Category Archives: Human Genetics

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In Gujarat, three siblings emerge as seventh case of rare mental disorder worldwide The Indian Express There could be similar cases in the country but they have not been registered or recorded yet, Dr Frenny Sheth, head of Cytogenetics department at the Institute of Human Genetics (IHG), Ahmedabad, said. Till date there have been six cases of this ... Rare 'Mental Retardation 42' hits family thriceTimes of India 3 siblings in Gujarat become the 7th case in the world to have 'rare intellectual disability'inUth.com all 2 news articles »

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In Gujarat, three siblings emerge as seventh case of rare mental disorder worldwide - The Indian Express

By Paula Haynes, PhD, University of Pennsylvania and Amita Sehgal, PhD, University of Pennsylvania, SWHR Interdisciplinary Network on Sleep Member

Patients visit sleep clinics seeking both treatment and the solace of understanding that accompanies a clinical diagnosis: knowing that their sleep problems are not their fault, but are due to physiology and genetics. When people are unable to fall asleep or wake up at normal times, they may have a circadian rhythm disorder caused by a disruption in the bodys internal clock [1, 2]. Surprisingly, much of the basic biology of the bodys internal clock has been discovered by working on the tiny kitchen pest, the fruit fly. The fruit fly, known to researchers as Drosophila melanogaster, is oddly enough a perfect model for scientists to study the genetic basis of seemingly complex behaviors.

Some people may wake up spontaneously in the morning, but those who do not get quite enough sleep might be awoken at exactly the same time every day by an alarm, the voices of young children, or a hungry pet. In fact, people and most animals possess an internal time-keeping mechanism that tells us when it is time to wake up and when it is time to go to sleep, keeping us synchronized to the day/night cycle. This internal time-keeping mechanism is called our circadian clock, derived from the Latin circa [about] dian [a day], and, just like a wall clock, runs on a daily cycle of 24 hours.

Just like people, fruit flies also have an internal circadian clock. In the 1960s, Ron Konopka, a student working with the famous Drosophila geneticist, Seymour Benzer began genetic studies of circadian rhythms in flies. Although Benzer was skeptical that specific genes would underlie daily behavioral rhythms, Konopka devised a way to identify mutant flies with disrupted circadian rhythms. Knowing that flies tend to emerge from their pupal cases at dawn, Konopka collected and bred the flies that emerged at inappropriate times. Konopkas mutant flies were found to have a mutation in a single gene, which was named period [3,4].

Years later, other genes affecting circadian rhythms, such as timeless [5,6], Clock [7], cycle [8], Doubletime [9] and Jetlag [10], were discovered in flies, with many of these genes functioning similarly in mice and humans. Indeed, scientists also studied these genes in families that exhibit unusual sleep-timing patterns, such as one in which many members fall asleep between 6 to 8pm and wake up between 1 to 3am. Thanks to work on flies, scientists considered the period genes in humans as possible culprits and sure enough, traced the earliness to a mutation in the Period2 gene [11].

Following the successful use of fruit flies in understanding circadian rhythms, researchers now use flies to figure out what makes us sleepy [12,13]. Just as with circadian timing, the genes that drive sleep in fruit flies and humans are likely to be similar as well. In fact, caffeine keeps flies awake, just as it does people [14]. We have also discovered other genes, named sleepless [15] and redeye [16], which are needed to maintain sleep in flies, and others have found similar genes in mammals [17,18, 19]. Moving forward, scientists hope to use the humble fruit fly to uncover even greater mysteries, including understanding why we sleep at all.

The Society for Womens Health Research Interdisciplinary Network on Sleep is committed to promoting awareness of sex and gender differences in sleep and circadian rhythms across the lifespan, and the impact they have on health and well-being. Learn more about the Sleep Network here.

1. Sehgal, A. & Mignot, E. Genetics of sleep and sleep disorders. Cell 146, 194207 (2011).

2. Jones, C. R., Huang, A. L., Ptek, L. J. & Fu, Y.-H. Genetic basis of human circadian rhythm disorders. Exp. Neurol. 243, 2833 (2013).

3. Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752754 (1984).

4. Zehring, W. A. et al. P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 36976 (1984).

5. Sehgal, A. et al. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270, 80810 (1995).

6. Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 16036 (1994).

7. Allada, R., White, N. E., So, W. V, Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791804 (1998).

8. Rutila, J. E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 80514 (1998).

9. Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94, 97107 (1998).

10. Koh, K., Zheng, X. & Sehgal, A. JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS. Science 312, 180912 (2006).

11. Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 10403 (2001).

12. Shaw, P. J., Cirelli, C., Greenspan, R. J. & Tononi, G. Correlates of sleep and waking in Drosophila melanogaster. Science 287, 18347 (2000).

13. Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 12938 (2000).

14. Nall, A. H. et al. Caffeine promotes wakefulness via dopamine signaling in Drosophila. Sci. Rep. 6, 20938 (2016).

15. Koh, K. et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 321, 3726 (2008).

16. Shi, M., Yue, Z., Kuryatov, A., Lindstrom, J. M. & Sehgal, A. Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount. Elife 3, e01473 (2014).

