivered the channel’s gene specifically to one area of the monkey’s brain called the frontal eye field.
They found that not only did the neurons in this region respond to light shone on the brain, but the monkey’s behavior changed as well. The stimulation caused saccades—quick eye movements. “Our findings clearly demonstrate the causal relationship between the signals transmitted through the FEF-SC [frontal eye field-superior colliculus] pathway and saccadic eye movements,” Matsumoto and his colleagues wrote in their report.
“Over the decades, electrical microstimulation and pharmacological manipulation techniques have been used as tools to modulate neuronal activity in various brain regions, permitting investigators to establish causal links between neuronal activity and behaviours,” they continued. “These methodologies, however, cannot selectively target the activity (that is, the transmitted signal) of a particular pathway connecting two regions. The advent of pathway-selective optogenetic approaches has enabled investigators to overcome this issue in rodents and now, as we have demonstrated, in nonhuman primates.”
Rocks
Do rocks have genes?
You can divide them to infinity and it's still a rock
Something makes them keep their form somehow
Understanding Gene Regulation Mechanisms
Genomic loop formation is a well-documented method that the cellular machinery uses to regulate the expression of various genes within human chromosomes. Yet, how these loops form and fold has eluded scientists for a number of years.
Now, researchers based at Houston's Texas Medical Center have found that a protein complex that forms the gene regulatory loop works like the sliding plastic adjusters on a grade schooler's backpack—a discovery that could provide new clues about genetic diseases and allow researchers to reprogram cells by directly modifying the loops in genomes.
"For months, we had no idea what our data really meant," explained senior author Erez Lieberman-Aiden, Ph.D., geneticist and computer scientist with joint appointments at Baylor and Rice Universities. "Then one day, we realized that we'd been carrying the solution around—literally, on our back—for decades!"
The findings from this study were published online recently in PNAS through an article entitled “Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes.”
Since many genes are activated by loops, it is impossible to understand gene activation without knowing how loops form. With that in mind, the researchers found a set of proteins that acts like the plastic slider, sometimes called a tri-glide, which adjusts a backpack strap.
"The protein complex that forms DNA loops appears to operate like the plastic slider that is used to adjust the length of the straps: it lands on DNA and takes up the slack to form a loop," noted co-first author Adrian Sanborn, graduate student in Dr. Aiden’s laboratory.
Because of their computer science and computational mathematics background, the investigators were able to create a tri-glide model to predict how a genome would fold. The team confirmed their predictions by making tiny modifications in a cell's genome and showing that the mutations changed the folding pattern exactly as expected.
"We found that changing even one letter in the genetic code was enough to modify the folding of millions of other letters," said co-first author Suhas Rao, graduate student in Dr. Aiden’s laboratory. "What was stunning was that once we understood how the loops were forming the results of these changes became extremely predictable."
The basic idea is that the tri-glide protein complex lands on the genome and pulls the strand from each side so that a loop forms in the middle—similar to the loop one might make if they wanted to tighten a backpack strap.
"The strand just keeps feeding through and feeding through from each direction until it hits the keyword, which acts as a brake," stated Rao.
The researchers were excited by their findings and are continuing to generate computational models to try and explain even more genomic folding structures. In the current model, the team was amazed by the implications of their new model that loops on different chromosomes tend not to become entangled.
"In the old model, scientists thought that a loop formed when two bits of the genome wiggled around and then met inside the cell nucleus," Dr. Aiden remarked. "But this process would lead to interweaving loops and highly entangled chromosomes. This is a big problem if you need those chromosomes to separate again when the cell divides.
"The tri-glide takes care of that," he continued. "Even in a big pile of backpacks, you can use your tri-glide to make a loop without any risk of entanglement."
