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Whole-exome sequencing discovers cause of glycosylation disorders

Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University

Sequencing a patient's entire genome to discover the source of his or her disease is not routine ? yet. But geneticists are getting close.

A case report, published this week in the American Journal of Human Genetics, shows how researchers can combine a simple blood test with an “executive summary” scan of the genome to diagnose a type of severe metabolic disease.

Researchers at Emory University School of Medicine and Sanford-Burnham Medical Research Institute used “whole-exome sequencing” to find the mutations causing a glycosylation disorder in a boy born in 2004. Mutations in the gene (called DDOST) that is responsible for the boy's disease had not been previously seen in other cases of glycosylation disorders.

Whole-exome sequencing is a cheaper, faster, but still efficient strategy for reading the parts of the genome scientists believe are the most important for diagnosing disease. The report illustrates how whole-exome sequencing, which was first offered commercially for clinical diagnosis in 2011, is entering medical practice. Emory Genetics Laboratory is now gearing up to start offering whole exome sequencing as a clinical diagnostic service.

It is estimated that most disease-causing mutations (around 85 percent) are found within the regions of the genome that encode proteins, the workhorse machinery of the cell. Whole-exome sequencing reads only the parts of the human genome that encode proteins, leaving the other 99 percent of the genome unread.

The boy in the case report was identified by Hudson Freeze, PhD and his colleagues. Freeze is director of the Genetic Disease Program at Sanford-Burnham Medical Research Institute. A team led by Madhuri Hegde, PhD, associate professor of human genetics at Emory University School of Medicine and director of the Emory Genetics Laboratory, identified the gene responsible. Postdoctoral fellow Melanie Jones is the first author of the paper.

“This is part of an ongoing effort to develop diagnostic strategies for congenital disorders of glycosylation,” Hegde says. “We have a collaboration with Dr. Freeze to identify new mutations.”

Glycosylation is the process of attaching sugar molecules to proteins that appear on the outside of the cell. Defects in glycosylation can be identified through a relatively simple blood test that detects abnormalities in blood proteins. The sugars are important for cells to send signals and stick to each other properly. Patients with inherited defects in glycosylation have a broad spectrum of medical issues, such as developmental delay, digestive and liver problems and blood clotting defects.

The boy in this case report was developmentally delayed and had digestive problems, vision problems, tremors and blood clotting deficiencies. He did not walk until age 3 and cannot use language. The researchers showed that he had inherited a gene deletion from the father and a genetic misspelling from the mother.

“Over the years, we've come to know many families and their kids with glycosylation disorders. Here we can tell them their boy is a true 'trail-blazer' for this new disease,” Freeze said. “Their smiles?that's our bonus checks.”

The researchers went on to show that introducing the healthy version of the DDOST gene into the patient's cells in the laboratory could restore normal protein glycosylation. Thus, restoring normal function by gene therapy is conceivable, if still experimental. However, restoration of normal glycosylation would be extremely difficult to achieve for most of the existing cells in the body.

###

The research was supported by the National Institutes of Health and by the Rocket Fund.

Reference: M.A. Jones et al. DDOST Mutations Identified by Whole-Exome Sequencing Are Implicated in Congenital Disorders of Glycosylation, online first, Am. J. Hum. Gen (2012). doi:10.1016/j.ajhg.2011.12.024

Writer: Quinn Eastman

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The Reality of Race – Video

By comparing DNA samples from hundreds of volunteers, a Penn
anthropologist and his colleagues have tied Native Americans to
a group of people living in a small region of Russia called the
Altai, near the borders of Mongolia, China, and Kazakstan.

The results, published in Friday's issue of the American
Journal of Human Genetics, add another chapter to the story of
the settlement of the Americas. Increasingly efficient DNA
technology is helping scientists flesh out the prehistory of
the Native Americans and of the human race in general.

Archaeologists have long surmised that Native Americans came
from Asia, migrating to Alaska during a time when sea levels
were lower and it was possible to walk over the Bering Strait.

But these latest results use the most complete genetic
profiling done on the Asian and American sides, offering new
insights into the ancestry of Native Americans, the routes they
took to the New World, and the timing of the migration.

Artifacts show that humans were living in North America 15,000
years ago; they reached the tip of South America over the next
2,000 years.

Using techniques akin to DNA fingerprinting, scientists have
continued to gather evidence that the majority of current
native people of North and South America derive their ancestry
from Asia.

University of Pennsylvania researcher Theodore Schurr's group
focused on two types of DNA – mitochondrial DNA, which is
passed down in eggs and traces maternal lines, and the Y
chromosome, which is passed down through male lines.

The Y chromosome analysis took advantage of non-coding regions,
which are not part of genes and which are used in criminal
forensics to match suspects to crime scenes.

These DNA regions differ from one person to another, Schurr
said. The more such quirks people share, the more recently they
are likely to have had a common ancestry.

Schurr said his group had collected about 1,500 DNA samples
from Native Americans, as well as 750 from people in the Altai.
The researchers also compared DNA from people from other parts
of Asia.

The scientists can use groups of variations on the Y chromosome
to identify specific human male lineages, and variations in
mitochondrial DNA to trace female lineages. Male lineages
called Q, and a subset of Q called Q-M3, appear widespread in
Native Americans and are thought to have come from a founder
population. Both also appear in people from the Altai region,
Schurr said.

Common sequences in mitochondrial DNA called A, B, C, and D
also appear to have been ubiquitous in pre-conquest America,
and Altains have them, too.

Though other Asians carry a few of those patterns, only the
Altains and some subgroups of Mongolians had them all.

Interestingly, Schurr said, the Altai is also where scientists
recently found a 41,000-year-old bone from a newly discovered
member of the human family tree dubbed a Denisovan. DNA
analysis of the bone showed that, like Neanderthals, Denisovans
apparently co-existed with modern humans and interbred with
some of them.

Schurr also used differences between Altain and Native American
DNA to suggest the two populations diverged 25,000 to 20,000
years ago.

He believes his data fit with the Beringian incubation theory,
which posits that people first moved to a region now under the
Bering Strait.

When the ice age started to subside around 15,000 years ago,
people from Beringia were able to spread out into North
America, by land or boat or both. At some point, they had to
leave before their homeland was submerged.

Anthropologist Connie Mulligan of the University of Florida
said that until the 1990s, linguists thought people must have
come over in waves of migrations, but genetics pointed to one
major wave.

Mulligan, who is among the originators of the Beringian
incubation theory, said she favored a different interpretation
in which the Altains are not ancestral to Native Americans, but
instead share a common ancestor with the Beringians, who may
have occupied the then-dry Bering Strait 30,000 years ago.

In her scenario, when the ice age ended, some Beringians moved
down into the Americas and some settled in the Altai. The
genetic relationship between Altains and modern Native
Americans would come from sharing a common ancestor with this
long-gone group.

Many details remain hazy before the crossing of the land
bridge, as well as after, when people made remarkable progress
in settling both continents.

University of Arizona anthropology professor Stephen Zegura
said analysis of other parts of the DNA promised to add much to
the story. The contribution from genetics, he said, has just
begun.

Contact staff writer Faye Flam at 215-854-4977, fflam@phillynews.com, or
@fayeflam on Twitter. Read her blog at www.philly.com/evolution.

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