17. Ni, K.-M. et al. Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep. Elife 5, 745752 (2016).

18. Puddifoot, C. A., Wu, M., Sung, R.-J. & Joiner, W. J. Ly6h Regulates Trafficking of Alpha7 Nicotinic Acetylcholine Receptors and Nicotine-Induced Potentiation of Glutamatergic Signaling. J. Neurosci. 35, (2015).

19. Wu, M., Puddifoot, C. A., Taylor, P. & Joiner, W. J. Mechanisms of inhibition and potentiation of 42 nicotinic acetylcholine receptors by members of the Ly6 protein family. J. Biol. Chem. 290, 2450918 (2015).

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What Fruit Flies Can Tell Us About Human Sleep and Circadian Disorders - Huffington Post

Researchers at Baylor College of Medicine have uncovered a new mechanism showing how microbes can alter the physiology of the organisms in which they live. In a paper published in Nature Cell Biology, the researchers reveal how microbes living inside the laboratory worm C. elegans respond to environmental changes and generate signals to the worm that alter the way it stores lipids.

Microbe-host interactions have been known for a long time, but the actual molecular mechanisms that mediate the interactions were largely unknown, said senior author Dr. Meng Wang, associate professor of molecular and human genetics at Baylor and the Huffington Center On Aging. Microbes living inside another organism, the host, can respond to changes in the environment, change the molecules they produce and consequently influence the normal workings of the hosts body, including disease susceptibility.

In this study, Wang and first author Dr. Chih-Chun Lin working in the Wang Lab have dissected for the first time a molecular mechanism by which E. coli bacteria can regulate C. elegans lipid storage.

How E. coli changes lipid storage in C. elegans

C. elegans is a laboratory worm model scientists use to study basic biological mechanisms in health and disease.

This worm naturally consumes and lives with bacteria in its gut and interacts with them in ways that are similar to those between humans and microbes. In the laboratory, we can study basic biological mechanisms by controlling the type of bacteria living inside this worm as well as other variables and then determining the effect on the worms physiology, Wang said.

In this study, Wang and Lin compared two groups of worms. One group received bacteria that had been grown in a nutritionally rich environment. The other group of worms received the same type of bacteria, but it had grown in nutritionally poor conditions. Both groups of worms received the same amount and type of nutrients, the only difference was the type of environment in which the bacteria had grown before they were administered to the worms.

Interestingly, the worms carrying bacteria that came from a nutritionally poor environment had in their bodies twice the amount of fat present in the worms living with the bacteria coming from the nutritionally rich environment.

The researchers then carried out more experiments and determined that it was the lack of the amino acid methionine in the nutritionally poor environment that had triggered the bacteria to adapt by producing different compounds that then initiated a cascade of events in the worm that led to extra fat accumulation. In addition, the researchers observed that the tissues showing extra fat accumulation also had their mitochondria fragmented. The activities of the mitochondria, the balance between their fusion and breaking apart, are known to be tightly coupled with metabolic activities.

A mechanism that reveals unsuspected connections

The researchers found that the bacteria were able to trigger mitochondrial fragmentation and then extra lipid accumulation because the molecular intermediates the bacteria had triggered allowed them to establish communication with the mitochondria.

We have found evidence for the first time that bacteria and mitochondria can talk to each other at the metabolic level, Wang said.

Bacteria and mitochondria are like distant relatives. Evolutionary evidence strongly suggests that mitochondria descend from bacteria that entered other cell types and became incorporated into their structure. Mitochondria play essential roles in many aspects of the cells metabolism, but also maintain genes very similar to those of their bacterial ancestors.

Its interesting that the molecules bacteria generate can chime in the communication between mitochondria and regulate their fusion-fission balance, Wang said. Our findings reveal this kind of common language between bacteria and mitochondria, despite them being evolutionary distant from each other.

Some components of this common language involve proteins such as NR5A, Patched and Sonic Hedgehog. The latter is of particular interest to the researchers because it has not been involved in regulating lipid metabolism and mitochondrial dynamics before.

Microbes in the microbiome can affect many aspects of their hosts functions, and here we present a new molecular mechanism mediating microbe-host communication, Wang said. Having discovered one mechanism encourages us to investigate others that may be related to other physiological aspects, such as the stress response and aging, among others.

This project is supported by the National Institutes of Health grants R01AG045183, R01AT009050, DP1DK113644 and grants from the Howard Hughes Medical Institute. It also is supported in part by a training fellowship from the Burroughs Wellcome Fund and The Houston Laboratory and Population Science Training Program in Gene-Environment Interaction of the University of Texas Health Science Center at Houston (BWF Grant 1008200).

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Mechanism of environment-microbe-host interactions revealed ... - Baylor College of Medicine News (press release)

Researchers from the Global Research Cluster in Japan have developed a potential mouse model for the genetic disorder known as an NGLY1 deficiency. Published in the journal PLOS Genetics, the study describes how a complete knockout of the Ngly1 gene in mice leads to death just before birth, which can be partially rescued by a second knockout of another gene called Engase. When related genes in the mice used for making the knockouts are variable, the doubled-deletion mice survive and have symptoms that are analogous to humans with NGLY1-deficiency, indicating that these mice could be useful for testing potential therapies.