Cryptic Higher-Order Genetic Interactions
Disruption of certain genes can reveal cryptic genetic variants that do not typically show phenotypic effects. Because this phenomenon, which is referred to as ‘phenotypic capacitance’, is a potential source of trait variation and disease risk, it is important to understand how it arises at the genetic and molecular levels. Here, we use a cryptic colony morphology trait that segregates in a yeast cross to explore the mechanisms underlying phenotypic capacitance. We find that the colony trait is expressed when a mutation in IRA2, a negative regulator of the Ras pathway, co-occurs with specific combinations of cryptic variants in six genes. Four of these genes encode transcription factors that act downstream of the Ras pathway, indicating that the phenotype involves genetically complex changes in the transcriptional regulation of Ras targets. We provide evidence that the IRA2 mutation reveals the phenotypic effects of the cryptic variants by disrupting the transcriptional silencing of one or more genes that contribute to the trait. Supporting this role for the IRA2 mutation, deletion of SFL1, a repressor that acts downstream of the Ras pathway, also reveals the phenotype, largely due to the same cryptic variants that were detected in the IRA2 mutant cross. Our results illustrate how higher-order genetic interactions among mutations and cryptic variants can result in phenotypic capacitance in specific genetic backgrounds, and suggests these interactions might reflect genetically complex changes in gene expression that are usually suppressed by negative regulation.
Some genetic polymorphisms have phenotypic effects that are masked under most conditions, but can be revealed by mutations or environmental change. The genetic and molecular mechanisms that suppress and uncover these cryptic genetic variants are important to understand. Here, we show that a single mutation in a yeast cross causes a major phenotypic change through its genetic interactions with two specific combinations of cryptic variants in six genes. This result suggests that in some cases cryptic variants themselves play roles in revealing their own phenotypic effects through their genetic interactions with each other and the mutations that reveal them. We also demonstrate that most of the genes harboring cryptic variation in our system are transcription factors, a finding that supports an important role for perturbation of gene regulatory networks in the uncovering of cryptic variation.
As a final part of our study, we interrogate how a mutation exposes combinations of cryptic variants and obtain evidence that it does so by disrupting the silencing of one or more genes that must be expressed for the cryptic variants to exert their effects. To prove this point, we delete the transcriptional repressor that mediates this silencing and demonstrate that this deletion reveals a similar set of cryptic variants to the ones that were discovered in the initial mutant background. These findings advance our understanding of the genetic and molecular mechanisms that reveal cryptic variation.
Additionally, to our knowledge, the present study, when considered with [42], represents the first comprehensive genetic characterization of a genetic background effect in any organism. Our work demonstrates how genetic background effects can arise due to complex epistatic relationships between mutations and cryptic variants at multiple modifier loci, as others have previously suggested [43]. Our findings also indicate that multiple epistatic configurations of cryptic variants may enable a given mutation to show a phenotypic effect. Although these results advance understanding of the causes of genetic background effects, determining the generality of these findings will require dissecting other genetic background effects that involve different mutations, species, and traits.
asdasdasd
all right guys.
I don't know shit about genes
ENLIGHTEN ME
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(Cav-1) Improving learning and memory in the old - mouse model
A scientific team from the Scripps Research Institute (TSRI), the Veterans Affairs San Diego Healthcare System (VA), and University of California (UC) San Diego School of Medicine reports that increasing a crucial cholesterol-binding membrane protein in neurons within the brain can improve learning and memory in aged mice.
"This is a novel strategy for treating neurodegenerative diseases, and it underscores the importance of brain cholesterol," said Chitra Mandyam, Ph.D., associate professor at TSRI and co-first author of the study (“Neuron-targeted caveolin-1 improves molecular signaling, plasticity and behavior dependent on the hippocampus in adult and aged mice”) that appears online in Biological Psychiatry.
Senior author Brian Head, Ph.D., a research scientist with the VA and associate professor at UC San Diego, added, "By bringing back this protein, you're actually bringing cholesterol back to the cell membrane, which is very important for forming new synaptic contacts."
The research focuses on a specific membrane protein called caveolin-1 (Cav-1) and expands scientists' understanding of neuroplasticity, the ability of neural pathways to grow in response to new stimuli.
