Category Archives: Genetics

Harvard team leads breakthrough on the genetics of parenting – Harvard Gazette

Why is it that some species seem to be particularly attentive parents while others leave their young to fend for themselves? For years, scientists have believed one of the major drivers is experience an animal raised by an attentive parent, the argument goes, is likely to be an attentive parent itself.

A Harvard study is challenging that idea, and breaking new ground by uncovering links between the activity of specific genes and parenting differences across species.

Led by Professor of Organismic and Evolutionary Biology and Molecular and Cellular Biology Hopi Hoekstra and postdoctoral researcher Andrs Bendesky, the study found not only that different genes may influence behaviors in males and females, but also that the gene for the hormone vasopressin appears to be closely tied to nest-building behavior in parenting mice. The research is described in an April 19 paper published in Nature.

This is one of the first cases in which a gene has been implicated in parental care in a mammal, Hoekstra said. In fact, its one of the few genes that has been implicated in the evolution of behavior in general but what I think is particularly exciting about this is the idea that, while in many systems we know that parenting behavior can be affected by your environment, we now have evidence that genetics can play an important role as well.

We know there is variation between species in how much parental behavior they provide for their young, Bendesky said. Its not that one is better or worse, theyre just different strategies but before our study we had no idea how these parental behaviors evolved, whether there was one gene that mediates all of the differences in behavior, or if it was 10 or 20.

The idea for the study grew out of differences in mating systems researchers had observed between two sister mouse species Peromyscus maniculatus, also known as the deer mouse, and P. polionotus, the oldfield mouse.

Like many rodents, the deer mouse is what we refer to as promiscuous, meaning both males and females mate with multiple individuals, Hoekstra said. Often when you genotype a litter, you will find pups from multiple fathers.

The oldfield mouse, by comparison, is monogamous, so all the pups in a litter are sired by one father.

Its been widely documented that these mice have different mating systems, Hoekstra said. When Andrs joined the lab, he was interested in asking the question: Do those differences translate into differences in parental care?

Bendesky first created a behavioral assay that tracked the behavior of males and females of each species and measured how often they engaged in parental behavior such as building nests and licking and huddling their pups.

In general, the data showed that females of both species were attentive mothers. The major differences, Hoekstra said, were in the fathers. Oldfield mice fathers were as involved in raising pups as oldfield mothers, but deer mice fathers werent.

To test the impact of different parenting styles, Bendesky performed a cross-fostering experiment, allowing oldfield mice parents to raise deer mouse pups, and vice versa. The researchers then observed the parenting behavior of the pups when they became parents themselves.

What we found was theres no measurable effect based on who raises them, Hoekstra said. Its all about who they are genetically.

To investigate those genetics, the researchers crossbred the species, then crossbred the offspring, creating second-generation hybrid mice that had regions of the genome from each species.

When the team began to identify regions in the genome that were associated with behavioral differences between the species, they discovered that some effects were sex-specific, but that some regions appeared to influence a handful of behaviors.

By Peter Reuell, Harvard Staff Writer | November 17, 2016 | Editor's Pick

What I find very interesting is that we found different genes may explain the evolution of paternal and maternal care, Bendesky said. Thats interesting because it tells us that if some mutation in a population increases maternal care, it may not affect the behavior of males. So these behaviors may be evolving independently.

The other significant result here is that there are some regions that affect multiple traits, and others that have very specific effects, Hoekstra added. For example, we found one region that affects licking, huddling, handling, and retrieving, but another that affected only nest-building.

Bendesky turned to locating individual genes that might be linked with parental behaviors.

We looked at expression in a region of the brain called the hypothalamus, which is known to be important in social behavior, Hoekstra said. Specifically, we were looking at which genes showed differences in expression between the two species. While each region might contain hundreds of candidate genes, there were only a handful that fit those criteria.

Almost immediately, she said, one gene for the production of vasopressin, part of a pathway past findings had linked to social behavior in voles jumped out at them.

To test whether vasopressin affected parental behavior, Bendesky administered doses of the hormone to male and female oldfield mice, and found that nest-building behavior in both dropped. A similar experiment in collaboration with Catherine Dulacs lab, which used genetic tools to manipulate the activity of vasopressin neurons in lab mice, confirmed these results.

The findings also open the door to new insight on the neurological circuitry involved in parental behavior.

This gives us molecular handles to start understanding the circuitry much better, Bendesky said. We can see what is happening in the brain not in the abstract but we can say vasopressin is going from this part of the hypothalamus to this other part of the brain, so we can see how the brain is organized.

By Jill Radsken, Harvard Staff Writer | April 20, 2017

Read the original post:
Harvard team leads breakthrough on the genetics of parenting - Harvard Gazette

Mosaic (genetics) – Simple English Wikipedia, the free …

In genetics, a mosaic (or mosaicism) means the presence of two different genotypes in an individual which developed from a single fertilized egg. As a result, the individual has two or more genetically different cell lines derived from a single zygote.[1]

Mosaicism may result from:

The phenomenon was discovered by Curt Stern. In 1936, he demonstrated that recombination, normal in meiosis, can also take place in mitosis.[2] When it does, it results in somatic (body) mosaics. These are organisms which contain two or more genetically distinct types of tissue.[3]

A genetic chimera is an organism composed of two or more sets of genetically distinct cells. Dispermic chimeras happen when two fertilized eggs fuse together. Mosaics are a different kind of chimerism: they originate from a single fertilized egg.

This is easiest to see with eye colours. When eye colours vary between the two eyes, or within one or both eyes, the condition is called heterochromia iridis (= 'different coloured iris'). It can have many different causes, both genetic and accidental. For example, David Bowie had the appearance of different eye colours due to an injury that caused one pupil to be permanently dilated.

On this page, only genetic mosaicism is discussed.

The most common cause of mosaicism in mammalian females is X-inactivation. Females have two X chromosomes (and males have only one). The two X chromosomes in a female are rarely identical. They have the same genes, but at some loci (positions) they may have different alleles (versions of the same gene).

In the early embryo, each cell independently and randomly inactivates one copy of the X chromosome.[4] This inactivation lasts the lifetime of the cell, and all the descendants of the cell inactivate that same chromosome.