NGLY1-deficiency is a relatively newly discovered genetic disorder, with the first patient identified in 2012. The symptoms are severe, and include delayed development, disordered movement, low muscle tone and strength, and the inability to produce tears. Understanding how lack of NGLY1 leads to these symptoms is critical when considering targets for therapeutic interventions, and creating useful animal models of the disease is therefore equally important.

The RIKEN team has already had some success studying the consequences of Ngly1 deficiency in cultured animal cells. The Ngly1 gene codes for an enzyme that helps remove sugar chains from proteins that are scheduled for degradation. Their research showed that when Ngly1 was absent, sugars normally removed by Ngly1 were improperly removed by another enzyme called ENGase. Knocking out the ENGase gene led to normal protein degradation.

In the current study, the researchers first examined the effects of knocking out Ngly1 in mice. They found that when mice lacked both Ngly1 genesone from each parentthey always died just before birth. However, a double knockout of both Ngly1 and ENGase genes resulted in mice that survived after birth, but not for very long.

This positive result was actually unexpected. We thought that ENGase acted further downstream to Ngly1 in the catabolism of glycoproteins notes team leader Tadashi Suzuki, and were surprised when the double knockout was able to suppress the lethality of Ngly1-KO mice. If ENGase was merely an enzyme downstream of Ngly1, nothing should have happened. This was truly a case of serendipity.

Although the double knockout mice survived, they shared several defects that are similar to the symptoms observed in people with NGLY1-deficiency. As these mice aged, they developed characteristics such as bent spines, trembling, limb-clasping and shaking, and by 45 weeks, the survival rate was reduced to 60%. These mice could therefore be useful model mice for developing treatments for the human genetic disorder.

Another factor affecting survival and symptoms turned out the be the genetic background of the mice, that is, the genotypes of all genes related to Ngly1 and Engase, which likely affect how they function. When mice were crossed with an outbred strain, the single Ngly1 knockout proved less lethal, and the double knockout proved to be even more helpful, with mice only showing hind-limb clasping after 30 weeks.

These findings show that the biological processes involved are quite complicated. Despite this however, it is clear that preventing ENGase from acting can alleviate symptoms of Ngly1 deficiency in mice. Figuring out which aspects of the genetic background help reduce symptoms is perhaps a long-term goal.

Although the condition was only recently discovered, research into NGLY1-deficiency has been facilitated through efforts from the Grace Science Foundation, and the RIKEN team has recently begun a collaboration with Takeda Pharmaceuticals and T-CiRA at Kyoto University.

For now, the next step, says Suzuki, will be to isolate an in vivo inhibitor for ENGase and determine whether it can improve the symptoms related to NGLY1-deficiency. As we do not know much about the pathophysiology of the disorder, this might help us find potential targets for therapy, but also might lead to a better understanding of other diseases. Such chains of unexpected results are the beauty of basic science!

This article has been republished frommaterialsprovided byRIKEN. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Fujihira, H., Masahara-Negishi, Y., Tamura, M., Huang, C., Harada, Y., Wakana, S., . . . Suzuki, T. (2017). Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene. PLOS Genetics, 13(4). doi:10.1371/journal.pgen.1006696

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A Promising Model for a Devastating Genetic Deficiency ... - Technology Networks

SYRACUSE A conference held last week at SUNY Upstate Medical University in Syracuse brought together scientists studying autism from different aspects and emphases of the disorder in a way that will benefit one another's research.

That is what Dr. Brian Howell, a Skaneateles resident who researches autism as it relates to brain development at Upstate, observed following the two-day "Autism Symposium 2017: Where We Are, Where We Are Going" that he organized through Upstate's Department of Neuroscience & Physiology.

Calling the symposium a success, Howell said it was the first such event that tried to include the public along with the scientists. The first day which featured "Nightline" correspondent John Donvan speaking about changing attitudes about autism was geared toward the general public.

But, Howell said, some people came back for the second day when scientists from a variety of institutions and backgrounds came together to share their research in a series of presentations.

Those presentations included "a good mix of people that probably don't even necessarily go to the same meetings," Howell said, because of the differences in their disciplines.

"We got people talking across sub-fields in this area, so a lot of scientists said to me that they really appreciated this in terms of not only the science that they heard but also the interpersonal connections that they made," he said.

That goes for him and his department as well, he added. He and his team work with mouse genetics in their research but follow the research in human genetics. There is so much data out there, though, that one needs to be a computer specialist in order to use the data.

"For us, to meet some really good data miners, I think, will help drive our research that we now can set up some collaborations and look more closely at the human data and see how that might inform our work in mice," Howell said. "For me, probably the most benefit I got out of all this work is being able to call up people in different specialties and get their point of view on things."

Along with Donvan, the first day of talks included Dr. Stephan Sanders, from University of California San Francisco, discussing his work sequencing the genomes of thousands of families with autism spectrum disorder to look for gene mutations that might be able to predict autism in children.

Following Sanders, Dr. Arthur Beaudet, from Baylor College of Medicine, talked about a new technology he is developing a blood test for pregnant mothers to isolate fetal cells in the bloodstream, sequence those cells and look for mutations known to be predictors for autism.