Previous work by Dr. Head's group at the VA and at UC San Diego had shown that raising Cav-1 levels supported healthy "rafts" of cholesterol involved in neuron growth and cell signaling. However, it wasn't clear if this new growth actually improved brain function or memory.
To find out, the researchers delivered Cav-1 directly into the hippocampus in adult and "aged" mice. The hippocampus is a structure thought to participate in formation of contextual memories, e.g., if one remembers a past picnic when later visiting a park.
In addition to improved neuron growth, treated mice demonstrated better retrieval of contextual memories, i.e., they froze in place, an indication of fear, when placed in a location where they'd once received small electric shocks.
Drs. Mandyam and Head believe that this type of gene therapy may be a path toward treating age-related memory loss. The researchers are now testing this gene therapy in mouse models of Alzheimer's disease and expanding it to possibly treat injuries such as spinal cord injury and traumatic brain injury.
This new understanding of Cav-1 and neuroplasticity could also be relevant to memory loss due to alcohol and drug use, according to Dr. Mandyam.
"We're very interested in studying whether we can manipulate Cav-1 in other areas of the brain," said Dr. Mandyam.
Transgenic Production of an Anti HIV Antibody in the Barley Endosperm
Barley is an attractive vehicle for producing recombinant protein, since it is a readily transformable diploid crop species in which doubled haploids can be routinely generated. High amounts of protein are naturally accumulated in the grain, but optimal endosperm-specific promoters have yet to be perfected. Here, the oat GLOBULIN1 promoter was combined with the legumin B4 (LeB4) signal peptide and the endoplasmic reticulum (ER) retention signal (SE)KDEL. Transgenic barley grain accumulated up to 1.2 g/kg dry weight of recombinant protein (GFP), deposited in small roundish compartments assumed to be ER-derived protein bodies. The molecular farming potential of the system was tested by generating doubled haploid transgenic lines engineered to synthesize the anti-HIV-1 monoclonal antibody 2G12 with up to 160 μg recombinant protein per g grain. The recombinant protein was deposited at the periphery of protein bodies in the form of a mixture of various N-glycans (notably those lacking terminal N-acetylglucosamine residues), consistent with their vacuolar localization. Inspection of protein-A purified antibodies using surface plasmon resonance spectroscopy showed that their equilibrium and kinetic rate constants were comparable to those associated with recombinant 2G12 synthesized in Chinese hamster ovary cells.
In summary, the endosperm-specific expression system based on the oat GLO1 promoter in combination with the LeB4 signal peptide has been shown to be effective in barley, and is appropriate as a technology for producing recombinant protein in the barley grain. The test protein, an anti-HIV antibody, was produced in a functional and soluble form and accumulated within the periphery of the PSV, alongside the hordeins. Its level of accumulation exceeded those achieved in transgenic tobacco, maize and rice.
Cpf1 CRISPR
Searching bacteria for an alternative to Cas9, the enzyme used in the CRIPSR system to cut DNA at a site specified by RNA guides, synthetic biologist Feng Zhang of the Broad Institute in Cambridge, Massachusetts, and his colleagues discovered a protein called Cpf1 in some bacteria that use CRISPR for viral defense. Taking a closer look at Cpf1 from 16 microbial species, the research team identified two that could cut human DNA, they reported last week (September 25) in Cell.
“It’s a noteworthy addition to the biology [of CRISPR] and a valuable addition to the tool box,” North Carolina State University molecular biologist Rodolphe Barrangou, who did not participate in the research, told Science.
Important differences exist between Cpf1 and Cas9. Cas9 relies on two RNA molecules to specify the DNA to be cut, while Cpf1 only requires one, for instance. And the nature of the cut is also different: Cas9 cuts both DNA strands at the same location, while Cpf1 snips DNA such that there are short, single-stranded pieces on either side of the cut. “The sticky ends carry information that can direct the insertion of the DNA,” Zhang told Nature. “It makes the insertion much more controllable.”
