Category Archives: Human Genetics

High cholesterol is the most commonly understood cause of atherosclerosis, a hardening of the arteries that raises the risk of heart attack and stroke. But now, scientists at Washington University School of Medicine in St. Louis have identified a gene that likely plays a causal role in coronary artery disease independent of cholesterol levels. The gene also likely has roles in related cardiovascular diseases, including high blood pressure and diabetes.

The study appears March 24 in the journal Science Translational Medicine.

Studying mice and genetic data from people, the researchers found that the gene calledSVEP1 makes a protein that drives the development of plaque in the arteries. In mice, animals missing one copy ofSVEP1had less plaque in the arteries than mice with both copies. The researchers also selectively reduced the protein in the arterial walls of mice, and this further reduced the risk of atherosclerosis.

Evaluating human genetic data, the researchers found that genetic variation influencing the levels of this protein in the body correlated with the risk of developing plaque in the arteries. Genetically determined high levels of the protein meant higher risk of plaque development and vice versa. Similarly, they found higher levels of the protein correlated with higher risk of diabetes and higher blood pressure readings.

Cardiovascular disease remains the most common cause of death worldwide, said cardiologistNathan O. Stitziel, MD, PhD, associate professor of medicine and of genetics. A major goal of treatment for cardiovascular disease has appropriately been focused on lowering cholesterol levels. But there must be causes of cardiovascular disease that are not related to cholesterol or lipids in the blood. We can decrease cholesterol to very low levels, and some people still harbor residual risk of future coronary artery disease events. Were trying to understand what else is going on, so we can improve that as well.

This is not the first nonlipid gene identified that has been implicated in cardiovascular disease. But the exciting aspect of this discovery is that it lends itself better to developing future therapies, according to the investigators.

The researchers including co-first authors In-Hyuk Jung, PhD, a staff scientist, and Jared S. Elenbaas, a doctoral student in Stitziels lab further showed that this protein is a complex structural molecule and is manufactured by vascular smooth muscle cells, which are cells in the walls of blood vessels that contract and relax the vasculature. The protein was shown to drive inflammation in the plaques in the artery walls and to make the plaques less stable. Unstable plaque is particularly dangerous because it can break loose, leading to the formation of a blood clot, which can cause heart attack or stroke.

In animal models, we found that the protein induced atherosclerosis and promoted unstable plaque, Jung said. We also saw that it increased the number of inflammatory immune cells in the plaque and decreased collagen, which serves a stabilizing function in plaques.

According to Stitziel, other genes previously identified as raising the risk of cardiovascular disease independent of cholesterol appear to have widespread roles in the body and are therefore more likely to have far-reaching undesirable side effects if blocked in an effort to prevent cardiovascular disease. AlthoughSVEP1is required for early development of the embryo, eliminating the protein in adult mice did not appear to be detrimental, according to the researchers.

The human genetic data showed a naturally occurring wide range of this protein in the general population, suggesting that we might be able to alter its levels in a safe way and potentially decrease coronary artery disease, Elenbaas said.

Ongoing work in Stitziels group is focused on seeking ways to block the protein or reduce its levels in an effort to identify new compounds or possible treatments for coronary artery disease and, perhaps, high blood pressure and diabetes. The researchers have worked with Washington UniversitysOffice of Technology Management (OTM)to file a patent for therapies that target the SVEP1 protein.

This work was supported in part by grants from the National Institutes of Health (NIH), grant numbers T32GM007200, T32HL134635, T32HL007081, R01HL53325, R01HL131961, UM1HG008853 and UL1TR002345; a career award from the National Lipid Association; and by The Foundation for Barnes-Jewish Hospital.

Jung I, Elenbaas JS, et al. SVEP1 is a human coronary artery disease locus that promotes atherosclerosis. Science Translational Medicine. March 24, 2021.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff ofBarnes-JewishandSt. Louis Childrenshospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked toBJC HealthCare.

Originally published by the School of Medicine

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Scientists find genetic link to clogged arteries | The Source - Washington University in St. Louis Newsroom

By Elizabeth PennisiMar. 25, 2021 , 2:00 PM

In 1935, French veterinarians observed a rabbit with a peculiar gait. Sometimes, when walking or running, the sauteur dAlfort rabbit would lift its back legs over its head, scrambling along the ground on its forelimbs like a circus performer (see video, above).

Now, scientists have pinned down the genetic mutation that likely causes this breed to have this strange form of locomotion. The gene involved holds clues to how the spinal cord enables walking, hopping, and even hand-standinga finding that dovetails with other work over the past decade on mice and horses. Together, the studies provide an emerging picture that may help explain how all vertebrates, including humans, move around.

The work could help scientists treat human motor deficits like Charcot-Marie-Tooth Disease, a nervous system disease characterized by muscle weakness, says Stephanie Koch, a neuroscientist at University College London who was not involved with any of the studies but has seen similar odd gaits in mice. The studys results are both surprising and exciting.