On the second day of presentations:

Dr. Steven Hicks, of Penn State College of Medicine, talked about a start-up company, Motion Intelligence, that is developing a noninvasive oral swab to test children's saliva for signs of autism and determine a treatment program when early intervention is most effective.

Dr. Gahan Pandina, of Janssen Research & Development, a branch of Johnson & Johnson, presented on the Autism Anchor app that allows parents to document the behavior of their children with autism in order to provide clinicians with more information during appointments.

Dr. Joseph Dougherty, of Washington University in St. Louis, spoke about computer programs he is using to determine what brain regions and cell types are being impacted by autism and the databases that can put together mutations, cell types and brain regions involved in autism.

Dr. Janine LaSalle, of University of California Davis, highlighted the environmental factors that lead to autism, citing a study that found that prenatal exposure to polychlorinated biphenyls may cause a particular chromosome duplication that leads a child to develop autism.

Weirui Guo, from University of Texas Southwestern, shared his research about a sub-class of autism found in those with fragile X syndrome, a male-specific disorder caused by a defect in the X chromose that results in the overproduction of a certain protein.

Howell gave a presentation about the developmental genes with which he and his team work mice and how mutations in those genes might contribute to autism in both mice and people when autism, unlike mental retardation, does not present obvious brain defects.

As far as where the research in autism goes from here following the symposium both personally and in the wider community, Howell said he and his team hope to take a closer look at human genetics to complement their studies using mice but need partners to be able to do that.

"The human genetic data now, there's so much of it. It's in these massive databases that you basically need a computer degree to be able to access," he said. "We hope to reach out to the computer experts that we've met and mine the genetic data to see if we can develop networks of genes that are involved in autism."

He noted that there is no single mutation that causes autism, but a collection of mutations in an individual adds up to the disorder. Using human genetic data and testing that data in mice, his team might be able to figure out what series of mutations in people lead to autism.

"There are hundreds of genes that might make you at risk for autism, but no one mutation on its own is sufficient," Howell said.

Journal Editor Jonathan Monfiletto can be reached at jonathan.monfiletto@lee.net or (315) 283-1615. Follow him on Twitter @WOC_Monfiletto.

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Research presentations at Syracuse autism symposium connect scientists across disciplines - Auburn Citizen

The International Association of HealthCare Professionals is pleased to welcome Dr. Luigi Boccuto, MD, to their prestigious organization with his upcoming publication in The Leading Physicians of the World. Dr. Luigi Boccuto is a highly trained geneticist and research scientist with an extensive expertise in all facets of his work, especially human genetics and molecular studies. He holds over 15 years of experience in his field and is currently an Assistant Research Scientist at the JC Self Research Institute of the Greenwood Genetic Center in Greenwood, South Carolina.

Dr. Boccuto graduated with his Medical Degree in 2002 from the Universit Cattolica del Sacro Cuore in Rome, Italy. Following his graduation, he completed specialized training in medical genetics within the same institution, and trained for years under Prof. Neri with a focus on hereditary cancer, overgrowth syndromes, and intellectual disability syndromes.

Dr. Boccuto is renowned for his important research in the field of medical genetics, focused on the study of the genetic causes of autism, ID, and conditions with segmental or generalized overgrowth. He remains a member of the American Society of Human Genetics, is the recipient of numerous awards and recognitions, and has been published extensively for his important research. He attributes his success to his life long quest for learning, problem solving, and desire to better the health of human beings. In his free time, Dr. Boccuto enjoys playing soccer, photography, traveling, and reading.

View Dr. Luigi Boccutos Profile Here: https://www.findatopdoc.com/doctor/8138568-Luigi-Boccuto-Geneticist-Greenwood-South-Carolina-29646

Learn more about Dr. Boccuto here:

http://www.ggc.org/ and be sure to read his upcoming publication in The Leading Physicians of the World.

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FindaTopDoc.com is a hub for all things medicine, featuring detailed descriptions of medical professionals across all areas of expertise, and information on thousands of healthcare topics. Each month, millions of patients use FindaTopDoc to find a doctor nearby and instantly book an appointment online or create a review. FindaTopDoc.com features each doctors full professional biography highlighting their achievements, experience, patient reviews and areas of expertise. A leading provider of valuable health information that helps empower patient and doctor alike, FindaTopDoc enables readers to live a happier and healthier life. For more information about FindaTopDoc, visit http://www.findatopdoc.com

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Reputable Geneticist and Research Scientist, Luigi Boccuto, MD, will be Presented in The Leading Physicians of the ... - PR NewsChannel (press...

The following is a script of Breeding out Disease which aired on Oct. 26, 2014. Norah ODonnell is the correspondent. Tanya Simon, producer.

There are few fields of medicine that are having a bigger impact on how we treat disease than genetics. The science of genetics has gotten so sophisticated so quickly that it can be used to not only treat serious diseases but prevent thousands of them well before pregnancy even begins. Diseases that have stalked families for generations - like breast cancer - are being literally stopped in their tracks. Scientists can do that by creating and testing embryos in a lab, then implanting into a mothers womb only the ones which appear healthy. While the whole field is loaded with controversy, those who are worried about passing on defective and potentially dangerous genes see the opportunity to breed out disease.

Norah ODonnell: Did you ever envision that you would have the capability you have today?

