Category Archives: Human Genetics

Researchers disagree over the whens and wheres of canine domestication

Les Hirondelles Photography/Flickr/Getty Images

Scientists investigating the transformation of wolves into dogs are behaving a bit like the animals they study, as disputes roil among those using genetics to understand dog domestication.

In recent months, three international teams have published papers comparing the genomes of dogs and wolves. On some matters such as the types of genetic changes that make the two differ the researchers are more or less in agreement. Yet the teams have all arrived at wildly different conclusions about the timing, location and basis for the reinvention of ferocious wolves as placid pooches. Its a sexy field, says Greger Larson, an archeogeneticist at the University of Durham, UK. He has won a 950,000 (US$1.5-million) grant to study dog domestication starting in October. Youve got a lot of big personalities, a lot of money, and people who want to get their Nature paper first.

In January, Erik Axelsson and Kerstin Lindblad-Toh, geneticists at Uppsala University in Sweden, and their colleagues reported in Nature that genes involved in the breaking down of starch seemed to set domestic dogs apart from wild wolves. In the paper and in media interviews, the researchers argued that dog domestication was catalyzed by the dawn of agriculture around 10,000years ago in the Middle East, as wolves began to loiter around human settlements and rubbish heaps (see Nature http://doi.org/mv4; 2013).

But Larson, who has worked with Lindblad-Toh on other projects, says that their claim is dubious. He notes that bones that look similar to those of domestic dogs predate the Neolithic revolution by at least several thousand years, so domestication must have occurred before then. Why waste space [in a paper] saying something that is patently untrue? he says.

Axelsson concedes that the changes in starch digestion in dogs could have occurred after they were domesticated. But he also counters that the Neolithic era lasted for thousands of years, and that dogs may have been domesticated during the earliest steps towards agrarian life when human hunter-gatherers settled down and began eating more starch-rich wild plants.

A second study, published last month in Nature Communications, argues that dogs were domesticated 32,000years ago when they began scavenging with Palaeolithic humans in southern China. A team led by Ya-ping Zhang at the Kunming Institute of Zoology in China drew that conclusion from studying the whole genomes of several grey wolves, modern European dog breeds and indigenous Chinese dogs.

But Larson says that there is no evidence to suggest that wolves ever lived in southern China, so how do you domesticate a wolf if there arent any? And Jean-Denis Vigne, an archeozoologist at the National Museum of Natural History in Paris, agrees, noting that in earlier work, Zhangs team completely ignored what has been published, even in the frame of genetics.

Peter Savolainen, a geneticist at the KTH Royal Institute of Technology in Solna, Sweden, who co-authored the Nature Communications paper, argues that Chinese scientific literature suggests that wolves did once live south of Chinas Yangtze River, but have since become extinct. But he acknowledges that the date that his team reported like all molecular dating efforts relies on several assumptions, such as the number of genetic mutations that develop in each generation.

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Dog Genetics Spur Scientific Spat

The breakthrough might set up another showdown about cloning for therapeutic purposes

OHSU Photos

From Nature magazine

It was hailed some 15 years ago as the great hope for a biomedical revolution: the use of cloning techniques to create perfectly matched tissues that would someday cure ailments ranging from diabetes to Parkinsons disease. Since then, the approach has been enveloped in ethical debate, tainted by fraud and, in recent years, overshadowed by a competing technology. Most groups gave up long ago on the finicky core method production of patient-specific embryonic stem cells (ESCs) from cloning. A quieter debate followed: do we still need therapeutic cloning?

A paper published this week by Shoukhrat Mitalipov, a reproductive biology specialist at the Oregon Health and Science University in Beaverton, and his colleagues is sure to rekindle that debate. Mitalipov and his team have finally created patient-specific ESCs through cloning, and they are keen to prove that the technology is worth pursuing.

Therapeutic cloning, or somatic-cell nuclear transfer (SCNT), begins with the same process used to create Dolly, the famous cloned sheep, in 1996. A donor cell from a body tissue such as skin is fused with an unfertilized egg from which the nucleus has been removed. The egg reprograms the DNA in the donor cell to an embryonic state and divides until it has reached the early, blastocyst stage. The cells are then harvested and cultured to create a stable cell line that is genetically matched to the donor and that can become almost any cell type in the human body.

Many scientists have tried to create human SCNT cell lines; none had succeeded until now. Most infamously, Woo Suk Hwang of Seoul National University in South Korea used hundreds of human eggs to report two successes, in 2004 and 2005. Both turned out to be fabricated. Other researchers made some headway. Mitalipov created SCNT lines in monkeys in 2007. And Dieter Egli, a regenerative medicine specialist at the New York Stem Cell Foundation, successfully produced human SCNT lines, but only when the eggs nucleus was left in the cell. As a result, the cells had abnormal numbers of chromosomes, limiting their use.