Gait is complex. Left, right, front, and back limbs must move at the right times. Muscles need to contract just the right amount to bend, straighten, lift, and twist the legs appropriately. And the body has to be able to switch from, say, walking to running, or going forward to sideways, in an instant should the senses detect danger or obstacles.

A set of nerve cells in the spinal cord called the central pattern generatornot the brainmakes most of these decisions. But just how has been unclear, says Snia Paixo, a neuroscientist at the Max Planck Institute of Neurobiology.

Researchers know nerve cells called interneurons, which relay sensory information from the rest of the body to the motor neurons that control muscles, play key roles. Several teams have been working to define classes of interneurons, often categorized by what genes are active in them. Then will come the hard work of figuring out what those neurons do. The exact nature and function of relevant interneurons have been hard to pin down, says Abdel El Manira, a neuroscientist at the Karolinska Institute (KI).

Thats where the sauteur, or jumperrabbit comes in. Geneticists Leif Andersson from Uppsala University (UU) and Miguel Carneiro from the University of Porto decided to try to track down the DNA behind the animal's strange gait after sequencing a rabbit genome in 2014. They mated jumper rabbits with another breed to create first- and second-generation animals with either the normal or hand-standing walk. Then the researchers compared DNA from affected and unaffected rabbits and pinned down one mutation in a gene called RORB. Working with UU developmental biologist Klas Kullander, they tracked down where and when this gene was active.

In these rabbits, the mutation causes aberrant versionsor sometimes none at allof the RORB protein to be produced in a specific group of interneurons, the team reports today in PLOS Genetics. This protein is a transcription factor, meaning it controls the activity of many other genes. Developmental studies showed that the result of two defective RORB genes is those interneurons are completely missing, and in rabbits with one copy there are 25% fewer of them. These interneurons are inhibitorythey stop nerve cells from firingand when they are missing, the rabbits flex certain muscles too much, lifting their hind legs more than they should.

I was impressed that the authors were able to identify a single gene mutation, says Jeremy Dasen, a neuroscientist at New York University. Because locomotion is such a complicated behavior, he expected multiple genes and multiple classes of interneurons would be involved. But this paper drives home that, like modular homes with independent sections put together to make a dwelling, locomotion is achieved through the combined efforts of individual classes of interneurons, he adds.

RORB also seems to control hind-limb coordination in mice: Rodents missing a functional RORB gene waddle like ducks. As a result, says KI neuroscientist Sten Grillner, the importance of RORB applies most likely to all limbed animals including humans. People with Charcot-Marie-Tooth disease also have atypical RORB proteins.

RORB is the second gene that Anderssons team has pinpointed as important to gait. In 2012, he and colleagues linked a mutation in a protein called DMRT3, which helps researchers identify a subset of interneurons, to an unusual walking gait called toelt. In Icelandic horses that exhibit toelt, the hind limbs support more weight than the front limbs, making the gait more fluid. Anderssons team confirmed the proteins role by making the same mutation in mice. Breeders have selected for this horse mutation because the altered gait gives a very smooth ride. Some of the horses carrying this mutation can also trot and pace at high speed, which makes them excellent for harness racing. And a connection exists between this group of interneurons and the RORB defect, the researchers now report: Rabbits with the mutation make lots more of the DMRT3 interneurons. The researchers do not yet know why.

Understanding how all the nervous system components interact is a challenge, Paixao says. Advances like the rabbit paper illustrate the progress made possible by combining developmental, genetic, and behavioral studies. We are now in a pivotal time to achieve these goals, she adds. It is an exciting time to see how all the pieces of motor control are coming together.

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This rabbit walks on its 'hands.' Scientists think they've found the genetic reason why - Science Magazine

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Triplet Therapeutics, Inc., a biotechnology company leveraging insights from the human genetics of repeat expansion disorders (REDs), today announced that Nessan Bermingham, Ph.D., Triplets chief executive officer, president and founder, will present at the following upcoming virtual events:

Dr. Bermingham will discuss Triplets recent activities, including plans to file an investigational new drug application for TTX-3360 in Huntingtons disease in the second half of 2021, pipeline development and completion of enrollment of SHIELD HD, its natural history study of Huntingtons disease.

About Triplet TherapeuticsTriplet Therapeutics is a biotechnology company developing transformational treatments for patients with repeat expansion disorders (REDs) a group of more than 50 known genetic diseases including Huntingtons disease (HD), myotonic dystrophy type 1 (DM1), spinocerebellar ataxias (SCAs), fragile X syndrome and familial amyotrophic lateral sclerosis (ALS) leveraging insights from patient genetics. Triplet uses a proprietary approach to design, develop and deliver potential therapeutics for REDs, enabling the Company to develop a single oligonucleotide targeting the DNA Damage Response (DDR) pathway to potentially treat multiple REDs.

Triplet is headquartered in Cambridge, Mass. For more information, please visit http://www.triplettx.com.