This phenomenon shows in the colouration of calico cats and tortoiseshell cats. These females are heterozygous for the X-linked colour genes: the genes for their coat colours are carried on the X chromosome. X-inactivation causes groups of cells to carry either one or the other X-chromosome in an active state.[5]

X-inactivation is reversed in the female germline, so that all egg cells contain an active X chromosome.

Mosaicism refers to differences in the genotype of various cell populations in the same individual, but X-inactivation is an epigenetic change, a switching off of genes on one chromosome. It is not a change in the genotype.[6] Descendent cells of the embryo carry the same X-inactivation as the original cells. This may give rise to mild symptoms in female 'carriers' of X-linked genetic disorders.[7]

More:
Mosaic (genetics) - Simple English Wikipedia, the free ...

Genetics to boost sugarcane production – SciDev.Net

Scientists in Brazil are taking steps towards genetically modifying sugar cane so it produces more sucrose naturally, looking to eventually boost the productivity and economic benefits of the tropical grass. Currently, it is common for producers to raise sucrose levels in sugar cane by applying artificial growth regulators or chemical ripeners. This inhibits flowering, which in turn prolongs harvest and milling periods. One of these growth regulators, ethephon, is used to manage agricultural, horticultural and forestry crops around the world. It is widely used to manipulate and stimulate the maturation of sugarcane as it contains ethylene, which is released to the plant on spraying. Ethylene, considered a ripening hormone in plants, contributes to increasing the storage of sucrose in sugar cane. "Although we knew ethylene helps increase the amount of sugar in the cane, it was not clear how the synthesis and action of this hormone affected the maturation of the plant," said Marcelo Menossi, professor at the University of Campinas (Unicamp) and coordinator of the project, which is supported by the Brazilian research foundation FAPESP. To study how ethylene acts on sugarcane, the researchers sprayed ethephon and an ethylene inhibitor, aminoethoxyvinylglycine (AVG), on sugar cane before it began to mature.

After spraying both compounds, they quantified sucrose levels in tissue samples from the leaves and stem of the cane. They did this five days after application and again 32 days later, on harvest. Those plants treated with the ethephon ripener had 60 per cent more sucrose in the upper and middle internodes at the time of harvest, while the plants treated with the AVG inhibitor had a sucrose content that was lower by 42 per cent. The researchers were then able to identify genes that respond to the action of ethylene during ripening of the sugar cane. They also successfully identified the genes involved in regulating sucrose metabolism, as well as how the hormone acts on sucrose accumulation sites in the plant. Based on the findings, the team has proposed a molecular model of how ethylene interacts with other hormones. "Knowing which genes or ripeners make it possible for the plant to increase the accumulation of sucrose will allow us to make genetic improvements in sugarcane and develop varieties that over-express these genes, without the need to apply ethylene, for example," explained Menossi. This research could also help with spotting the most productive sugar cane, as some varieties that do not respond well to hormones, he added. "It will be possible to identify those [varieties] that best express these genes and facilitate the ripening action." Taken from anewsletterbyFAPESP, aSciDev.Netdonor, edited byour Latin America and the Caribbean desk

View post:
Genetics to boost sugarcane production - SciDev.Net

Of Slavs, Slaves, Vikings, and Genetics – Patheos (blog)

I recently had a DNA test to help trace my ancestry, and the result surprised me. The larger story might shed light on one of the grimmest and most forgotten horrors of European history, an era of brutal slave trading.

By way of background, my known genealogy is very straightforward indeed. It shows close to 100 percent Welsh not just Welsh, but one specific bit of south Welsh. That means mainly West Glamorgan, within a few miles of the city of Swansea, although with a couple of English guysin the 17th-18th centuries (In Wales, we call that diversity). Ican identify all my ancestors through all lines back to about 1840, and far beyond that in some lines.

Hence, I am near pure 100 percent Welsh on all sides. However, through the years, I have faced a nagging question. Welsh people are stereotypically short and dark, which I am not. (I am 62, and not so dark). Nor were my uncles and aunts, who were all pretty tall people. At least they were on my maternal side, and Ill explain in a moment why that distinction matters.

When I am in Europe, people all over the continent often have me marked as German, and address me as such. They greet a line of tourists like this: Good morning sir! Good morning sir! Then they come to me: Guten Tag, mein Herr! WhenI am in Norway, the locals assume I am Norwegian.

What on earth is happening? Something was amiss. I was amiss.

Hence my inspiration to take the DNA test, and the result is fascinating. (I used FamilyTreeDNA). In total contrast to the genealogy, the DNA gives me as 90 percent British Isles origins and eight percent Eastern Europe, plus a smattering from south-east Europe. Now, it never pays to take such percentages precisely, but this is suggestive. And I can confirm that Eastern Europe linkage from another source.

More specifically, I had my mitochondrial DNA done, which only traces descent in the female line mother to daughter to daughter, so that I cannot pass it on to my children. We measure this by the MtDNA haplogroup, of which there are a couple of dozen world-wide, and each is given a capital letter, so that for instance M is found among people in south east Asia, D in Japan, O in China, etc.There are also lots of subsets of those larger families. British Isles haplogroups are often J or T. The main MtDNA hapologroup in Wales is H.

My haplogroup, though, is none of the above, it is U, and specifically U4. It is in fact a striking (and quite rare) U4a1a, which points to Eastern Europe or the Baltic.

https://en.wikipedia.org/wiki/Haplogroup_U_(mtDNA)#Haplogroup_U4

Inthe available databases online, most people with that haplogroup tend to be Swedish, German, Danish, Polish . Now, that statement is a bit slanted, as these databases only include people who have paid quite a bit to get their DNA results done, so that would lead to a massive over-representation of wealthy northern Europeans. In no sense are these reliable scientific samples, nor do they say anything definitive about the actual distribution of U4 across Europe. Even so, U4 is not too common as a Welsh (or British) pattern. The furthest I can go back in my own female line is my great grandmother, and like all names on my chart, she was definitely south Welsh, with not a Pole or a Ukrainian in sight.