Monkeying around Mitalipov and his group began work on their new study last September, using eggs from young donors recruited through a university advertising campaign. In December, after some false starts, cells from four cloned embryos that Mitalipov had engineered began to grow. It looks like colonies, it looks like colonies, he kept thinking. Masahito Tachibana, a fertility specialist from Sendai, Japan, who is finishing a 5-year stint in Mitalipovs laboratory, nervously sectioned the 1-millimetre-wide clumps of cells and transferred them to new culture plates, where they continued to grow evidence of success. Mitalipov cancelled his holiday plans. I was happy to spend Christmas culturing cells, he says. My family understood.

The success came through minor technical tweaks. The researchers used inactivated Sendai virus (known to induce fusion of cells) to unite the egg and body cells, and an electric jolt to activate embryo development. When their first attempts produced six blastocysts but no stable cell lines, they added caffeine, which protects the egg from premature activation.

None of these techniques is new, but the researchers tested them in various combinations in more than 1,000 monkey eggs before moving on to human cells. They made the right improvements to the protocol, says Egli. Its big news. Its convincing. I believe it.

Continued here:
Patient-Specific Human Embryonic Stem Cells Created by Cloning

See Inside

A look at some of the most promising medical devices now in development

Photographs by Dan Saelinger

Over the past few years researchers have taken advantage of unprecedented advances in biology, electronics and human genetics to develop an impressive new tool kit for protecting and improving human health. Sophisticated medical technology and complex data analysis are now on the verge of breaking free of their traditional confines in the hospital and computer lab and making their way into our daily lives.

Physicians of the future could use these tools to monitor patients and predict how they will respond to particular treatment plans based on their own unique physiology, rather than on the average response rates of large groups of people in clinical trials. Advances in computer chip miniaturization, bioengineering and material sciences are also laying the groundwork for new devices that can take the place of complex organs such as the eye or pancreasor at least help them to function better.

2014 Scientific American, a Division of Nature America, Inc.

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Tomorrow's Medicine

ATLANTA Fighting hereditary disease among Jews is the aim of a multi-state public health initiative launched today, called JScreen. The JScreen program (www.jscreen.org), is a non-profit, community-based public health initiative managed by Emory University School of Medicines Department of Human Genetics. It provides at-home genetic screening and private counseling for people with Jewish lineage to determine their risk for hereditary diseases that could be passed to their children.

JScreen is a collaboration among clinical geneticists, socially minded businesses and nonprofits to provide everyday people with a ready access point to cutting-edge genetic testing technology, patient education and genetic counseling services.

Todays geneticists have identified genetic markers for 19 genetic diseases that are more common in the Jewish-Ashkenazi community, including Tay-Sachs and Canavan disease. The carriers are healthy but they can pass the diseases along to their children. Couples who are both carriers can risk unknowingly having children with one of these diseases. JScreen also offers an expanded panel, useful for couples of mixed descent and interfaith couples, which screens for a total of 80 diseases.

By leveraging advances in genetic testing and online education that allow people to be screened in the comfort of their homes, we are removing barriers to allow more people to be screened, said Patricia Zartman Page, JScreen senior director at the Emory School of Medicines Department of Human Genetics.

JScreen makes testing for common genetic diseases simple providing an easy-to-use at-home saliva test that gives people who are planning to have children an unprecedented understanding of their own genetic makeup and risks relating to their childrens health. If a person or couples risk is elevated, genetic counselors from Emory University School of Medicine will privately address their results, options and resources to help ensure a healthy pregnancy and healthy baby.

Most of the time, we are able to reassure couples that their future children are not at increased risk for these devastating diseases, said Karen Arnovitz Grinzaid, JScreen senior director at the Emory School of Medicines Department of Human Genetics. When we dofind a carrier couple, we offer a variety of options to help them have healthy children. Without screening, the couples would not have known they were at risk.

For more information, visit http://www.JScreen.org.

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JScreen public health initiative fights Jewish genetic diseases

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Newswise Philadelphia, March 4, 2014 Two recent genetic studies expand the list of genes involved with body fat and body mass index, and their connection to major Western health problems: heart disease, high blood pressure and diabetes. One study showed that higher body mass index (BMI) caused harmful effects on the risk of type 2 diabetes, high blood pressure and inflammation, while another study found gene signals linked to higher levels of body fat metrics, without showing causality.