The sticky ends could also improve the efficiency of CRISPR gene editing, as the blunt ends left by Cas9 cuts are often simply stuck back together, rather than incorporating new DNA. “Boosting the efficiency would be a big step for plant science,” Iowa State University plant biologist Bing Yang, who was not involved in the study, told Nature. “Right now, it is a major challenge.”
The new discovery could also hold financial value, as the Broad and the University of California, Berkeley, continue to duke it out over who first invented CRISPR editing tools such as Cas9. While the US Patent and Trademark Office considers intervening in the case, Cpf1 could sidestep the problem altogether. “The greatest value may be more in terms of the patent landscape than a scientific advancement,” the University of Minnesota’s Dan Voytas told MIT Technology Review.
Tethering Transposons
Panoramix, a newly identified transcription repressor, takes the bounce out of jumping genes.
A paper published, October 15, in Science provides a greater understanding of how cells shut down these rogue jumping genes. Greg Hannon of the Cancer Research UK Cambridge Institute and his colleagues have identified a protein in fruit flies that appears to halt transposons before they begin to leap.
“This is a mountain of impressive work, a huge amount of data, [the result of which] is that we now understand something about how piRNAs are transcriptionally silencing their targets,” said molecular geneticist Keith Slotkin of Ohio State University who was not involved in the work. “We knew that this was happening, but the mechanism was all question marks and hand-waving.”
Piwi-interacting RNAs, or piRNAs, are short noncoding RNAs that, as their name implies, interact with a protein called Piwi—a highly conserved transposon-suppressing factor. To protect the host against damaging tranposon-induced mutations, Piwi-piRNA complexes both destroy transposon transcripts in the cytoplasm (post-transcriptional silencing) and block transposon transcription in the nucleus (transcriptional silencing). Essentially, the piRNA pathway “mops up the water” and “turns off the spigot,” explained human geneticist John Moran of the University of Michigan who also did not participate in the study. How the spigot is turned off, however, was largely a mystery.
In fact, with the exception of Piwi itself and a protein called Asterix—a nucleus-specific component of Piwi complexes—the machinery responsible for transcriptional silencing of transposons was unknown. To identify possible candidates, Hannon’s team scoured the results of their own and others’ genome-wide screens for piRNA pathway components in the fruit fly Drosophila melanogaster, finding one that seemed to fit the bill: the protein CG9754.
Suppression of CG9754 in fruit fly ovaries not only ramped up transposon transcription, but also erased the repressive epigenetic marks normally present at suppressed transposon loci—indicating that the protein was acting at the genetic loci rather than post transcriptionally.
However, Hannon’s team supposed that CG9754 was most likely targeting nascent transcripts at the loci rather than the DNA. For one thing, Piwi-piRNA complexes bind transcripts in the cytoplasm, explained Hannon. Moreover, previous studies suggested that silencing of transposons in the nucleus depended, somewhat counterintuitively, on their transcription.
To test whether CG9754 was acting as they suspected, the team devised a method for artificially recruiting CG9754 to the nascent RNA transcript of a reporter gene, and then intergrated the reporter into the fruit fly genome. The researchers showed that when tethered in this way, CG9754 could both suppress reporter gene expression and establish repressive epigenetic marks at the reporter locus. Recruiting Asterix or Piwi to the reporter’s RNA in the same manner did not result in transcriptional or epigenetic repression. Hannon said he thinks CG9754 “forms a bridge between the very specific piRNA pathway components [Asterix and Piwi] and the general transcription silencing machinery.”
Indeed, the team then went on to show that CG9754 directly interacted with Piwi and utilized a number of epigenetic regulatory proteins to exert its suppressive effects.
Concluding that CG9754 was clearly a critical component of Piwi-mediated transcriptional silencing, the team opted to give the protein a catchy moniker: “Panoramix”—after the supportive friend of the comic-strip character Asterix.