I should say by the way that I am not uncritically relying on these findings, which might be erroneous. But I have good reason to accept what I was told. In the paternal line, the results suggested individuals to whom I might be related, and I happen to know that those people and I share relatives with common surnames multiple generations back. There is no way a company could have cooked up such obscure, and uncannily accurate, findings. By extension then, I tend to trust the mitochondrial results.

My genealogy says one thing. My genetic information suggests something radically different.

Making life more difficult, in order to find the root of this genetic pattern, we would have to locate a woman, as only women carry MtDNA. We could not for instance assume an earlier woman in my ancestry who had a fling with a wandering Hungarian hussar in Napoleonic times. Nor, more seriously, can we invoke the many documented examples of skilled European workers traveling to Britain in early modern times, especially in pioneering Welsh industries like coal and iron. As far as I know, these visitors or migrants were all male.

So where does that U4 come from? I have an explanation not the right one, necessarily, but an interesting speculation.

Wouldnt it be wonderful if we could somehow place a woman from the Baltic/Slavic regions in South Wales in the pre-modern period, preferably very close to where my maternal family originated? Surely, that is a very tall order. Oddly enough, though, there is a historical window in which we can do something very much like that, and with remarkable geographical precision.

Over the past two centuries or so, my maternal family simply has not moved around much (Nor has my paternal line, but that is a different story). They have in fact remained within that small area of West Glamorgan, around Swansea and Neath, never really moving more than twenty miles or so in any direction. For the sake of argument, let us then assume they have in fact been in that small part of south Wales for centuries. Aha, but then we find an interesting connection. What we know about that area is that it is right next to one of the key regions of Scandinavian settlement in the British Isles in the Viking era, the ninth and tenth centuries.

The most important Scandinavian center in South Wales was Sweyns Inlet or Island, Sweyns-eye that is, Swansea. Its an open question whether Sweyn or Sveinn refers to a famous Norse king of that name, or just a lone adventurer. Near Swansea, Scandinavian names occur across the region of lower Gower, but not upper. The wonderful coastal landmark of the Worms Head in Gower is actually the head of the Ormr, Norse for a great Serpent (and it really looks like a sea serpent). A lot of the islands around the Welsh coast have pure Norse names like holm or -ey, as in Caldey. Flatholm is the Island of the Fleet. Such names scatter all across the coastal map to West Wales places like Tenby, another Scandinavian name.

Not only did the Norse name such places, but they and their descendants remained long enough to ensure that other people adopted and remembered the names. These areas were not just temporary camps: they were important enough to be real settlements, over decades or generations. At least along the coasts, the Vikings were there in force.

So what was the gender balance of these Scandinavian ventures? We tend to think of chiefs and raiders as all male communities, seizing local women, but there was more to the story. As settlements became more established, they might have brought wives or prospective (free) marriage partners. Over the years, archaeologists have recognized ever more examples of Scandinavian women buried in Britain. But other, more sinister, factors were also at work. As I say, we are looking at the 9th-10th centuries. At this very time, one of the worlds largest slave trading operations was centered on the Baltic Sea, particularly seeking out slaves from the Slav and Baltic peoples. The word slave comes from Slav, but Finland was another great center for slaves. There is a huge scholarly literature on all this.

Recent scholarship suggests that slavery and slave trading were a major incentive for the whole Viking enterprise, from the eighth century onwards. In a polygamous aristocratic society, lower status men found it hard to obtain wives within their own communities, driving them to seek women elsewhere, by force. Initially, they did this in Baltic lands like Estonia, but then mightily extended their reach. Following the rivers, some pushed deep into Russia, while others ventured into the Atlantic realms, but the basic goals remained the same. Reporting one major raid in 821, the Irish Annals of Ulster note that the heathens carried off a great number of women into captivity.

Gradually, isolated slave raids evolved into a transnational business operation that ranged across Europe, and took many slaves to the Islamic lands. Captives would have been kidnapped and taken to one of the great Swedish slave markets at Birka or Gotland, or Denmarks Hedeby. Scandinavians did much of the raiding, while Arab traders served as financiers and middlemen, and the distribution of these slave markets is indicated by the hoards of Arabic coins, dirhems, in trading centers like Birka.

A great many of those captives and slaves must have had U4 MtDNA. As we look at the map of lands where the U4 MtDNA pattern is most common, we also see the regions most heavily raided for their slaves precisely around this time.

Slave trading was thus a very large part of the economic life of the Viking world. Among other things, their enterprises ensured that large numbers of Irish and British slaves (thralls) ended up in early Iceland, where they have left a large genetic mark on the modern population. It would have been very natural for a Viking, maybe even the Sweyn who founded Swansea, to have had some slave girls along, whether as bed partners or as inventory for sale. In Iceland at least, some unfree women achieved the higher status of an acknowledged concubine, a frilla. Or possibly, a freeborn Norse woman brought along her unfree serving women and maids, even her nursemaid or her ladys maid. A female slave, by the way, was usually called an ambtt rather than a thrall. Over time, slaves might be freed and join the mainstream community.

Let us suppose that those unfree women had daughters, who intermarried with local Welsh men perhaps married, or else they were sexually exploited without their consent. They might have been sold, traded, or used as gifts. Whatever the exact process at work, any of these interactions would explain the importation of the U4 lineage into Wales.

Life for these slaves was as miserable as you might expect. In Norwegian law, slaves and thralls were described in the neuter gender: they were it rather than he or she, and were classified as just slightly superior to cattle. This is very much confirmed by the horrible portrayals of thralls that we repeatedly find in the large literature of the Icelandic sagas. But that observation leads to a major point about the nature of our historical evidence. Material evidence for free or aristocratic Scandinavian women is easy enough to find in the archaeological record, because they were deposited in substantial graves and accompanied by possessions such as brooches or other jewelry, or even weapons. Slave women, in contrast, owned nothing either in this world or in the grave, and their humble burials left very little for archaeologists to identify. You just did not bury rich grave goods when a slave woman an it died. We will likely never find material remains of Viking slaves in Britain. All they might have left just conceivably was their genes.

So could Baltic or Slavic girls have brought their MtDNA to South Wales? Very easily. Might my own maternal family even be descended from one of Sweyns slaves or concubines, someone from what we would now call Poland or Lithuania? I cant prove it, but it is plausible. If not Sweyn himself, there were lots of other comparable chieftains, who might have had girls recently imported from Birka or Gotland.

