Genetic sequencing alone doesn't offer a true picture of human disease

Duke University Medical Center ^ | January 23, 2011 | Unknown

[decimon]

DURHAM, N.C. – Despite what you might have heard, genetic sequencing alone is not enough to understand human disease. Researchers at Duke University Medical Center have shown that functional tests are absolutely necessary to understand the biological relevance of the results of sequencing studies as they relate to disease, using a suite of diseases known as the ciliopathies which can cause patients to have many different traits.

"Right now the paradigm is to sequence a number of patients and see what may be there in terms of variants," said Nicholas Katsanis, Ph.D. "The key finding of this study says that this approach is important, but not sufficient. If you really want to be able to penetrate, you must have a robust way to test the functional relevance of mutations you find in patients. For a person at risk of type 2 diabetes, schizophrenia or atherosclerosis, getting their genome sequenced is not enough – you have to functionally interpret the data to get a sense of what might happen to the particular patient."

"This is the message to people doing medical genomics," said lead author Erica Davis, Ph.D., Assistant Professor in the Duke Department of Pediatrics, who works in the Duke Center for Human Disease Modeling. "We have to know the extent to which gene variants in question are detrimental – how do they affect individual cells or organs and what is the result on human development or disease? Every patient has his or her own set of genetic variants, and most of these will not be found at sufficient frequency in the general population so that anyone could make a clear medical statement about their case."

Davis, working in the lab of Katsanis, and in collaboration with many ciliopathy labs worldwide, sequenced a gene, TTC21B, known to be a critical component of the primary cilium, an antenna-like projection critical to cell function.

While a few of the mutations could readily be shown to cause two main human disorders, a kidney disease and an asphyxiating thoracic condition, the significance of the majority of DNA variants could not be determined. Davis then tested these variants in a zebrafish model, in which many genes are similar to humans, and showed that TTC21B appears to contribute disease-related mutations to about 5 percent of human ciliopathy cases.

The study, which appears in Nature Genetics online on Jan. 23, shows how genetic variations both can cause ciliopathies and also interact with other disease-causing genes to yield very different sets of patient problems.

Katsanis, the Jean and George Brumley Jr., M.D., Professor of Pediatrics and Cell Biology, and Director of the Duke Center for Human Disease Modeling, is a world expert in ciliopathies such as Bardet-Biedl Syndrome, in which the primary cilium of cells is abnormal and leads to a host of problems. About one child in 1,000 live births will have a ciliopathy, an incidence that is in the range of Down's syndrome, said Katsanis.

"By sequencing genes to identify genetic variation, followed by functional studies with a good experimental model, we can get a much better idea of the architecture of complex, inherited disorders," Katsanis said. "Each individual with a disease is unique," Davis said. "If you can overlay gene sequencing with functional information, then you will be able to increase the fidelity of your findings and it will become more meaningful for patients and families."

It will take more laboratories doing more pointed studies like this one to get a fuller picture of the ciliopathies and other diseases, Davis said.

Katsanis noted that it will take true collaboration within many scientific disciplines as well as scientific finesse to get at the true roots of complex diseases.

"Brute force alone – sequencing – will not help," he said. "Technology is of finite resolution. You must have synthesis of physiology, cell biology, biochemistry and other fields to get true penetration into medically relevant information."

###

Numerous scientists from other institutions were involved, including those from Johns Hopkins University, University of Pennsylvania, University of Birmingham in the United Kingdom, Universite Louis Pasteur, St. James University Hospital in Leeds, University of Michigan, Baylor College of Medicine, the National Human Genome Research Institute and others.

Funding for the study came from the National Institutes of Health grant from the National Institute of Child Health and Development, other NIH grants, the National Research Service Award (NRSA), a fellowship from the National Institute of Diabetes, Digestive and Kidney disorders, the National Eye Institute the Macular Vision Research Foundation, the Foundation Fighting Blindness, the F.M. Kirby Foundation, the Rosanne Silbermann Foundation, the Polycystic Kidney Disease Foundation, the German Kidney Foundation, the German Research Foundation and a Medical Research Council research training fellowship. This work was also supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Howard Hughes Medical Institute.