About TTX-3360TTX-3360, an antisense oligonucleotide, is Triplets first clinical candidate. TTX-3360 is the first clinical candidate with the potential to modify the course of REDs, including HD, by targeting the DDR pathway. Triplet plans to file an investigational new drug application for TTX-3360 in the second half of 2021, with a focus on HD. TTX-3360 may also be a candidate for the treatment of other central nervous system diseases including SCAs, DM1 and approximately 30 additional potential REDs impacting the central nervous system.

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Triplet Therapeutics to Present at Upcoming Events - Business Wire

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Gaucher Disease Treatment Market trends and review through quantitative analysis, comprehensive landscape, current and future growth : Acetelion...

Swim test: Locating an underwater platform activates specific neurons, which are labeled with a genetic marker, in a mouse model of Rett syndrome.

Courtesy of Nathan Achilly

Motor and memory training early in life postpones the onset of difficulties in those areas in a mouse model of Rett syndrome, according to a study published today in Nature. Stimulating neurons involved in those skills appears to mimic the effects of training.

Mutations in the gene MECP2 cause Rett syndrome, which often overlaps with autism and almost exclusively affects girls. Many children with Rett syndrome develop typically until toddlerhood and then suddenly lose the ability to speak, crawl or walk. Other traits, including breathing problems, intellectual disability, seizures and changes in social behavior, can also emerge.

Gene therapy to replenish missing MECP2 protein holds the potential restore some abilities, but too much MECP2 protein can cause challenges similar to Rett syndrome, and a successful treatment may be more than a decade away.

In the meantime, intensive early therapy may help to delay the conditions progress and maintain abilities such as walking, the new work suggests.

That will hopefully benefit these children long-term as new therapies come on board, says lead investigator Huda Zoghbi, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas.

The findings demonstrate the importance of using behavioral therapy to maintain abilities in Rett syndrome, and reiterate that neuron function is recoverable, says Michela Fagiolini, associate professor of neurology at Harvard University, who was not involved in the work.

We must stress that behavioral therapy, cognitive therapy, motor therapy early in life can be very useful, as beneficial as taking medication, Fagiolini says. Thats what you get from this.

Mice missing one copy of MECP2 develop motor problems at about 12 weeks of age, roughly equivalent to adolescence in people. The researchers trained some of these Rett mice, starting at 8 or 22 weeks old, to balance and run on a rotating rod. They also trained controls at different ages. At 24 weeks, the trained Rett mice stayed on the rod longer than untrained Rett mice. The Rett mice with earlier training performed the best, and all of the controls performed better than the trained Rett mice, as expected.

At 32 weeks, the early-trained mice did as well as untrained mice at 12 weeks, before the latters motor skills declined.

The researchers also taught Rett mice to swim to a hidden platform in a water tank, a test of spatial memory. At 12 weeks old, mice that had been trained on this task at 4 weeks old did better than those trained at 11 weeks old and untrained mice. With continued training, the early-trained mice did not show memory deficits as severe as those of untrained Rett mice until 24 weeks.

Training on either task had no effect on other traits, such as sociability or anxiety.

The team then used a genetic marker to identify and label neurons that were active during the swimming test. Silencing those neurons after early training impaired the animals performance on the test, whereas activating them after only one training session helped the mice retain their memory of the platforms location.

In early-trained mice, those same neurons had more complex dendrites branches that receive signals from other neurons and were more active than those in untrained mice.

When you put them through intense training, youre really training those neurons and youre changing their behavior, Zoghbi says.

The demonstration that training affects only neurons involved in a task is very elegant, Fagiolini says.

Its difficult to know how the findings translate to people with Rett syndrome, she says, particularly because the conditions signs emerge much later in the mice than in people. In other words, even the early-trained mice were trained after the point in development at which traits would appear in children. Still, its possible that neuronal function in children changes before any related behaviors become apparent, and could benefit from early training, she says.

[The brain is] always plastic; its always able to readjust, Fagiolini says. I think we have to take advantage of that, and thats what Dr. Zoghbi is showing here.

The findings suggest that therapy early in life before traits become apparent could be similarly helpful in autistic children without MECP2 mutations and those with other neurodevelopmental conditions, Zoghbi says.

Future clinical trials could confirm whether such therapy is effective, she says, but that would require identifying children with relevant gene mutations at or shortly after birth.

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Early training forestalls motor, memory difficulties in mouse model of Rett syndrome - Spectrum

Mound 4 of the Eleke Sazy necropolis in eastern Kazakhstan. Credit: Zainolla Samashev

Because of their interactions and conflicts with the major contemporaneous civilizations of Eurasia, the Scythians enjoy a legendary status in historiography and popular culture. The Scythians had major influences on the cultures of their powerful neighbors, spreading new technologies such as saddles and other improvements for horse riding. The ancient Greek, Roman, Persian, and Chinese empires all left a multitude of sources describing, from their perspectives, the customs and practices of the feared horse warriors that came from the interior lands of Eurasia.

Still, despite evidence from external sources, little is known about Scythian history. Without a written language or direct sources, the language or languages they spoke, where they came from and the extent to which the various cultures spread across such a huge area were in fact related to one another, remain unclear.