My suggestion, then, is that Slav-raiding and slave-trading are the main means by which U4 MtDNA found its way to the British Isles, and perhaps to other parts of Western Europe.

I am still puzzled by that eight-plus percent figure for my own East European blood, which goes far beyond a single woman a thousand years ago. And as I say, that element must have entered the bloodline well before the mid-nineteenth century. (Modern Wales has plenty of later migrants from that region, but they are not the explanation). I wonder: maybe those Vikings in Wales imported other slaves from the Baltic and eastern Europe, whose descendants merged completely into the local genetic mix. Their descendants perhaps became local Welsh families, called Jones or Evans, or Williams, or even Jenkins.

Even a handful of slaves leaving offspring could make a sizable genetic impact in such a tiny overall population. How many people did the whole of Wales have in, say, 1000 AD? Barely 100,000 in all? And perhaps 5,000 in West Glamorgan? Those were very small genetic pools.

What I can say confidently is that those Slavs or Balts did not originally migrate of their own accord.

For the regional context, see Michael North, The Baltic (Harvard 2015). On Viking society generally, see Jesse Byock, Viking Age Iceland (Penguin 2001). Kirsten A. Seaver has a chapter on Viking women slaves in her Thralls and Queens, in Gwyn Campbell, Suzanne Miers, and Joseph Calder Miller, eds., Women and Slavery (Ohio University Press, 2007), vol. 1: 147-167. See also Ruth Mazo Karras , Concubinage and Slavery in the Viking Age, Scandinavian Studies, 62 (1990) 141-162.

I have not read it yet, but Alice Rio has a forthcoming book on Slavery After Rome, on the period 500-1100 AD (Oxford University Press, 2017).

More here:
Of Slavs, Slaves, Vikings, and Genetics - Patheos (blog)

Genetics: A study shows which facial features are most likely to be … – Hindustan Times

Examining 3D face models of nearly 1,000 female twins, researchers have found that the shapes of the end of the nose, the area above and below the lips, cheekbones and the inner corner of the eye are highly influenced by genetics.

The notion that our genes control our face is self-evident. Many of us have facial traits that clearly resample those of our parents and identical twins are often indistinguishable, said lead researcher Giovanni Montana, Professor at Kings College London.

However, quantifying precisely which parts of the face are strongly heritable has been challenging so far, Montana said.

For the study, published in the journal Scientific Reports, the research team took scans of twins faces using 3D cameras and custom built statistical software to generate thousands of points that were perfectly aligned across the faces and then measured how curved each face looked at each one of those locations.

The researchers then compared how similar these measurements were between identical twins, who have the same genes, and non-identical twins, who only share half of the genes.

By seeing which parts of the face are the most similar in shape in a pair of identical twins, the researchers then calculated the likelihood that the shape of that part of the face is determined by genetics.

This likelihood is quantified as the heritability, a number between zero and one, where a larger number implies that it is more likely that the shape of the face is controlled by genes, the researchers said.

By combining 3D models of the face with a statistical algorithm that measures local changes in shape, we have been able to create detailed face heritability maps, Montana said.

These maps will help identify specific genes shaping up the human face, which may also be involved in diseases altering the face morphology, Montana added.

Follow @htlifeandstyle for more

Go here to see the original:
Genetics: A study shows which facial features are most likely to be ... - Hindustan Times

Cattle producers offered intro to genetic technology – Tri-State Neighbor

Cattle produers can learn about using genetic technology to improve cattle herds at a program offered in Rapid City by the King Ranch Institute for Ranch Management in May.

Sessions on Application of Advanced Genetic Technology in Beef Cattle will be offered May 11-12 at the Rushmore Inn and Suites in Rapid City. South Dakota State University West River Ag Center is co-hosting the lectureships. The cost is $300, which covers materials and meals.

"We hear many of our producers are beginning or wanting to use genetic technology to improve their herds. Some question if they are using it correctly; some feel it is information overload," said Kristi Cammack, director of the West River Ag Center.

Keeping up with genetic selection and evaluation innovations can be challenging. Early adopters who have been trying the technology as well as those who are interested but don't know where to start can learn from the classes.

The sessions are meant to strengthen the understanding of the genetic principles and help attendees build on the information. Faculty contracted by the King Institute will share how to apply advanced genetic technologies in the real world of seedstock and commercial cattle production.

Instructors will be Bob Weaber, Ph.D., extension specialist in animal sciences and industry from Kansas State University and Matt Spangler, Ph.D., beef genetics extension specialist in the animal science department at the University of Nebraska-Lincoln. Along with the basics, they will look at the application of advanced genetic tools including genomically enhanced expected progeny differences and marker assisted management in genetic advancement.

Cammack expects that the sessions will appeal to both commercial and seed stock producers from across the state, region and throughout the country.

Information will focus on developing breeding objectives for the herd and determining the economics relative for each operation as that may vary within a region. Owners want to know what will work for them at their location, taking into consideration different feedstuffs and different markets.

The tools have advanced so they are producer friendly. Cammack said the speakers will share knowledge that producers can apply and use in their operation, including an applied understanding of how to use genomic selection tools.

Cattle producers will get a lot out of the 1 -day program, she said. Producers will participate in interactive sire selection scenarios where they will break out into groups and practice how to pick sires.

"We hope the result is that cattle producers will learn to use advanced genetics. Applying these tools, in the correct way, will pay off with improved genetics. Producers will find it advancing herd genetics really pays it forward," Cammack said.

Contact Cammack at 605-394-2236, or email Kristi.Cammack@sdstate.edu. To see the agenda and make a reservation, go to the King Ranch Institute website.

See the original post here:
Cattle producers offered intro to genetic technology - Tri-State Neighbor

Closer look at brain circuits reveals important role of genetics – Medical Xpress

April 19, 2017 A serial electron microscopy reconstruction of a single synaptic connection. Credit: Anton Maximov

Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can form networks in the absence of synaptic activity.

"Our results imply that assembly of neural circuits in areas required for cognition is largely controlled by intrinsic genetic programs that operate independently of the external world," Maximov explained.