Suppression of transposon activity—especially in germline cells—is essential for preserving genome integrity. “If you lose this machinery, you are sterile,” said Hannon. “It is universally essential for fertility.”
Although the Piwi-piRNA pathway is highly conserved across many species, including mammals, Panoramix does not appear to have a mammalian equivalent. “I’m certain that there is one, it’s just not obvious,” Hannon said. “It’s something we’ll have to go and look more deeply for.
“Though details may differ between mammalian cells and drosophila,” said Moran, the work “opens up new grounds for exploration, which is what good science is supposed to do.”
CRISPR Pigs
The work was presented on 5 October at a meeting of the US National Academy of Sciences (NAS) in Washington DC on human gene editing. Geneticist George Church of Harvard Medical School in Boston, Massachusetts, announced that he and colleagues had used the CRISPR/Cas9 gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs’ genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients.
Church’s group also modified more than 20 genes in a separate set of pig embryos, including genes that encode proteins that sit on the surface of pig cells and are known to trigger a human immune response or cause blood clotting. Church declined to reveal the exact genes, however, because the work is as yet unpublished. Eventually, pigs intended for organ transplants would need both these modifications and the PERV deletions.
Preparing for implantation
“This is something I’ve been wanting to do for almost a decade,” Church says. A biotech company that he co-founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as cheap as possible.
Church released few details about how his team managed to remove so many pig genes. But he says that both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.
Sweet board
I'm doing hw but I just found this and will be hanging out alot. Im working this year data mining expression data from mouse cerebral cortex. Two groups, one trisomy and the other wt were used in the study, which was designed to see how expression of critters in learning environments is different between normal mice and retarded trisomy models who can't learn.
Genetic Modification
Later Summer 2015 Genetics Updates
The Right way to use Genetic Modification
Throughout history, people have relied on plants for medicines. Even modern drugmakers get about half their new drugs from plants. But that’s harder to do when plants are slow growing and endangered, as is the Himalayan mayapple (Podophyllum hexandrum). The short, leafy plant was the original source of podophyllotoxin, a cytotoxic compound that’s the starting point for an anticancer drug called Etoposide. The drug has been on the U.S. market since 1983 and is used to treat dozens of different cancers, from lymphoma to lung cancer. Today, podophyllotoxin is mainly harvested from the more common American mayapple. But this plant is also slow growing, producing only small quantities of the compound.
Mayapples churn out podophyllotoxin to defend against would-be munchers. To do so, the plants use a step-by-step approach to synthesize their chemical defense. But because the synthetic pathway of the compound had never been worked out, no one knew precisely which genes were involved in stitching together the molecule. What researchers did know was that podophyllotoxin isn’t always present in the plant. “It’s only when the leaf is wounded that the molecule is made,” says Elizabeth Sattely, a chemical engineer at Stanford University in Palo Alto, California, who led the current research effort.
Sattely and her graduate student Warren Lau reasoned that the podophyllotoxin-building proteins were likely themselves only made by the plant in response to an injury. So the pair made tiny punctures in the leaves of healthy Himalayan mayapples provided to them by a commercial nursery, testing them before and after to see which new proteins appeared around the damaged tissue. They discovered 31, which they categorized by probable function.
The pair then narrowed the likely candidates for enzymes in podophyllotoxin production by focusing on members of four classes known to carry out the right types of chemical reactions. They then spliced genes for each of these enzymes into bacteria known to infect Nicotiana benthamiana, a fast-growing relative of tobacco that serves as a sort of lab rat of plant biologists. The bacteria readily infect tobacco and insert their genes into the plant tissue. Sattely and Lau inserted numerous combinations of genes for the enzymes they thought might produce their desired compound. As they report online today in Science, they eventually hit on a group of 10 enzymes that allowed the plant to make a molecule called (-)-4’–desmethyl-epipodophyllotoxin, a direct precursor to Etoposide and a potent cancer drug in its own right.