A new study published inScience Advances by an international team of geneticists, anthropologists, and archeologists lead by scientists from the Archaeogenetics Department of the Max Planck Institute for the Science of Human History in Jena, Germany, helps illuminate the history of the Scythians with 111 ancient genomes from key Scythian and non-Scythian archaeological cultures of the Central Asian steppe.

The burial of a social elite known as Golden Man from the Eleke Sazy necropolis. Credit: Zainolla Samashev

The results of this study reveal that substantial genetic turnovers were associated with the decline of the long-lasting Bronze Age sedentary groups and the rise of Scythian nomad cultures in the Iron Age. Their findings show that, following the relatively homogenous ancestry of the late Bronze Age herders, at the turn of the first millennium BCE, influxes from the east, west, and south into the steppe formed new admixed gene pools.

The study goes even further, identifying at least two main sources of origin for the nomadic Iron Age groups. An eastern source likely originated from populations in the Altai Mountains that, during the course of the Iron Age, spread west and south, admixing as they moved. These genetic results match with the timing and locations found in the archeological record and suggest an expansion of populations from the Altai area, where the earliest Scythian burials are found, connecting different renowned cultures such as the Saka, the Tasmola and the Pazyryk found in southern, central and eastern Kazakhstan respectively.

An aerial view of Hun-Xianbi culture burials. Both horses and warriors can be identified. Credit: Zainolla Samashev

Surprisingly, the groups located in the western Ural Mountains descend from a second separate, but simultaneous source. Contrary to the eastern case, this western gene pool, characteristic of the early Sauromatian-Sarmatian cultures, remained largely consistent through the westward spread of the Sarmatian cultures from the Urals into the Pontic-Caspian steppe.

The study also covers the transition period after the Iron Age, revealing new genetic turnovers and admixture events. These events intensified at the turn of the first millennium CE, concurrent with the decline and then disappearance of the Scythian cultures in the Central Steppe. In this case, the new far eastern Eurasian influx is plausibly associated with the spread of the nomad empires of the Eastern steppe in the first centuries CE, such as the Xiongnu and Xianbei confederations, as well as minor influxes from Iranian sources likely linked to the expansion of Persian-related civilization from the south.

Although many of the open questions on the history of the Scythians cannot be solved by ancient DNA alone, this study demonstrates how much the populations of Eurasia have changed and intermixed through time. Future studies should continue to explore the dynamics of these trans-Eurasian connections by covering different periods and geographic regions, revealing the history of connections between west, central and east Eurasia in the remote past and their genetic legacy in present day Eurasian populations.

Reference: 26 March 2021, Science Advances.DOI: 10.1126/sciadv.abe4414

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Ancient Genetics Trace the Origin and Decline of the Legendary Scythians - SciTechDaily

Selective breeding by humans has led to some incredibly odd and unfortunate pets over the years, and the sauteur d'Alfort rabbit is among the strangest of the lot.

This rare breed of bunny does not hop or walk like any other rabbit or hare in existence. When the sauteur is ready to go, it kicks its hind legs into the air and bounces forward on its front paws, like a human acrobat walking on their hands.

While this may seem like an amusing trait, it sadly comes with other debilitating problems too. Now, the one bunny that can't hop properly has helped us better understand the genetics of hopping in mammals.

Crossing a single male sauteur with a single female of the New Zealand white breed and then crossing the resulting offspring, researchers raised 52 bunnies, 23 percent of which carried two copies of the mutant gene similar to the original father.These numbers match the statistics expected when there is only one recessive gene involved in a mutation.

Pooling the DNA of the sauteur and non-sauteur young, researchers used whole-genome sequencing to compare the two groups. In the end - as they anticipated - there was only one gene that stood out.

The cause of the sauteur's defective jumping appears to lie with a mutation in an evolutionary conserved site of a gene known as RORB, which provides instructions to mammalian cells so they can create certain proteins.

RORB proteins are generally found throughout the rabbit nervous system, where they help turn genetic code into a protein building template. This particular mutation, however, causes a sharp decrease in the number of spinal cord neurons that can actually produce this protein.

Two copies of the RORB mutation, in fact, resulted in no proteins in the spinal cord at all, and this was tied to an inability to hop.Other rabbits in the litter capable of jumping with their hind legs showed no such protein loss.

The RORB gene, the authors conclude, must be what allows rabbits to bound around. It could also be the key to other mammal hopping, too.

Over the years, there's been a lot of scientific interest in the special physiology and biomechanics that allow mammals-like kangaroos, bunnies, hares and some mice - to hop, but the underlying genetics of this feat have rarely been considered.

One of the few studies out there recently found mice with the same RORB mutation as sauteur rabbits alsocannot hop like normal. Instead, these rodents waddle around on their front paws like a duck, with their tails and hind legs sticking up in the air.

"I spent four years looking at these mice doing little handstands, and now I get to see a rabbit do the same handstand," neuroscientist Stephanie Koch from the University College London told Science News. "It's amazing."