A similar phenomenon was observed by the group of Professor Nils Brose at the Max Planck Institute for Experimental Medicine in Germany. The two complementary studies were co-published as cover stories in the April 19, 2017, issue of the journal Neuron.

The "Nature vs. Nurture" Question

Experience makes every brain unique by changing the patterns and properties of neuronal connections. Vision, hearing, smell, taste and touch play particularly important roles during early postnatal life when the majority of synapses is formed. New synapses also appear in the adult brain during learning. These activity-dependent changes in neuronal wiring are driven by chemical neurotransmitters that relay signals from one neuron to another. Yet, animals and humans have innate behaviors whose features are consistent across generations, suggesting that some synaptic connections are genetically predetermined.

The notion that neurons do not need to communicate to develop networks has also been supported by earlier discoveries of synapses in mice that lacked transmitter secretion in the entire brain. These studies were performed in the laboratory of Professor Thomas Sdhof, who won the 2013 Nobel Prize in Physiology or Medicine.

"We thought these experiments were quite intriguing," Maximov said, "but they also had a major limitation: mice with completely disabled nervous systems became paralyzed and died shortly after birth, when circuitry in the brain is still rudimental."

The TSRI team set out to investigate if neurons can form and maintain connections with appropriate partners in genetically engineered animals that live into adulthood with virtually no synaptic activity in the hippocampus, a brain region that is critical for learning and memory storage. "While the idea may sound crazy at the first glance," Maximov continued, "several observations hinted that this task is technically feasible." Indeed, mammals can survive with injuries and developmental abnormalities that result in a massive loss of brain tissue.

Inspired by these examples, Richard Sando, a graduate student in the Maximov lab, generated mice whose hippocampus permanently lacked secretion of glutamate, a neurotransmitter that activates neurons when a memory is formed. Despite apparent inability to learn and remember, these animals could eat, walk around, groom, and even engage in rudimental social interactions.

Working closely with Professor Mark Ellisman, who directs the National Center for Microscopy and Imaging Research at the University of California, San Diego, Sando and his co-workers then examined the connectivity in permanently inactive areas. Combining contemporary genetic and imaging tools was fruitful: the collaborative team found that several key stages of neural circuit development widely believed to require synaptic activity were remarkably unaffected in their mouse model.

The outcomes of ultra-structural analyses were particularly surprising: it turns out that neurotransmission is unnecessary for assembly of basic building blocks of single synaptic connections, including so-called dendritic spines that recruit signaling complexes that enable neurons to sense glutamate.

Maximov emphasized that the mice could not function normally. In a way, their hippocampus can be compared to a computer that goes though the assembly line, but never gets plugged to a power source and loaded with software. As the next step, the team aims to exploit new chemical-genetic approaches to test if intrinsically-formed networks can support learning.

Explore further: Mice offer a window into sleep's role in memory

More information: "Assembly of excitatory synapses in the absence of glutamatergic neurotransmission," Neuron (2017). DOI: 10.1016/j.neuron.2017.03.047

Sleep provides essential support for learning and memory, but scientists do not fully understand how that process works on a molecular level. What happens to synapses, the connections between neurons, during sleep that helps ...

Scientists at The Scripps Research Institute (TSRI) have identified a new pathway that appears to play a major role in information processing in the brain. Their research also offers insight into how imbalances in this pathway ...

Scientists from the Institut Pasteur and the CNRS were able to make real-time observations over a period of several months that reveal how new adult-born neurons are formed and evolve in the olfactory bulb of mice. They made ...

One goal in neurobiology is to understand how the flow of electrical signals through brain circuits gives rise to perception, action, thought, learning and memories.

A number of psychiatric and neurological disorders may result from abnormal synapses, the neuron-to-neuron connection sites that enable chemical communication between brain cells. The timing, frequency, and intensity of neuronal ...

Research led by SUNY Downstate Medical Center has identified a brain receptor that appears to initiate adolescent synaptic pruning, a process believed necessary for learning, but one that appears to go awry in both autism ...

Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can ...

For people with severe brain injuries, researchers have found that the rhythm of daily fluctuations in body temperature is related to their level of consciousness, according to a preliminary study published in the April 19, ...

Each time we get feedback, the brain is hard at work updating its knowledge and behavior in response to changes in the environment; yet, if there's uncertainty or volatility in the environment, the entire process must be ...

Most left-handers can rattle off a list of their eminent comrades-in-arms: Oprah Winfrey, Albert Einstein, and Barack Obama, just to name three, but they may want to add on cockatoos, "southpaw" squirrels, and some house ...

When we learn to read, we say one word at a time. But how does the brain actually put words together when we read full sentences?

Johns Hopkins researchers today published new evidence refuting the long-held scientific belief that the gut nerve cells we're born with are the same ones we die with.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Read more from the original source:
Closer look at brain circuits reveals important role of genetics - Medical Xpress

NewLink Genetics: Initiating Coverage With Buy Rating And First … – Seeking Alpha

NewLink Genetics (NASDAQ:NLNK) is Ames, Iowa, based emerging biotechnology company in the field of immuno-oncology. The company's common stock sank last year after the failure of two Phase 3 trials of its HyperAcute cellular immunotherapy in metastatic pancreatic cancer. Afterwards, the stock more than doubled from its 2016 lows in anticipation of data from its IDO inhibitor pipeline and has pulled back from the recent highs, thus providing an attractive long entry point.

(NewLink Genetics, common stock price chart. Source: Bloomberg)

Product Pipeline:

(NewLink Genetics, IDO inhibitor immuno-oncology product pipeline)

The company's immuno-oncology pipeline is focused on the inhibition of IDO (indoleamine-2, 3-dioxygenase) pathway which is believed to be an immune checkpoint similar to PD-1 and CTLA-4 pathways. It is one of the handful of companies which are developing IDO inhibitors (and the one of two public ones). The IDO pathway regulates the immune response by suppressing T cell activation, which enables the tumor cells to evade the host immune response. IDO inhibitors are believed to be the next potential blockbuster class of checkpoint inhibitors. Incyte (NASDAQ:INCY)'s direct IDO enzyme inhibitor epacadostat is being tested in various solid tumors in partnership with Merck's (NYSE:MRK) Keytruda. Peak sales estimates for epacadostat are as high as $9 billion in various solid tumor indications.