[decimon]

To each their own ping.

[Eyes Unclouded]

What we need is a human transcriptome project. It’s a real shame money is being wasted on plenty of junk science that is politically connected instead of truly useful endeavors.

[Sacajaweau]

I’m concerned that some of our meds are maneuvering our genes. While after the child bearing years, it may not matter. We’re providing so many meds to younger people for “whatever”, it scares me.

[Pharmboy]

This is meaningless arm-waving...nothing new here. Of course it’s complicated...haven’t these people ever heard of proteomics? Sheesh...looking for headlines is what these people are doing.

[bigheadfred]

That’s why we the Polaroid. Pictures in a minute...

[Hawthorn]

Agreed that they’re publicity seekers, with nothing much new to report. But: The source link for this FR thread takes us not to an “objective” report, but rather to a press release from the Duke Medical Center. Nothing wrong with putting out a press release. On the other hand, there are a number of medical press releases from the past few days that are much more interesting IMO. See:

http://www.eurekalert.org/pubnews.php

[Paladin2]

Apparently cell membranes (and other cell structures) can acquire characteristics independent of the genome DNA that can not only cause problems, but be passed along to progeny.

[decimon]

Coupla things about EurekAlert: Monday is usually a big day for new releases and the newest releases are not always on top. If you’re interested then especially on Mondays check at least to page two for new stuff.

[decimon]

Apparently cell membranes (and other cell structures) can acquire characteristics independent of the genome DNA that can not only cause problems, but be passed along to progeny.

I'm afraid this is too far beyond me for anything to truly be apparent. What I'm getting from this, in short, is that old fashioned individual diagnosis is still needed.

[Paladin2]

"old fashioned individual diagnosis is still needed. "

AND individual treatment (drugs) are likely indicated.

[decimon]

AND individual treatment (drugs) are likely indicated.

That looks right to me.

[Paladin2]

It likely turns out that we all are “Special” after all.

[SunkenCiv]

· GGG managers are SunkenCiv, StayAt HomeMother, and Ernest_at_the_Beach · · join list or digest · view topics · view or post blog · bookmark · post a topic · subscribe ·
	Antiquity Journal  & archive  Archaeologica  Archaeology  Archaeology Channel  BAR  Bronze Age Forum  Discover  Dogpile  Eurekalert  Google  LiveScience  Mirabilis.ca  Nat Geographic  PhysOrg  Science Daily  Science News  Texas AM  Yahoo  Excerpt, or Link only?	Thanks decimon. The Scars of Evolution: What Our Bodies Tell Us About Human Origins by Elaine Morgan "The most remarkable aspect of Todaro's discovery emerged when he examined Homo Sapiens for the 'baboon marker'. It was not there... Todaro drew one firm conclusion. 'The ancestors of man did not develop in a geographical area where they would have been in contact with the baboon. I would argue that the data we are presenting imply a non-African origin of man millions of years ago.'" To all -- please ping me to other topics which are appropriate for the GGG list.
· History topic · history keyword · archaeology keyword · paleontology keyword · · Science topic · science keyword · Books/Literature topic · pages keyword ·

[decimon]

It likely turns out that we all are “Special” after all.

I know I've been so accused. ;-)

And speaking of special, check out these Ukrainian feminists: Topless feminist protesters show what they're made of.

[SunkenCiv]

I won’t do it I tell ya, I won’t click there!

[decimon]

I won’t do it I tell ya, I won’t click there!

Then the rumors are true. ;-)

[SunkenCiv]

Okay, so, I did click that link (euphemism). I thought it was going to be some hideous joke, but they turned out be pretty hot babes.

[decimon]

Some of the links in the thread are better. They sure ain’t like the Code Pink mutants.

[gleeaikin]

If the common ancestor of the human line and the baboon line did not have the marker, and it developed in the baboon line after the separation, then the human line could easily have developed in Africa.

In fact, according to Stewart and Disotell in 1998, the separation point for the lines leading to humans and apes, and to colobus monkeys and baboons was around 25 million years ago. The baboon and mandrill line separated from the monkey line around 14 million years ago.