Koch's study on rabbits is the first to describe a specific gene required for leaping or hopping, and it lines up extremely well with what she's been observing in mutant mice.

Similar to mutant rodents, sauteur rabbits also show other anatomical defects beyond their strange walk. Many are born blind and develop cataracts in their first year of life. RORB knock-out mice also show retinal degeneration.

In mice, the RORB gene appears to play an essential role in differentiating cells in both the brain's cortex and the retina. It might also do something similar in the spinal cord, which is involved in the regulation of sensory information and locomotion among mammals.

As such, this lack of proteins might be what is causing the hind legs of rabbits and mice to lift instead of leaping. In sauteur rabbits, for instance, the RORB mutation appears to cause defects in the differentiation of spinal cord interneurons, although whether this is actually causing the bizarre locomotion remains unclear.

"In addition to its expression in the spinal cord, RORB is also expressed in many regions in the brain such as the primary somatosensory, auditory, visual and motor cortex, in some thalamus and hypothalamus nuclei, in the pituitary gland and in the superior colliculus," the authors write.

"Thus, we cannot exclude the possibility that an alteration of RORB function in the brain contributes to the locomotion phenotype characteristic for the sauteur rabbits."

The effects of the RORB mutation will require more study, but it's obvious it's involved somehow. This was theonly variant identified in the whole genome sequence of rabbits that had any impact on hopping.

While there might well be more genes involved in bunny hopping, it seems that poor sauteur rabbits have certainly pointed us in the direction of one.

The study was published in PLOS Genetics.

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We Finally Know The Genetic Reason Why This Bunny Walks on Its Front Paws - ScienceAlert

Abstract

Hamer et al. argue that the variable ever versus never had a same-sex partner does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer et al. neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.

Genetic research on sexuality had been constrained by the unavailability of samples large enough to achieve the statistical power required to detect variants with small effect sizes typical of complex traits. To address this, our study aimed to maximize statistical power in two ways: (i) combining the largest samples available with sexuality data from UK Biobank and 23andMe, and (ii) choosing the variable that yielded the largest effective sample size. Only the dichotomous variable we used in the main genome-wide association study (GWAS) satisfied both considerations. This variable we chose is straightforward and easy to understand, and was clearly described in the paper, including characterizing it as ever versus never had a same-sex partner as suggested by Hamer et al. (1). We made it clear that this variable did not capture the diversity and complexity of sexual behavior, and we did not intend or claim to measure sexual orientation or attraction with this variable. However, we reported follow-up analyses with subsets of the data and independent samples that showed overlap in the genetic signal for our main variable and for traditional measures of sexual orientation based on sexual attraction and identitycontrary to Hamer et al.s assertion that the study did not in fact investigate attraction or sexual orientation.

As is common for large-scale genetic studies, our analyses were constrained by the available phenotypic data, which were not collected for the particular purposes of our study. The UK Biobank, which comprised most of the available data, did not include sexual attraction or identity items. The only UK Biobank items relevant to sexual behavior were one question asking whether the participant had ever had a same-sex partner, and two questions asking their lifetime number of opposite-sex and same-sex partners (9% fewer respondents). Only the variable based on the dichotomous item maximized the absolute sample size. This variable also had the advantage of having an equivalent variable in the 23andMe sample (i.e., Other sex only response versus other responses to the question With whom have you actually had sex?). It also had a far greater effective sample size than the other dichotomous variables with a direct equivalent in 23andMe, namely restricting the non-heterosexual group to those who had only had same-sex partners, which in the UK Biobank can be derived from the items on numbers of same- and opposite-sex partners (effective UK Biobank sample size N = 53,688 for our main variable, versus N = 9775 when comparing heterosexuals with those who only had same-sex partners; effective sample size derived from the formula 4/[(1/Ngroup 1) + (1/Ngroup 2)].)

Without nuanced measures of behavior, fantasy, attraction, and identity in the large majority of our sample, our best option was to use the variable with maximal power available in the full sample (while acknowledging its limitations) and perform more nuanced follow-up analyses in subsets of the data to explore these important research questions about the complexity of sexuality. Hamer et al. seemingly disregard these follow-up analyses, which show evidence for substantial overlap in the genetic influences on sexual behavior with the kinds of measures that Hamer et al. recommend. First, in the UK Biobank there was a genetic correlation between our main dichotomous variable and a continuous variable measuring the proportion of total partners who were same-sex partners [rg = 0.92; supplementary materials of (2), p. 12]. Second, the 23andMe data included Klein scales for sexual fantasy, identity, attraction, and behavior, and these measures were genetically correlated with the main dichotomous measure in the UK Biobank [rg = 0.83, 0.79, 0.75, and 0.70, respectively; table S5 of (2)]. Third, we replicated three single-nucleotide polymorphisms identified by the main GWAS in a much smaller independent sample [MGSOSO; table S10 of (2)] whose comparison groups were predominantly heterosexual and predominantly homosexual individuals, per self-reported identity and feelings. Fourth, polygenic scores based on the main GWAS significantly predicted the identity-based groups in MGSOSO [table S12 of (2)] and continuous measures of same- versus opposite-sex attraction in two other small independent samples of young adults [Add Health and CATSS; tables S13 and S14 of (2)]. So, again, although we did not intend or claim to measure sexual identity or attraction with our main dichotomous variable, follow-up analyses showed that the genetic signal does substantially overlap for these phenotypes.