Dr. Mark Hughes: No, but thats the fun of science. Its constantly surprising you.

[Dr. Mark Hughes: Wow. Look at that.]

Dr. Mark Hughes is one of the scientists leading the way in a rapidly growing field known as reproductive genetics. He pioneered a technique called preimplantation genetic diagnosis, or PGD, an embryo screening procedure that can identify deadly gene mutations - and alter a childs genetic destiny.

[Dr. Mark Hughes: This ones got a minus two.]

Dr. Mark Hughes: We all throw genetic dice when we have children. But when you know the dice are loaded and that theres a really reasonable chance that your baby will have an incurable, dreadful condition, youre looking for an alternative.

Dr. Hughes helped develop PGD two decades ago to screen embryos for one disease: cystic fibrosis. Today, because of advances in the mapping of the human genome, he says it can be used to root out virtually any disease caused by a single defective gene.

Norah ODonnell: Let me do a rapid fire yes or no. Can you use PGD for Tay-Sachs?

Dr. Mark Hughes: Yes.

Norah ODonnell: Muscular dystrophy?

Dr. Mark Hughes: Yes.

Norah ODonnell: Sickle-cell anemia?

Dr. Mark Hughes: Yes.

Norah ODonnell: Hemophilia?

Dr. Mark Hughes: Yes.

Norah ODonnell: Huntingtons disease?

Dr. Mark Hughes: Its one of the most common disorders we test for, yes.

Norah ODonnell: Alzheimers disease?

Dr. Mark Hughes: If its a mutation in a particular gene that causes early onset, we can test for it, yes.

Norah ODonnell: So you can test for Alzheimers.

Dr. Mark Hughes: This is a small subset of a particular kind of Alzheimers that attacks very early in life.

Norah ODonnell: Colon cancer?

Dr. Mark Hughes: If we know which of the colon cancer genes, yes.

Norah ODonnell: Breast cancer?

Dr. Mark Hughes: We do it regularly.

Dr. Hughes lab is one of a handful in the country that provides this genetic testing, which is why 3,000 couples turn to him each year. Among them, Matt and Melinda, who asked that we not use their last name. If they hadnt done the embryo screening procedure, their four-year-old son Mason and his baby sister, Marian, might very well have been born with a genetic mutation that increases the risk of breast, ovarian, prostate, and pancreatic cancer. It wasnt until Melinda herself was diagnosed with an aggressive form of breast cancer seven years ago that she found out she carried that gene mutation known as BRCA1.

Norah ODonnell: Did you know what BRCA1 was?

Melinda: Not a clue.

But as it turned out, it had haunted her family for generations. At age 29, facing chemotherapy and a double mastectomy, Melinda was afraid that if she had children one day, they would also be cursed with that potentially deadly mutation.

Norah ODonnell: What did doctors tell you about the risk of passing on this BRCA mutation?

Melinda: Fifty percent. So flip a coin.

Norah ODonnell: And I bet that weighed on you even heavier.

Melinda: Yes. Its a lifetime of having to worry about it. And I just didnt want my kids to have to do that.

The best way to ensure that was to do embryo screening for the BRCA1 gene mutation, which Dr. Hughes says is among the fastest-growing parts of his business.

Dr. Mark Hughes: This takes the risk. For example, in breast cancer, it takes the risk if you have this mutation from 50/50 of passing it to the next generation down to less than one percent.

Play Video

Kendra Lesta tells Norah ODonnell about losing her son Christopher to a rare disease and why she did PGD to prevent passing it on again. Watch N...

But the screening isnt easy. All couples, even fertile ones, must first go through in-vitro fertilization, the process in which a mans sperm is injected into a womans eggs under a microscope to create embryos. Then, five days later, a tiny tube just one twentieth the diameter of a human hair is used to extract from each embryo one single cell to be genetically tested for disease.

Norah ODonnell: Its just one cell?

Dr. Mark Hughes: Yes.

Norah ODonnell: You can tell that much from one cell?

Dr. Mark Hughes: You can tell an awful lot in one cell.

That cell is packed up at fertility clinics across the country and shipped overnight in ordinary looking boxes like these to screening labs. We followed the process at Dr. Hughes lab, called Genesis Genetics just outside Detroit, where a team of scientists took over.

Norah ODonnell: So what do you do with that one cell when it arrives here?

Dr. Mark Hughes: Well were busy. We have to break the cell open; they have to pull out this enormous encyclopedia of genetic information.

Hes talking about the cells DNA, our genetic code that scientists represent with four letters - A, C, T and G. For a gene to work properly, the letters have to be strung together in the right order. If theyre not, that could spell trouble. Its Dr. Hughes job to find the mutation - or typo - in a gene that could cause disease.

Dr. Mark Hughes: So you have to find that typo in effectively six billion letters.

Norah ODonnell: A typo in six billion letters?

Dr. Mark Hughes: Yeah.

Norah ODonnell: So how do you do that?

Dr. Mark Hughes: Technology is amazing.

Dr. Hughes used the technology to screen Matt and Melindas embryos in 2010 - ruling out the ones that carried the BRCA1 mutation, which would have given their children a reasonable chance of getting breast or other cancers.

Norah ODonnell: About how many of them tested positive for the BRCA1 gene?

