Montreal, QUE, USA. New research shows that the vast majority of genetic samples used in large-scale studies come in the form of blood.

However, blood and tissue cells do not match genetically, calling into question the genome-wide association studies that have assumed DNA is essentially identical in every cell in the body.

This discovery may undercut the rationale behind genetic studies conducted over the last 15 years which were supposed to isolate the causes of scores of human birth conditions and diseases.

Except for cancer, samples of diseased tissue are difficult or even impossible to take from living patients. Thus, the vast majority of genetic samples used in large-scale studies come in the form of blood. However, if it turns out that blood and tissue cells do not match genetically, these ambitious and expensive genome-wide association studies may prove to have been essentially flawed from the outset.

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Human Genome Project (HGP)

A genome is all the DNA in an organism, including its genes and other materials.

Genes carry information for making all the proteins required by all organisms. These proteins determine, among other things, how the organism looks, how well its body metabolizes food or fights infection, and to an extent even how it behaves.

The HGP identified all of the genes in the human genome and mapped their individual sequencing. Basic work began in 1990 and reached completion in 2005, sparking continuous refinements and new projects. Though the HGP is finished, data analyses will continue for many years.

DNA is made up of four similar chemicals (called bases and abbreviated A, T, C, and G) that are repeated millions or billions of times throughout a genome.

The human genome, for example, has 3 billion pairs of bases. The particular order of As, Ts, Cs, and Gs is extremely important.

The order underlies all of life's diversity, even dictating whether an organism is human or another species such as yeast, rice, or fruit fly, all of which have their own genomes and are themselves the focus of genome projects.

Because all organisms are related through similarities in DNA sequences, insights gained from nonhuman genomes often lead to new knowledge about human biology.

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Video: An introduction to the ongoing Human Genome Project, courtesy of the US National Institutes of Health (NIH) (18 May 2007). Time: 00:03:33. Creative Commons license: Attribution-NonCommercial-NoDerivs.

For more information see the TS-Si.org section, Genetics & Genome.

From a genetic perspective, the observation that DNA is not the same in every cell of the body is extremely important.

Genome-wide association studies were introduced several years ago and people expected tremendous breakthroughs. They were going to draw blood samples from thousands or hundreds of thousands of individuals, and find the genes responsible for disease.This discovery sprang from an investigation into the underlying genetic causes of abdominal aortic aneurysms (AAA). The researchers focused on BAK, a gene that controls cell death. They were surprised by what they found.

AAA is one of the rare vascular diseases where tissue samples are removed as part of patient therapy.

When they compared samples, the researchers discovered major differences between BAK genes in blood cells and tissue cells coming from the same individuals, with the suspected disease "trigger" residing only in the tissue.

Moreover, the same differences were later evident in samples derived from healthy individuals.

"In multi-factorial diseases other than cancer, usually we can only look at the blood," explained Gottlieb, a geneticist with McGill's Centre for Translational Research in Cancer. "Traditionally when we have looked for genetic risk factors for, say, heart disease, we have assumed that the blood will tell us what's happening in the tissue. It now seems this is simply not the case."

"From a genetic perspective, therapeutic implications aside, the observation that not all cells are the same is extremely important. That's the bottom line," he added.

Genome-wide association studies were introduced with enormous hype several years ago, and people expected tremendous breakthroughs. They were going to draw blood samples from thousands or hundreds of thousands of individuals, and find the genes responsible for disease.

"Unfortunately, the reality of these studies has been very disappointing, and our discovery certainly could explain at least one of the reasons why."

Human Blood Smear New research calls into question one of the most basic assumptions of human genetics: that when it comes to DNA, every cell in the body is essentially identical to every other cell.

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AAA is a localized widening and weakening of the abdominal aorta, and primarily affects elderly Caucasian men who smoke, have high blood pressure and high cholesterol levels.

It often has no symptoms, but can lead to aortic ruptures which are fatal in 90 per cent of cases.

If the mutations discovered in the tissue cells actually predispose for AAA, they present an ideal target for new therapies, and may have even wider therapeutic implications.

"This will probably have repercussions for vascular disease in general," said Schweitzer, of McGill's Department of Medicine.

"We have not yet looked at coronary or cerebral arteries, but I would suspect that this mutation may be present across the board."

Schweitzer is optimistic that this discovery may lead to new treatments for vascular disease in the near to medium term.

"The timeline might be five to 10 years," he said. "We have to do in-vitro cell culture experiments first, prove it in an animal model, and then develop a molecule or protein which will affect the mutated gene product. This is the first step, but it's an important step."

CitationBAK1 gene variation and abdominal aortic aneurysms. Bruce Gottlieb, Lorraine E. Chalifour, Benjamin Mitmaker, Nathan Sheiner, Daniel Obrand, Cherrie Abraham, Melissa Meilleur, Tomoko Sugahara, Ghassan Bkaily, Morris Schweitzer. Human Mutation 2009; 30(7): 1043-1047. doi: 10.1002/humu.21046

Abstract

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism ( SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in minority forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny.

Keywords: intercellular gene variation, tissue specific gene alterations, abdominal aortic aneurysm, BAK1.

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TS-Si is dedicated to the acceptance, medical treatment, and legal protection of individuals correcting the misalignment of their brains and their anatomical sex, while supporting their transition into society as hormonally reconstituted and surgically corrected citizens.

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