Responding to our suggestion that some of our findings cast doubt on popular measures of sexuality, Hamer et al. contend that genetic research cannot inform sexology research and that such an idea is an inversion of the scientific process. We disagree with this contention. To suggest that either sexology research or genetic research has supremacy in scientific enquiry is misguided. Both sexology research and genetic research can and should inform each other. Our genetic analyses revealed insights into the underlying structure of variation in sexual behavior that could not have been obtained using traditional methods of sexology researchfor example, that there is partial overlap in the influences on male and female sexual behavior.

The traditional and most popular measure of sexual orientation is the Kinsey scale (Fig. 1), which is bipolar and implies a continuum between exclusive heterosexuality and exclusive homosexuality, measuring the relative incidence of a composite of same-sex versus opposite-sex sexual behavior and psychological responses (not simply preference, as claimed by Hamer et al.). A concern with the Kinsey scale is that it inappropriately measures homosexuality and heterosexuality on a single dimensional scale, making one trade-off of the other (3). This enforced trade-off would not be a problem if it reflected the true underlying structure of individual variation in sexuality, such that the amount of same-sex behavior (and/or psychological responses) were indeed perfectly inverse to their opposite-sex counterparts. However, other research suggests that this is not the case (46). Individuals can be high on both same-sex and opposite-sex behavior or attraction (some bisexual individuals), and individuals can be low on both (asexual). This variation is not captured by a bipolar scale. Our findings (2) reinforced the point at the genetic level: The genetic variants that increase the likelihood of having had any (versus no) same-sex partners do not increase the likelihood of having a greater (versus lesser) proportion of total partners who are same-sex partners. That is, on the genetic level, there is no one continuum from exclusively opposite-sex to exclusively same-sex behavior. The 23andMe data showed genetic correlations (rg = 0.83 to 1.0) of same-sex behavior with attraction and fantasy [figure S7 of (2)], which suggests that the finding on same-sex sexual behavior might extend to these other aspects of sexuality too. For future genetic research on sexuality, if the phenotypic measure does not reflect the structure of the underlying genetic influences, then the precision and accuracy of the findings will be impaired. For this reason, we, like others [e.g., (35, 79)], suggest that sexual attraction, behavior, and feelings toward men and women be measured separately in future research.

The ratings are based on both psychologic reactions and overt experience. [Source: figure 161 of (10)]

Although we would much prefer even massive biobank-based samples to have deep phenotyping on our topic of interest (i.e., sexuality measures), data of this nature are not currently available. Generally, there is a practical trade-off between phenotypic detail and sample size. Our approach was to acknowledge the limitations but make reasoned use of the available data to move the field forward, recognizing that others may prefer to avoid examining such datasets altogether. In any event, we share Hamer et al.s concern to minimize public confusion, which is why we liaised with community groups on reporting and communication strategy, provided lay-oriented explanatory boxes 1 and 2 in our manuscript, developed a companion educational website (www.geneticsexbehavior.info), welcomed the public posting of alternative perspectives and concerns about our work (www.broadinstitute.org/news/perspectives-complex-genetics-same-sex-sexual-behavior), and held an informational press conference.

R. L. Sell, in The Health of Sexual Minorities: Public Health Perspectives on Lesbian, Gay, Bisexual and Transgender Populations, I. H. Meyer, M. E. Northridge, Eds. (Springer, 2007), pp. 355374.

A. C. Kinsey, W. B. Pomeroy, C. E. Martin, Sexual Behavior in the Human Male (Saunders, 1948).

See the article here:
Response to Comment on Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior - Science Magazine

Combined entity creates an innovative platform to de-risk and accelerate the discovery and development of preclinical and clinical pipelines with biopharma partners as well as the proprietary pipeline of the combined company

RUTHERFORD, N.J., March 25, 2021 (GLOBE NEWSWIRE) -- Cancer Genetics, Inc. (the Company) (Nasdaq: CGIX), an emerging leader in novel drug discovery techniques, announced the results of its March 24, 2021 shareholder meeting to approve the upcoming merger with StemoniX, Inc. ("StemoniX").

At a Special Meeting of Stockholders, CGIs stockholders, upon the unanimous recommendation of the board of directors of CGI: (a) voted in favor of the issuance of shares of Common Stock, warrants and options pursuant to the Agreement and Plan of Merger and Reorganization, dated as of August 21, 2020, as amended, with StemoniX; (b) voted in favor of the amendment to the certificate of incorporation of CGI effecting a reverse stock split of the issued and authorized shares of Common Stock, at a ratio in the range from 1-for-2 to 1-for-10, with such specific ratio to be determined by the CGI board; (c) voted to approve the Cancer Genetics, Inc. 2021 Equity Incentive Plan and to authorize for issuance 4,500,000 shares of Common Stock thereunder; and (d) voted to approve on an advisory basis, the compensation that may be paid or become payable to CGIs named executive officers in connection with the merger.