These findings are highly relevant to the obesity pandemic in the United States and many other countries, said geneticist Brendan J. Keating, D. Phil., of the Center for Applied Genomics at The Childrens Hospital of Philadelphia. Of course, much research remains to be performed to discover further genes involved in these complex metabolic diseases, and to better understand how to improve treatments.

Keating, who previously helped create a large gene-discovery tool called the Cardio Chip, was a co-leader of both studies, which drew on large international teams of scientists using DNA, laboratory and disease data from tens of thousands of people.

In the BMI research, published in the Feb. 6 issue of the American Journal of Human Genetics, Keating collaborated with clinical epidemiologist Michael V. Holmes, M.D., Ph.D., of the Perelman School of Medicine at the University of Pennsylvania. That study used a recently developed epidemiology tool called Mendelian randomization (MR) that rules out confounding factors such as behavioral and environmental influences to construct genetic risk scores for specific traits of interest.

The study team analyzed eight population cohorts including over 34,000 individuals of European descent, of whom over 4,400 had type 2 diabetes, over 6,000 had coronary heart disease and over 3,800 had a previous stroke.

Their analysis, concluded the authors, supports the importance of BMI in regulating cardiometabolic traits and the risk of type 2 diabetes. Our findings suggest that lowering BMI is likely to result in multiple reductions of cardiovascular traits: in blood pressure, inflammation, fasting glucose and insulin, and in the risk of type 2 diabetes, said Keating.

This study is the first to use this emerging MR technique with a combination of genetic markers known to impact BMI, to assess the causal relationship of BMI and a comprehensive repertoire of traits, said Holmes. He added that, although the study showed that increasing BMI has an undesirable effect on cardiometabolic factors, interestingly, it did not show that higher BMI increased the risk of coronary heart disease.

Keating also co-led a second study, published Jan. 6 in Human Molecular Genetics, analyzing genes associated with central adiposity. Measures of central adiposity, or body fat, can be derived using waist circumference and waist-to-hip ratio. For assessing the influence of weight-related genes, central adiposity is preferable to BMI, because BMI also reflects the influence of genes affecting height, said Keating.

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Researcher Finds More Genetic Signals Linking Weight and Risk Factors in Heart Health

March 3, 2014

Brett Smith for redOrbit.com Your Universe Online

A massive new study from a team of international researchers has identified mutations in a gene that can significantly reduce the risk of developing type 2 diabetes regardless of risk factors such as old age and being overweight. Seen in patients from multiple ethnic groups, the results showed a drug that imitates the influence of these mutations could be effectively used around the world.

In the study published in Nature Genetics the genetic evaluation of 150,000 patients showed that uncommon mutations in a gene called SLC30A8 scale back risk of type 2 diabetes by 65 percent. In previous research, the protein produced by SLC30A8 had been shown to play a critical role in the insulin secretion in the pancreas, and a typical variant in that gene was known to affect the risk of type 2 diabetes.

This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions knowing which targets to go after, said study author David Altshuler, a Harvard Medical School professor at Massachusetts General Hospital.

To find mutations that reduce a persons probability of type 2 diabetes, the study team looked at participants with acute risk factors for diabetes, such as old age and obesity, who had not developed the disease and had healthy blood sugar levels. The team focused on a set of genes recognized earlier as playing a role in type 2 diabetes and looked for uncommon mutations.

They were able to find a genetic mutation that knocked out function of the SLC30A8 gene and that was highly prevalent in non-diabetic participants from Sweden and Finland. The protection against the disease was surprising, because scientific studies in mice had indicated that mutations in SLC30A8 might have the reverse effect increasing risk of type 2 diabetes. However, because this specified genetic variation was exceedingly uncommon outside of Finland, it proved difficult to obtain added evidence to corroborate the primary find.

These unpublished findings the result of a collaboration between American and Swedish scientists were shared with a group from deCODE genetics, a biopharmaceutical company based in Reykjavk, Iceland. The company researchers then found a subsequent mutation in an Icelandic population. The second mutation independently decreased risk for type 2 diabetes and decreased blood sugar in non-diabetics without apparent unfavorable effects.

Finally, the joint study team was able to identify ten more protective mutations in the same gene. With all the mutations considered together, one copy of a defective version of SLC30A8 was shown to have a 65 percent reduction in risk of diabetes.

This discovery underscores what can be accomplished when human genetics experts on both sides of the Atlantic come together to apply their craft to founder populations, enabling us to find rare mutations with large effects on disease risk, said Kari Stefannson, CEO of deCODE genetics.

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Genetic Mutation Found That Lowers Odds Of Developing Diabetes

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.

Type 2 diabetes affects over 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a "drug target" -- a human protein that, if activated or inhibited, results in prevention and treatment of the disease.

The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk -- and how large an effect could be expected.