Dr. Mark Hughes: About half and indeed, if you look at her embryos, here is an affected, an affected, an affected, an affected. Thats four. Its about half. It is just what youd expect.

Its just what youd expect in nature. But with the powerful intervention of science, embryos that carry a harmful mutation are often discarded, which is one reason the decision to go ahead with the screening was a difficult one for Matt and Melinda.

Melinda: We prayed a lot about it. Its a hard decision to make.

Norah ODonnell: What did you struggle with?

Melinda: Was it right? Was it the right thing to do? Is it playing God? Is it ethical? And the more we learned about it and got comfortable with the idea, it was like, Yes, absolutely.

Norah ODonnell: You have said, The breast cancer stops with me.

Melinda: Yes. Its not just my children. Its their children and my grandchildren and great grandchildren. Forever and all for time, in my bloodline, yeah.

The entire process cost them around $16,000 - a small price to pay, Melinda says, for her childrens health.

But Anne Morriss didnt get to change the odds for her child. By the time she learned she carried a dangerous mutation, she had already passed it on to her son, whos now seven. At birth, Alec seemed the picture of health, but then came an unexpected call from a doctor.

Anne Morriss: He started by saying, Can you please go check and make sure that your child is still alive and then come back and we can continue this discussion.

Norah ODonnell: So a doctor calls you and says, I need to tell you something but can you go check that your son is still alive.

Anne Morriss: Thats how the conversation started.

Norah ODonnell: What was your reaction?

Anne Morriss: You know, your heart just falls out of you.

A newborn screening test revealed Alec had a rare and sometimes fatal metabolic disorder called MCAD deficiency; he had to be fed every few hours just to stay alive.

Unlike breast cancer, MCAD deficiency is a recessive disorder, meaning a child must inherit a copy of the faulty gene from both parents. Anne Morriss had used an anonymous sperm donor to conceive, but in an incredible case of bad luck, he just happened to carry the same mutation she did.

Anne Morriss: Every human being walking the planet is a carrier for a rare disease. But what matters is who we choose to partner with reproductively. Like, thats where the risk shows up.

Now she wants to reduce the risk of a bad genetic match for others - well before they start the reproductive process. She just started a company called GenePeeks with Lee Silver, a Princeton University professor whos also a molecular biologist -- though his latest idea doesnt take place in a lab. Its entirely virtual.

Lee Silver: We are creating digital babies.

Norah ODonnell: Digital babies?

Lee Silver: Yes.

Norah ODonnell: So youre simulating the process of reproduction, but on a computer.

Lee Silver: Exactly.

Silver says all it takes is a saliva sample to obtain DNA. He then combines the genetic information from both prospective parents in a computer to make a thousand digital babies.

Norah ODonnell: this is a digital baby.

Lee Silver: This is a digital baby.

It contains virtual DNA - which like real DNA, is represented by those same four letters - A, C, T and G.

Lee Silver: This baby has a mutation.

He says that by analyzing the DNA in all those digital babies, he is able to calculate the risk of two people conceiving a child with any one of 500 severe recessive pediatric disorders.

Play Video

On assignment for 60 Minutes, CBS News correspondent Norah O'Donnell describes how she created her own "digital babies"

For now, GenePeeks is available for $2,000 to clients using sperm banks and egg donors to conceive, though its founders say the goal is to expand it to all couples who want to have a baby.

Norah ODonnell: You think everyone whos going to have a baby should go and have a digital baby first?

Lee Silver: I see a future in which people will not use sex to reproduce. Thats a very dangerous thing to do.

That may sound far-fetched, but the way Lee Silver sees it, there will come a time when couples will no longer want to conceive naturally because its too risky.

Lee Silver: Its safer to have a baby with this pre-knowledge, this genetic information that might help them avoid disease.

But with the promise of this technology also comes the fear that some parents would want to use it to select genetic traits in their children that have nothing to do with disease - a debate Lee Silver himself stoked when he wrote the patent for GenePeeks.

Norah ODonnell: We read your patent and it says your technology could be used to assess whether a child could have other traits, like eye color, hair color, social intelligence, even whether a child will have a widows peak? If your company is so focused on preventing disease, why would you include those traits?

Lee Silver: The purpose of the list of traits is simply to demonstrate that our technology can be used to study anything thats genetically influenced. That doesnt mean were going to actually do that.

Norah ODonnell: OK. But youre running a company? That could be big business?

Lee Silver: We are the ones who invented this technology and were going to use it to study pediatric disease. At the moment, we will make sure the technology is used only for that purpose.

And at the moment, youll have to take his word for it because there are no real rules in this country limiting what this kind of technology can be used to screen for, leaving those decisions up to scientists like Lee Silver and Mark Hughes.

Norah ODonnell: So we should trust you to set the boundaries?

Dr. Mark Hughes: If Im setting a boundary saying, Im not willing to do that, thats no different from any other field of medicine. So sure.

Norah ODonnell: But do you wrestle with this at all? I mean, who is the gatekeeper?