Chief Executive Officer of Cancer Genetics, Jay Roberts, stated, "The Cancer Genetics team is thankful for the participation and support of our shareholders for voting in favor of the merger with StemoniX. In addition, we are thankful to our management teams and board members from both Cancer Genetics and StemoniX for their effort in bringing the merger to this point. We are proud to be combining forces and we are prepared to execute on our business plan.

ABOUT CANCER GENETICS

Through its vivoPharm subsidiary, Cancer Genetics offers proprietary preclinical test systems supporting clinical diagnostic offerings at early stages, valued by the pharmaceutical industry, biotechnology companies and academic research centers. The Company is focused on precision and translational medicine to drive drug discovery and novel therapies. vivoPharm specializes in conducting studies tailored to guide drug development, starting from compound libraries and ending with a comprehensive set of in vitro and in vivo data and reports, as needed for Investigational New Drug filings. vivoPharm operates in The Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) accredited and GLP compliant audited facilities. For more information, please visit http://www.cancergenetics.com.

ABOUT STEMONIX, INC.

StemoniX is empowering the discovery of new medicines through the convergence of novel human biology and software technologies. StemoniX develops and manufactures high-density, at-scale human induced pluripotent stem (iPSC) cell-derived neural and cardiac screening platforms for drug discovery and development. Predictive, accurate, and consistent, these human models enable scientists to quickly and economically conduct research with improved outcomes in a simplified workflow. Through collaborations with drug discovery organizations, StemoniX tests compounds in-house, creates new cell-based disease models, and operationalizes custom human iPSC disease models at large scale for high-throughput screening. With leading-edge iPSC technologies and data science, StemoniX is helping global institutions bring the most promising medicines to patients. To learn more about how StemoniX products and services are accelerating discoveries, please visit http://www.StemoniX.com.

For more information, please visit or follow CGI at:

Internet: http://www.cancergenetics.com

Twitter: @Cancer_Genetics

Additional Information about the Proposed Merger and Where to Find It

In connection with the proposed merger between StemoniX and CGI, CGI has filed relevant materials with the Securities and Exchange Commission, or the SEC, including a registration statement on Form S-4 that has been filed and contained a proxy statement/prospectus/information statement, and which registration statement was declared effective on February 12, 2021. A definitive proxy statement/prospectus/information statement was filed on February 16, 2020, and was mailed to stockholders on February 16, 2021. INVESTORS AND SECURITY HOLDERS OF CGI AND STEMONIX ARE URGED TO READ THESE MATERIALS BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT CGI, STEMONIX AND THE PROPOSED MERGER. The proxy statement, prospectus and other relevant materials, and any other documents filed by CGI with the SEC, may be obtained free of charge at the SEC website at http://www.sec.gov. In addition, investors and security holders may obtain free copies of the documents filed with the SEC by CGI by directing a written request to: CGI Holdings, c/o John A. Roberts, Chief Executive Officer, 201 Route 17 North 2nd Floor, Rutherford, New Jersey 07070. Investors and security holders are urged to read the proxy statement, prospectus and the other relevant materials when they become available before making any voting or investment decision with respect to the proposed merger.

This report shall not constitute an offer to sell or the solicitation of an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. No offering of securities in connection with the proposed merger shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended.

Participants in the Solicitation

CGI and its directors and executive officers and StemoniX and its directors and executive officers may be deemed to be participants in the solicitation of proxies from the shareholders of CGI in connection with the proposed transaction under the rules of the SEC. Information about the directors and executive officers of CGI and their ownership of shares of CGIs Common Stock is set forth in the proxy statement/prospectus referred to above. Additional information regarding the persons who may be deemed participants in the proxy solicitations and a description of their direct and indirect interests in the proposed merger, by security holdings or otherwise, are included in the proxy statement/prospectus. These documents are available free of charge at the SEC web site (www.sec.gov) and from the Chief Executive Officer at CGI at the address described above.