"This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions -- knowing which targets to go after," said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.

The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. The new type 2 diabetes study, which appears this week in Nature Genetics, suggests that CCR5 and PCSK9 are likely just the beginning but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.

The Nature Genetics study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person's risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing (then a new technology) to search for rare mutations.

The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in non-diabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect -- increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer Inc./Lund team.

Then, in 2012, these unpublished results were shared with deCODE genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for type 2 diabetes and also lowered blood sugar in non-diabetics without any evident negative consequences.

"This discovery underscores what can be accomplished when human genetics experts on both sides of the Atlantic come together to apply their craft to founder populations, enabling us to find rare mutations with large effects on disease risk," said Kari Stefannson, CEO of deCODE genetics.

Finally, the team set out to ask if the effects of SLC30A8 protective mutations were limited to the two mutations found in populations in Finland and Iceland. As part of the NIH-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan, the Broad Institute had performed sequencing of 13,000 samples drawn from multiple ethnicities. The T2D-GENES Project joined the collaboration, found ten more mutations in the same gene, and again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.

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Protective mutations for type 2 diabetes pinpointed

PUBLIC RELEASE DATE:

2-Mar-2014

Contact: Haley Bridger hbridger@broadinstitute.org Broad Institute of MIT and Harvard

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.

Type 2 diabetes affects over 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a "drug target" a human protein that, if activated or inhibited, results in prevention and treatment of the disease.

The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk and how large an effect could be expected.

"This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions knowing which targets to go after," said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.

The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. The new type 2 diabetes study, which appears this week in Nature Genetics, suggests that CCR5 and PCSK9 are likely just the beginning but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.

The Nature Genetics study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person's risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing (then a new technology) to search for rare mutations.

The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in non-diabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer Inc./Lund team.

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Study pinpoints protective mutations for type 2 diabetes

It has long been known that men have a greater risk for developing autism and other neurodevelopmental disorders, compared to women. While boys have a one in 52 chance of developing autism spectrum disorders (ASD), the risk is only one in 252 for girls, according to the U.S. Centers for Disease Control and Prevention (CDC).

Now, a new study published by the American Journal of Human Genetics reveals why so many more men are affected by these diseases.

Previously, researchers had speculated that mutations on the X chromosome may be to blame for the prevalence of ASD among men. However, study author Evan Eichler, a professor of genome sciences at the University of Washington School of Medicine, said that doesn't seem to be the case.

"Five percent of genes responsible for brain development map to the X chromosome," Eichler told FoxNews.com. "There are not enough brain development genes on the X chromosome to account for that big of a difference in terms of gender bias."

In an effort to puzzle out the gender disparity seen in autism and other disorders, Eichler and his colleague Sbastien Jacquemont, of the University Hospital of Lausanne in Switzerland, paired up to analyze DNA samples from nearly 16,000 people with neurodevelopmental disorders. They also analyzed additional samples from a separate cohort of 800 families affected by ASD.

Through their analyses, the researchers began to notice that despite the fact that more boys are affected by ASD, the serious genetic mutations responsible for these diseases were more likely to be passed to children through their mother's DNA, as opposed to from their father.

"We started to see this bias coming from mothers, who were supposed to be unaffected, that they were more likely to be transmitting mutations we thought were deleterious," Eichler said.

After analyzing the cohort of 16,000 individuals with neurodevelopmental disorders, Eichler and his colleagues also discovered that female children seemed to have a larger number of genetic mutations associated with neurodevelopmental disorders, compared to male children.

"If we divide the cohort into females and males, and look at really big mutations, do we see a difference between boys and girls in terms of frequency?" Eichler said. "The answer was, unequivocally, yes. Girls tend to have more of these than boys. Boys have fewer than females."

In analyzing the cohort of 800 families affected by ASD, the researchers also saw that girls had more major genetic deletions - and more small mutations - compared to boys.

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Study reveals why autism is more common in males

Girls require more extreme genetic mutations to develop the condition So, it is less likely they will be pushed over the diagnostic threshold About 1.8% of boys have autism compared to 0.2% of girls

By Emma Innes

PUBLISHED: 06:23 EST, 28 February 2014 | UPDATED: 09:24 EST, 28 February 2014

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Boys are more likely to have autism that girls are because they have 'less robust brains', research suggests

Researchers claim to have discovered why autism is more common in boys than girls.

A study, published in the American Journal of Human Genetics, suggests girls require more extreme genetic mutations than boys to develop the condition.

As a result, it is less likely that they will be pushed over the diagnostic threshold for autism.

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Why men are more likely to have autism: Their brains are more prone to genetic flaws, study finds