Gene modification in untransformed human intestinal cells is an attractive approach for studying gene function in intestinal diseases. However, because of the lack of practical tools, such studies have largely depended upon surrogates, such as gene-engineered mice or immortalized human cell lines. By taking advantage of the recently developed intestinal organoid culture method, we developed a methodology for modulating genes of interest in untransformed human colonic organoids via electroporation of gene vectors. Here we describe a detailed protocol for the generation of intestinal organoids by culture with essential growth factors in a basement membrane matrix. We also describe how to stably integrate genes via the piggyBac transposon, as well as precise genome editing using the CRISPR-Cas9 system. Beginning with crypt isolation from a human colon sample, genetically modified organoids can be obtained in 3 weeks
The Hinxton Group, which describes itself as an international consortium on stem cells and bioethics, also said in a statement released on Wednesday that the engineering of GM babies—a concept commonly called designer babies—could be "morally acceptable" in the future, although it said it was not in favour of the procedure at present.
Currently, the U.S. National Institutes of Health (NIH) refuses to provide funding for any research involving the genetic modification of human embryos, The Guardian reports. In the U.K., the use of embryos which have been genetically altered where these edits could be passed on to offspring is illegal.
They claimed that new gene-editing technology, which could be used to correct genetic defects or introduce beneficial changes, "provides vast scope for applications in human disease and health" and that genome editing has "tremendous value" for scientific research.
Modern gene-editing tools such as CRISPR/Cas9—a technique which can reportedly edit the genomic sequence in a highly targeted way—are "not only very precise, but also easy, inexpensive, and, critically, very efficient," the group said.
Earlier this year, Chinese scientists reportedly edited the genomes of human embryos in what was described as "a world first" by the journal Nature.
New Genes Expressed Early: Human Brain
New Genes Are Expressed in the Early Developing Human Brain
>Previous analyses of the molecular evolution of the human brain did not find consistent evidence of rapid evolution in the protein-coding genes expressed in the adult human brain [8]–[9]. Faster evolution in the human lineage was not observed at the gene expression level either [2].
>However, we noticed that all these analyses were based on the adult brain, just one stage of brain development. It is thus understandable that they were inconclusive as to the understanding of the genetic basis for the evolution of how the brain develops.
>Our analyses revealed an unexpected pattern: the expression patterns and protein sequences of new genes appear to contribute to the early (fetal and infant) brain development of humans.
>This pattern supports the argument that genes formed by duplication and by de novo origination could escape pleiotropic constraints [42]. On the other hand, the enrichment of transcription factors in human young genes also suggests the important role of regulation in the development of the human brain [1],[4]–[6].
>Our results show that regulatory evolution can occur in both cis [5] and trans, in the protein sequence of transcription factors [32],[43], and in the creation of new transcription factors through gene duplication. From this aspect, fine-tuning of gene regulation by human-specific genes [44] might underlie many human-specific characteristics and behaviors.
>However, we also observed that young genes were associated with diverse functions, ranging from nuclear pore proteins to ribosomal proteins (Table 1).
>In fact, the striking correspondence of the origination times of the neocortex and PFC with the ages of new genes suggests the functional association of these young genes with the development of these expanding brain structures. Specifically, new genes began to be recruited into neocortex or PFC after their morphological origination (Figure 5B, 5C).
>The recruitment of young genes into the early developmental stages of neocortex, regardless of the various processes which created these genes (Figures 3, S6), and their accelerated sequence evolution (Figures 4, S6; Tables 2, S8) suggest that the young genes may have evolved new functions as a consequence of positive selection for novel functions in the newly evolved brain structures.
>Compared to the early developing brain, the adult brain does not show an increased recruitment of young genes in the primate-specific lineage (Figure S2).
>Additional expressional data confirmed that young genes were less frequently upregulated in adult neocortex (Figure 2). This result is consistent with a previous study [3] arguing that novel aspects of the human brain are usually manifested in the early development.
>Thus, the expansion of DUF1220 family expressed in adult brain [20] might be an interesting exception, rather than a rule.