(Mechanisms of actions of Indoximod and GDC-0919)

Indoximod: It acts on the T cells by mimicking tryptophan and, thus, signals the activation of T cells. It, thus, acts as an indirect inhibitor of IDO pathway. Indoximod attracted widespread investor attention after its recent data release in the treatment of advanced melanoma at the recently concluded AACR meeting. In an ongoing Phase 1b/2 trial in 60 patients enrolled so far, Indoximod and Keytruda combination resulted in 59% overall response rate (ORR) and 74% disease control rate (DCR). The cohort also included ocular melanoma patients (which have poor treatment response) and when these were excluded, ORR was 59% and DCR was 80%. The results were spectacular considering that Keytruda alone has shown ORR of only 33% in this patient population. A combination of Bristol-Myers Squibb's (NYSE:BMY) Opdivo and Yervoy (anti-CTLA-4) resulted in 58% ORR in advanced melanoma but had higher incidence of Grade 3 and 4 treatment-related adverse events (58% in the combination vs. 21% in Opdivo alone).

In a smaller Phase 1 study of 19 patients with advanced melanoma, Incyte's epacadostat and Keytruda combination resulted in 58% ORR, 26% complete remission rate (CR) and 74% DCR. The CR was lower in the above mentioned Phase 1b/2 trial of Indoximod+Keytruda (10%). However, Indoximod+Keytruda have shown efficacy and safety in the largest patient population of advanced melanoma treated with anti-PD1+anti-IDO combination so far, and till Incyte and Merck show efficacy and safety in a similar sized patient population, we like Indoximod in this indication so far.

In a Phase 1/2 trial, Indoximod+gemcitabine+abraxane resulted in impressive 45% ORR in metastatic pancreatic cancer (compared with 34% for Folfirinox regime and 9.4% for gemcitabine).

Indoximod is also being tested in various other cancers, and data from these indications is expected to be released over next 12 months. NewLink Genetics hold all worldwide commercialization rights to Indoximod. It will pay royalty payments on net sales of Indoximod (single-digit percentage) to Lankenau Institute of Medical Research, Augusta University, and Iowa State Department of Economic Development (ISDED). Various patents for Indoximod extend till 2027.

GDC-0919: It is a direct IDO enzyme inhibitor. Roche/Genentech (OTCQX:RHHBY) has licensed its worldwide commercial rights, thus showing confidence in its potential. In exchange, NewLink Genetics received $150 million of upfront payment and may receive up to $1 billion in future milestone payments and double-digit percentage of net sales as royalty payments.

A combination of GDC-0919 and Roche's anti-PDL1 Tecentriq is being tested in an ongoing Phase 1b, open-label study in various solid tumors like melanoma, NSCLC, head & neck squamous cell cancer, gastric cancer, ovarian cancer, Merkel cell cancer, cervical cancer, endometrial cancer, renal cell cancer, triple-negative breast cancer, and urothelial/bladder cancer. About 305 patients are planned to be enrolled. The estimated completion date of the trial is December 2018, but interim data is expected in mid-2017.

Various patents for GDC-0919 extend till 2032.

NLG802: NewLink Genetics is also developing NLG802, a prodrug of Indoximod to increase bioavailability and exposure. An IND was filed in 2017, and Phase 1 trial is expected to start this year.

Potential competition:

Other companies developing IDO inhibitors include Incyte, iTeos Therapeutics, and Redx Pharma.

HyperAcute Cellular Immunotherapy Program:

Despite failing in metastatic pancreatic cancer, a tough to treat cancer, this program is not dead yet. A combination of Tergenpumatucel with Indoximod and docetaxel is being tested in a Phase 1b trial in advanced non-small cell lung cancer (NSCLC). Dorgenmeltucel-C is being tested in combination with checkpoint inhibitors in a Phase 2 trial in advanced melanoma. Results from these trials are expected in 2018. Various patents for this program extend till 2029.

Vaccine program:

The company's Ebola Zaire vaccine has Breakthrough therapy designation from FDA. Interim data from a Phase 3 trial showed the vaccine's efficacy in preventing Ebola infection. Merck has licensed worldwide commercial rights to the rVSVG-ZEBOV GP vaccine (Ebola). NewLink Genetics received upfront $30 million and $20 million in milestone payments so far. It may also receive royalty payments on net sales of the vaccine.

Leadership:

CEO, chief scientific officer, and chairman of the board, Charles J. Link Jr. MD: He co-founded NewLink Genetics in 1999 and was a practicing oncologist for 18 years. He also served as the director of the Human Gene Therapy Research Institute at the Iowa Methodist Medical Center.

Co-founder and chief medical officer, Nicholas Vahanian, MD: He has led the algenpantucel-L (HyperAcute Cellular) program and worked at the National Cancer Institute and National Center for Human Genome Research Institute (both at the NIH).

Lead Director, Thomas Raffin, MD: He was the faculty member at the Stanford University School of Medicine for 30 years where he was the Colleen and Robert Haas Professor Emeritus of Medicine and Biomedical Ethics.

Director of the board, Paul R. Edick: He was the CEO of Durata Therapeutics, GANIC Pharmaceuticals, and MedPointe Healthcare.

Director of the board, Paolo Pucci: He is the current CEO of ArQule, Inc. He also worked as the senior VP of Bayer-Schering Global Oncology/Specialized Therapeutics Business Unit at Bayer AG.

Director of the board, Lota S. Zoth: She worked as the senior VP and CFO of MedImmune.

Financials and valuation:

NewLink Genetics is expected to have $131.5 million in cash reserves at the end of 2016. The operating cash burn was $65.9 million in 2016. The management expects to end 2017 with cash reserves of $75 million. We don't see any risk of equity dilution in 2017. The company has long-term debt of about $0.5 million and $6 million of royalty obligation to ISDED.