Forward-Looking Statements

This report contains forward-looking statements based upon CGIs and StemoniXs current expectations. This communication contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. CGI and StemoniX generally identify forward-looking statements by terminology such as may, should, expects, plans, anticipates, could, intends, target, projects, contemplates, believes, estimates, predicts, potential or continue or the negative of these terms or other similar words. These statements are only predictions. CGI and StemoniX have based these forward-looking statements largely on their then-current expectations and projections about future events and financial trends as well as the beliefs and assumptions of management. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond each of CGIs and StemoniXs control. CGIs and StemoniXs actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to: (i) risks associated with CGIs ability to obtain the shareholder approval required to consummate the proposed merger transaction and the timing of the closing of the proposed merger transaction, including the risks that a condition to closing would not be satisfied within the expected timeframe or at all or that the closing of the proposed merger transaction will not occur; (ii) the outcome of any legal proceedings that may be instituted against the parties and others related to the Merger Agreement; (iii) the occurrence of any event, change or other circumstance or condition that could give rise to the termination of the Merger Agreement, (iv) unanticipated difficulties or expenditures relating to the proposed merger transaction, the response of business partners and competitors to the announcement of the proposed merger transaction, and/or potential difficulties in employee retention as a result of the announcement and pendency of the proposed merger transaction; and (v) those risks detailed in the proxy statement/prospectus. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Neither CGI nor StemoniX can assure you that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. The forward-looking statements made in this communication relate only to events as of the date on which the statements are made. Except as required by applicable law or regulation, CGI and StemoniX undertake no obligation to update any forward-looking statement to reflect events or circumstances after the date on which the statement is made or to reflect the occurrence of unanticipated events.

Investor Contacts:Jennifer K. Zimmons. Ph.D.Investor RelationsZimmons International Communications, Inc.Email: jzimmons@zimmonsic.comPhone: +1.917.214.3514

Link:
Cancer Genetics Announces Shareholder Approval of All Proposals in Connection with the Proposed Merger with StemoniX - GlobeNewswire

The publication in the journal Cell Death & Disease (Nature) of the study involving I3C

The journal Cell Death & Disease (Nature) has published an international study on COVID-19 coordinated by Professors Giuseppe Novelli (University of Tor Vergata University of Nevada, USA) and Pier Paolo Pandolfi (University of Turin University of Nevada, USA), in collaboration with the Bambino Ges Hospital (Rome), Istituto Spallanzani (Rome), San Raffaele University (Rome) and several US (Harvard, Yale, Rockefeller, NIH, Mount Sinai, Boston University), Canadian (University of Toronto) and French (INSERM Paris, Hpital Avicenne) institutions.

The international team identified a class of enzymes (E3-ubiquitin ligases) needed by the SARS-CoV-2 virus to leave infected cells and spread to all tissues in the body.

These same proteins have a similar effect on other viruses such as Ebola.

Researchers have shown that levels of these enzymes are elevated in patients lungs and other tissues infected with the virus.

The study also identified rare genetic alterations in the genes coding for these proteins in a subset of patients (about 1300) with a severe form of the disease selected from the cohorts of the International Consortia: COVID Human Genetic Effort, French COVID Cohort Study Group, CoV-Contact Cohort, and Healthy Nevada Project.

These alterations increase enzyme activity and favour the exit of the infecting virus.

The genetic mutations that favour the development of the COVID-19 infection have been identified at the Bambino Ges Childrens Hospital: researchers from the Medical Genetics Laboratories, led by Prof. Antonio Novelli, with the aid of NGS Next Generation Sequencing platforms have sequenced the genome of the 130 Italian patients (adults and paediatric) enrolled in the study, tracing the variants of the genes (HECT, WWP1 and NEDD4) involved in the virus multiplication process.

The team demonstrated that the activity of E3-ubiquitin ligase enzymes can be inhibited by a natural compound that is well-tolerated by the human body, known as Indole-3 Carbinol (I3C), and therefore potentially usable as an antiviral in a single form or in combination with other therapies.

The I3C compound has been shown to block, in vitro, the exit and multiplication of the virus from infected cells.

The study, co-funded by the Fondazione Roma, contributes to the understanding of the molecular mechanisms that govern the life cycle of SARS-CoV-2, paving the way for the identification of host-pathogen relationships necessary for the identification and development of new drugs capable of interfering with viral replication, blocking its transmission.

A vaccine, says Prof. Giuseppe Novelli, is only a prophylactic measure.

We need to test the drug in clinical trials with Covid-19 patients to rigorously assess whether it can prevent the onset of severe and potentially fatal symptoms.

Having options for treatment, particularly for patients who cannot be vaccinated, is of paramount importance to save more and more lives and contribute to better public health status and management.

We need to think long-term, says Prof. Pier Paolo Pandolfi.

Vaccines, while very effective, may no longer be so in the future, because the virus mutates, and therefore more weapons are needed to fight it.

The discovery on I3C is important, and we now need to start clinical trials to demonstrate its potential effectiveness.

It will be important to assess whether I3C can also reduce the very serious clinical complications that many patients experience after they have overcome the acute phase of infection.

This will be a major problem in the years to come, which we will have to manage.

We also need to move forward in drug research, to identify additional compounds and therapies that are effective now for Covid-19, and for other viruses that we will face in the future.

Bambino Ges Hospital And University Of Genoa: Study On New Stem Cells In Viral Infections

Kawasaki Syndrome And COVID-19, Pediatricians In Peru Discuss The First Few Cases Of Affected Children

Pediatrics, MicroRNA Analysis Predictive Of Future Heart And Kidney Disease: Research From Mount Sinai

Bambino Ges Childrens Hospital official website

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Drug that traps COVID-19 discovered in Italy: it is called 'I3C'. - Emergency-Live