Original post:
Breeding out disease - CBS News

April 21, 2017 by Sam Sholtis Penn State researchers identified 832 genes that have low coverage across multiple whole-exome sequencing platforms. These genes are associated with leukemia, psoriasis, heart failure and other diseases, and may be missed by researchers using whole-exome sequencing to study these diseases. Credit: Penn State University, Carley LaVelle

Whole-exome DNA sequencinga technology that saves time and money by sequencing only protein-coding regions and not the entire genomemay routinely miss detecting some genetic variations associated with disease, according to Penn State researchers who have developed new ways to identify such omissions.

Whole-exome sequencing has been used in many studies to identify genes associated with disease, and by clinical labs to diagnose patients with genetic disorders. However, the new research shows that these studies may routinely miss mutations in a subset of disease-causing genesassociated with leukemia, psoriasis, heart failure and othersthat occur in regions of the genome that are read less often by the cost-saving technology. A paper describing the research appeared online April 13 in the journal Scientific Reports.

"Although it was known that coveragethe average number of times a given piece of DNA is read during sequencingcould be uneven in whole-exome sequencing, our new methods are the first to really quantify this," said Santhosh Girirajan, assistant professor of biochemistry and molecular biology and of anthropology at Penn State and an author of the paper. "Adequate coverageoften as many as 70 or more reads for each piece of DNAincreases our confidence that the sequence is accurate, and without it, it is nearly impossible to make confident predictions about the relationship between a mutation in a gene and a disease. In our study, we found 832 genes that have systematically low coverage across three different sequencing platforms, meaning that these genes would be missed in disease studies."

The researchers developed two different methods to identify low-coverage regions in whole-exome sequence data. The first method identifies regions with inconsistent coverage compared to other regions in the genome from multiple samples. The second method calculates the number of low-coverage regions among different samples in the same study. They have packaged both methods into an open-source software for other researchers to use.

"Even when the average coverage in a whole-exome sequencing study was high, some regions appeared to have systematically low-coverage," said Qingyu Wang, a graduate student at Penn State at the time of the research and the first author of the paper.

Low-coverage regions may result from limited precision in whole-exome sequencing technologies due to certain genomic features. Highly-repetitive stretches of DNAregions of the genome where the same simple sequence of As, Ts, Cs and Gs can be repeated many timescan prevent the sequencer from reading the DNA properly. Indeed, the study showed that at least 60 percent of low-coverage genes occur near DNA repeats. As an example, the gene MAST4 contains a repeated sequence element that leads to a three-fold reduction in coverage compared to non-repeating sequences. Even when other genes have sufficient coverage, this region of the MAST4 gene falls well below the recommended coverage to detect genetic variations in these studies.

"One solution to this problem is for researchers to use whole-genome sequencing, which examines all base pairs of DNA instead of just the regions that contain genes," said Girirajan. "Our study found that whole-genome data had significantly fewer low-coverage genes than whole-exome data, and its coverage is more uniformly distributed across all parts of the genome. However, the costs of whole-exome sequencing are still significantly lower than whole-genome sequencing. Until the costs of whole-genome sequencing is no longer a barrier, human genetics researchers should be aware of these limitations in whole-exome sequencing technologies."

Explore further: Whole genome or exome sequencing: An individual insight

More information: Qingyu Wang et al. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity, Scientific Reports (2017). DOI: 10.1038/s41598-017-01005-x

Focusing on parts rather than the whole, when it comes to genome sequencing, might be extremely useful, finds research in BioMed Central's open access journal Genome Medicine. The research compares several sequencing technologies ...

(Medical Xpress)An international team of researchers has developed a way to use RNA sequencing to help in diagnosing patients with rare genetic muscle conditions. In their paper published in the journal Science Translational ...

Researchers have analysed 44 exome datasets from four different testing kits and shown that they missed a high proportion of clinically relevant regions. At least one gene in each exome method was missing more than 40 percent ...

UCLA researchers have found that a state-of-the-art molecular genetic test greatly improves the speed and accuracy with which they can diagnose neurogenetic disorders in children and adults. The discovery could lead directly ...

Published in today's edition of Nature, the research led by Dr Monkol Lek of the University of Sydney and Dr Daniel MacArthur of The Broad Institute of MIT and Harvard Universities reveals patterns of genetic variation worldwide ...

A new study that assesses the accuracy of modern human-genome-sequencing technologies found that some medically significant portions of an individual's DNA blueprint are situated in complex, hard-to-analyze regions that are ...

Whole-exome DNA sequencinga technology that saves time and money by sequencing only protein-coding regions and not the entire genomemay routinely miss detecting some genetic variations associated with disease, according ...

Research published this week in Scientific Reports uses computer image and statistical shape analysis to shed light on which parts of the face are most likely to be inherited.

Salk scientists and collaborators have shed light on a long-standing question about what leads to variation in stem cells by comparing induced pluripotent stem cells (iPSCs) derived from identical twins. Even iPSCs made from ...

In a study published today in PLoS ONE, a team of researchers reports solving a medical mystery in a day's work. In record-time detective work, the scientists narrowed down the genetic cause of intellectual disability in ...

After nearly 40 years of searching, Johns Hopkins researchers report they have identified a part of the human genome that appears to block an RNA responsible for keeping only a single X chromosome active when new female embryos ...

It's not so hard anymore to find genetic variations in patients, said Brown University genomics expert William Fairbrother, but it remains difficult to understand whether and how those mutations undermine health.