The size of melanoma market is $2.06 billion globally in the US and is expected to grow to $4.7 billion globally by 2020. About 76,000 new cases of melanoma are seen every year in the US and another 80,000 cases per year are seen in the EU. About 10% of these are diagnosed at advanced stage, thus providing our target market for Indoximod+Keytruda combination in advanced melanoma = 7,600 cases/year in the US and 8,000 cases/year in the EU. A combination of Opdivo and Yervoy is priced at average wholesale price = $256,000 in the US. Opdivo alone is priced at AWP of $150,000 in the US. We expect Indoximod to be priced in a similar range, thus providing us AWP = $106,000 in the US. At average sales price = 74% of AWP (average per Pharmagellan guide), we input ASP = $78,440 in the US. ASP of drugs in the EU and Japan is about 50% of that in the US. We input ASP = $39,220 in the EU. We input probability of reaching the market = 65% for the combination at this stage (average for drugs who passed Phase 2). The biggest competition for the combination in the melanoma market is Keytruda+epacadostat and Opdivo+Yervoy combinations. We input peak 20% market penetration in this indication for Indoximod+Keytruda combination in this combination in a base conservative scenario. Using these inputs, we modeled peak $106 million risk-adjusted revenue in this indication in the US+EU in 2024. Peak estimates for Opdivo+Yervoy combination in advanced melanoma is $350 million.

Peak sales estimate for epacadostat in various cancers is expected to be as high as $9 billion. Peak sales estimate for Tecentriq in various cancers is $3.5 billion in 2020. We are optimistic that GDC-0919 can achieve $1 billion in worldwide sales at the peak in combination with Tecentriq in various cancer mentioned above. Using probability of reaching the market = 60% at this stage and 20% of revenue as royalty payments for NewLink Genetics, we modeled peak $120 million risk-adjusted royalty revenue from GDC-0919 in 2024.

We also added NPV of potential $1 billion milestone payment from Genentech (equally distributed from 2017 to 2024, risk-adjusted at 60% probability and discounted at 15% for NPV of $336.5 million).

Using rNPV method (20% cost of capital), we calculated fair value of equity = $850.3 million after adjusting for non-operating assets, operating loss carry-forwards, and liabilities (using diluted share count) or $23.80 per share.

We are initiating coverage on NewLink Genetics common stock with Buy rating and first price target = $24.

We have not yet modeled revenue from Indoximod in other non-melanoma indications mentioned above, revenue from HyperAcute cellular immunotherapy pipeline, and Ebola vaccine program, which could add to further upside. We will adjust our model for these indications as we get more data.

Bristol-Myers acquired Flexus Therapeutics, another company developing IDO inhibitor pipeline (in preclinical stage) for $1.25 billion in 2015. In 2016, Merck acquired IOmet Pharma for its preclinical stage IDO inhibitor pipeline for $400 million.

OrbiMed Advisors, one of the largest healthcare institutional investors in the world, is the second largest investor in NewLink Genetics, and owns $33 million worth of stock (6.8% of the outstanding shares).

Several sell-side analysts reiterated Buy ratings on the stock recently, including Cantor Fitzgerald (PT = $20, April 4), and Stifel (PT = $26, April 4). SunTrust Robinson Humphrey considers NewLink Genetics as a takeover target and has price target of $30 on the stock.

Upcoming catalysts:

Risks in the investment:

It is possible that the ongoing clinical trials may fail, regulatory agencies might not approve the products, unexpected side effects might be seen in the future, clinicians might not widely prescribe the products, or insurers might not reimburse them. Competing products from other companies might gain significant market share in the planned clinical indications. The company may also need to raise additional capital in future.

Author's note: To get more investment ideas like this as soon as they are published, click on my profile and hit the big orange "Follow" button and choose the real-time alerts option.

Premium Research Service

Get more investment ideas like this by subscribing to Vasuda Healthcare Analytics, our premium equity research service (listed in Seeking Alpha's Marketplace). Subscribers have earlier access to the research reports, have access to the model portfolio (with price targets and suggested allocation) with regular updates, conviction buy list (more than 30 companies), a contrarian portfolio and a subscriber-only chat room. Link to subscribe.

Disclosure: This article represents my own opinion and is not a substitute for professional investment advice. It does not represent solicitation to buy or sell any security. Investors should do their own research and consult their financial adviser before making any investment.

Disclosure: I am/we are long NLNK, INCY, BMY.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

See the article here:
NewLink Genetics: Initiating Coverage With Buy Rating And First ... - Seeking Alpha

Regulators holding fistful of livestock genetics magic at the gate – Agri-Pulse

WASHINGTON, April 19, 2017- A mounting wave of new genetics technology is on its way, promising improved health and growth to farm animals, along with improved management tools and profits to livestock owners.

Still, use of this new channel of technological wonders, called gene or genome editing (see text box) apparently awaits the Trump administrations decisions about what kind of regulations theyll impose.

Bubbling up from technology companies and universities, and research collaborators in both, are gene editing techniques to breed cattle and swine immunity to foot-and-mouth disease, cattle that produce antibodies for fighting cancer in people, poultry resistant to highly pathological bird flu and, for example, improved heat-tolerance into cattle breeds that built their genomes in cool, northern-European climates.

The world market for shares of promising genome editing products in human and animal physiology, immune responses and other medical and agricultural applications is likely to grow to $8.1 billion by 2025, according to a projections by Grand View Research of California.

In the agricultural arena, for example, already at least two developers, Acceligen (the agricultural genetics subsidiary of Recombinetics) and a collaborative of university and Genus researchers, can offer genome editing technology to ensure strong resistance to PRRSV (the disastrous porcine reproductive and respiratory syndrome virus).

But thats just one item on Acceligens gene-editing menu of marvels. For the dairy sector, it has the right stuff for hornless (polled) cattle. It is a trait dairy farmers have long been able to select for Holsteins, which would relieve cattle from the stressful removal of horns or horn buds plus save dairy farm labor. However, unfortunately, choosing the trait has meant sacrificing other desired traits for health, milk production and more.

So, says Tad Sonstegard, Acceligens chief scientific officer: How do you get polled cattle without having to physically dehorn the animal or backcross in polled genetics, slowing your genetic improvement program? That is where our technology comes in.

With its new gene editing for hornless cattle, we could make (the genetics for) that animal tomorrow in a laboratory . . . and move it into an animal once we validated that it has been properly edited, Sonstegard explains. His company secured a USDA grant to edit the cattle genome for the polled trait, qualifying for the funds because the trait is associated with both animal welfare and safety for people handling cattle. Acceligen then hired scientists at the University of California, Davis, to produce the technology.

Amid the stream of such animal gene editing magic, the Food and Drug Administration posted its intent in January to regulate genome editing as it has transgenic processes, generally called genetic engineering. It is part of a move that the FDA, USDA and the Environmental Protection Agency took at the end of the Obama administration to modernize the regulatory system for biotechnology products, as then-President Obama had suggested in a 2015 memorandum. FDAs proposed guidance would specifically apply regulatory authority over animals intentionally altered through use of genome editing techniques.

Sonstegard says that, even though the agency has no regulation on use of gene editing products currently, its proposed guidance leaves commercial use of gene editing of farm animals in limbo until FDA moves to waive regulation, or require pre-market or post-market regulation.

That may not be helpful for industry, he says, because we made animals (genetic changes) two to three years ago in some cases. So at a minimum, the regulation is three years behind the technology. And, he says, I just dont know if . . . they (FDA) have reached the place where that approach is equal to their proposed regulation. And, he worries, If its too expensive and it takes too long, it wont fit into the (livestock) system.

Meanwhile, Kellye Eversole, a veteran biotechnology policy consultant in Bethesda, Md., doesnt agree that commercial production of gene-edited animals must wait for FDA to act. The agency doesnt regulate genome editing now, and it would be a change in FDA principles if they did look at what technology was used. Instead, theyve always been very product oriented. That is, she says, the results of gene editing arent different than what is done every day in conventional breeding practices . . . modifications that go on all the time within an organisms genetic makeup.

Regulators would be unable to differentiate with certainty the products of gene editing from other conventionally bred specimens because gene editing involves no introductions of foreign genetic matter, according to Eversole and Sonstegard.

Brad Shurdut, an Intrexon vice president for regulatory and government affairs, emphasizes that a product-based approach is needed by FDA. Intrexon is known for developing a host of transgenic products, including male mosquitos that cause female mosquitos offspring to die before adulthood. A subsidiary, AquaBounty, is developing a fast-growing freshwater salmon calledAquAdvantage. Intrexon is also editing the genomes of tilapia, for example, to produce large, higher-quality fillets, so genome editing looms large, for that company, too.

FDAs regulations must ensure that products are safe and effective, Shurdut says. But also, it is important to us and to agriculture that we have a transparent, predictable regulatory system so we can understand . . . the regulatory pathway. Obviously that has impact on our ability to bring innovation forward.

#30

Follow this link:
Regulators holding fistful of livestock genetics magic at the gate - Agri-Pulse

Weekly genetics review: Dramatic increase seen in AI use – Beef Central

THE use of artificial insemination in Australian beef herds is accelerating dramatically, and surprisingly the biggest increase is being seen in commercial herds.

Beef seedstock herds have traditionally been the biggest users of AI as they attempt to more efficiently multiply superior genetics.

Bovine semen marketing industry veteran Bill Cornell, who for the past 14 years has headed the beef division of ABS Australia, said unit sales of beef semen for the company had doubled over the past two years, and there was no sign of the trend abating.

Bill Cornell

Its just been amazing the response in terms of dollar turnover domestically for beef semen for us, he said.

Fixed time AI and confidence in Breedplan are the main reasons commercial producers are prepared to take on AI programs aimed at introducing superior genetics into their herds.

While the swing to AI may raise questions as to the number of bulls required for natural matings, back-up bulls are still required and seedstock producers will still be rewarded when they breed a potential donor bull combining superior phenotype and Breedplan figures.

And in more good news for Australian seedstock producers, two out of every three beef semen units sold in Australia today is produced domestically. In addition, Australia now exports more beef semen than it imports.

Australia has developed a strong reputation worldwide as the developer of superior genetics, the result of the preparedness of Australian seedstock producers over many years to use the best genetics available globally and Australias highly-regarded Breedplan performance recording system that can describe those genetics, Mr Cornell said.

Australian-based semen producing companies are buying, leasing or making partnership arrangements with more and more Australian seedstock producers to generate product to satisfy increasing demand.

At the top end was the sale of the Angus bull Millah Murrah Kingdom for $150,000 a couple of years ago, to a syndicate comprising Angus studs Ascot, Gilmandyke and Witherswood, and ABS Australia. The stud syndicate members have the paddock rights, while ABS Australia controls the semen rights world-wide.

Kingdoms sales have gone really well, not only in Australia but to several overseas countries. There are calves on the ground showing great promise, said Mr Cornell.

ABS Global and sister company Genus is the worlds largest provider of domesticated livestock semen and also head the lists as the largest providers of beef bovine semen.

Fixed time AI is all the rage in commercial beef herds performing artificial breeding programs, meaning no more tedious and often erroneous heat detection.

While overall well-being, being properly vaccinated, well managed and on a rising plane of nutrition are still important in getting females in calf in AI programs, the seven day co-sync program results in good conception rates with only three visits to the yards.

Australia is now punching above its weight in the semen production industry relative to its beef herd size

The program can differ slightly for heifers and cows, but basically it comprises CIDR (Controlled Internal Drug Release, based on progesterone) input on day 1, seven days later remove the CIDR and treat with prostaglandin and 2.5 days later AI and treat with GNRH.

ABS Globals conception average is 58pc to the first AI, the company says. Producers using the system for the first time may achieve a 45-50pc conception rate while the experienced operator on their fifth or sixth run can achieve up to 65pc success rates.

Australia is now punching above its weight in the semen production industry relative to its beef herd population, and now sells semen to around 22 countries, Mr Cornell said.

We now export more semen than we import, he said.

Mr Cornell also listed Australias disease-free status as a reason for Australias attraction as a semen supplier.

Of all the countries that we export to, the United Kingdom would be the hardest because of their IBR requirements, he said.

Many bulls fail the UKs IBR test, but they are mainly the older bulls. If a bull is 12-14 months old and been running in groups of similarly aged bulls, they are generally OK.

But older bulls that have been out in the paddock with cows have a bigger chance of testing positive. Interestingly some farms and even some districts dont seem to test positive for IBR, Mr Cornell said.

Excerpt from:
Weekly genetics review: Dramatic increase seen in AI use - Beef Central