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Originally posted here:
Disease-associated genes routinely missed in some genetic studies - Medical Xpress

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SALT LAKE CITY -- Saturday, Earth Day, marked the first ever March For Science, and people from around the world gathered in more than 600 cities.

The march evolved from a social media campaign to thousands of scientists and science enthusiasts taking to the streets.

In Utah, thousands marched in Salt Lake City, Logan, Moab, Park City, and Saint George.

I stand for science," said Heidi Redd, a San Juan County Rancher and Conservationist. "I will fight for science, and I must say that without science we would not be the leaders we are today.

Redd, a cattle rancher, said research done on grasslands and water conservation has helped her and others become leaders in agriculture.

For others, the importance of science goes far beyond the physical world.

As a person of faith, I think one of the greatest blessings God has given us is science, said Professor Brigham Daniels.

Daniels teaches environmental law at Brigham Young University and is the Chair of the Board of Directors for the LDS Earth Stewardship.

Daniels said he marched in support of his faith and his fight to protect the environment. Utah recently made its debut on a list of cities with the worst air pollution.

We owe it, not only to our kids, but we owe it to the elderly," Daniels said. "We owe it to the asthmatics. We owe it to ourselves.

Scientists and supporters at the march said it's a lot about taking care of our world and those in it, but it's also about making a political statement.

Professor Mario Capecchi teaches human genetics at the University of Utah. He's also a Nobel Laureate. He said more scientists should get involved in politics.

I take part of the blame," he said. "I think scientists, you know, were comfortable in the lab, but were not trained, we arent capable of communicating with the public, but we have to because we see terrible things are happening.

He went on to say change should have "happened yesterday", but he said now is better than never.

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Thousands of Utahns join worldwide March For Science - fox13now.com

UNIVERSITY PARK, Pa. Whole-exome DNA sequencing a technology that saves time and money by sequencing only protein-coding regions and not the entire genome may routinely miss detecting some genetic variations associated with disease, according to Penn State researchers who have developed new ways to identify such omissions.

Whole-exome sequencing has been used in many studies to identify genes associated with disease, and by clinical labs to diagnose patients with genetic disorders. However, the new research shows that these studies may routinely miss mutations in a subset of disease-causing genes associated with leukemia, psoriasis, heart failure and others that occur in regions of the genome that are read less often by the cost-saving technology. A paper describing the research appeared online April 13 in the journal Scientific Reports.

Although it was known that coverage the average number of times a given piece of DNA is read during sequencing could be uneven in whole-exome sequencing, our new methods are the first to really quantify this, said Santhosh Girirajan, assistant professor of biochemistry and molecular biology and of anthropology at Penn State and an author of the paper. Adequate coverage often as many as 70 or more reads for each piece of DNA increases our confidence that the sequence is accurate, and without it, it is nearly impossible to make confident predictions about the relationship between a mutation in a gene and a disease. In our study, we found 832 genes that have systematically low coverage across three different sequencing platforms, meaning that these genes would be missed in disease studies.

The researchers developed two different methods to identify low-coverage regions in whole-exome sequence data. The first method identifies regions with inconsistent coverage compared to other regions in the genome from multiple samples. The second method calculates the number of low-coverage regions among different samples in the same study. They have packaged both methods into an open-source software for other researchers to use.

Even when the average coverage in a whole-exome sequencing study was high, some regions appeared to have systematically low-coverage, said Qingyu Wang, a graduate student at Penn State at the time of the research and the first author of the paper.

Low-coverage regions may result from limited precision in whole-exome sequencing technologies due to certain genomic features. Highly-repetitive stretches of DNA regions of the genome where the same simple sequence of As, Ts, Cs and Gs can be repeated many times can prevent the sequencer from reading the DNA properly. Indeed, the study showed that at least 60 percent of low-coverage genes occur near DNA repeats. As an example, the gene MAST4 contains a repeated sequence element that leads to a three-fold reduction in coverage compared to non-repeating sequences. Even when other genes have sufficient coverage, this region of the MAST4 gene falls well below the recommended coverage to detect genetic variations in these studies.

One solution to this problem is for researchers to use whole-genome sequencing, which examines all base pairs of DNA instead of just the regions that contain genes, said Girirajan. Our study found that whole-genome data had significantly fewer low-coverage genes than whole-exome data, and its coverage is more uniformly distributed across all parts of the genome. However, the costs of whole-exome sequencing are still significantly lower than whole-genome sequencing. Until the costs of whole-genome sequencing is no longer a barrier, human genetics researchers should be aware of these limitations in whole-exome sequencing technologies.

In addition to Girirajan and Wang, the research team at Penn State includes Matthew Jensen, graduate student; Naomi S. Altman, professor of statistics; and Cooduvalli Shashikant, professor of molecular and developmental biology, all of whom are also members of the Penn State Huck Institutes of the Life Sciences Bioinformatics and Genomics Program. The work was funded by the March of Dimes Foundation, the U.S. National Institutes of Health, the Brain and Behavior Research Foundation, the Huck Institutes of the Life Sciences, and the Penn State Experiment Station.

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Disease-associated genes routinely missed in some genetic studies ... - Penn State News