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What mystery genes scientists found in the healthy blood of a super centenarian

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Interested in genome research now that the annual National DNA Day is coming around again? Hundreds of genetic mutations found in healthy blood of a supercentenarian, says a new study, "Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis," published online April 23, 2014 in the journal Genome Research.

Since April 25, 2014 is National DNA Day, you may find noteworthy the fact that genetic mutations are commonly studied because of links to diseases such as cancer. However, little is known about mutations occurring in healthy individuals.

In a study published online in Genome Research, researchers detected over 400 mutations in healthy blood cells of a 115-year-old woman, suggesting that lesions at these sites are largely harmless over the course of a lifetime. Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells.

Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulate genetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.

In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine whether, over a long lifetime, mutations accumulate in healthy white blood cells

The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other," says lead author of the study, Dr. Henne Holstege, according to an April 23, 2014 news release, "Hundreds of genetic mutations found in healthy blood of a supercentenarian."

The authors also examined the length of the telomeres, or repetitive sequences at the ends of chromosomes that protects them from degradation

After birth, telomeres progressively shorten with each cell division. The white blood cell telomeres were extremely short, numerous times shorter than telomeres in the brain.

"Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions," explains Holstege, according to the news release. Whether stem cell exhaustion is likely to be a cause of death at extreme ages needs to be determined in future studies.

The white blood cells in this study were donated by a supercentenarian woman, who at the time of her death in 2005, was the oldest person in the world, and likely the oldest person ever to donate her body to science

The research suggests that lesions at certain sites studied by the researchers are largely harmless over the course of a lifetime. Scientists from VU University Medical Center, Delft University of Technology, Scripps Translational Science Institute, Life Technologies, University of California San Francisco, Leiden University, and University of Queensland contributed to this study. This work was supported by funding from the National Institutes of Health, Life Technologies, and a Scripps Health Dickinson fellowship. You also may wish to check out the site, Cold Spring Harbor Laboratory or the National Institutes of Health, Life Technologies, Scripps Health Dickinson Fellowship.

On another note, you may wish to check out the news of another genetic-related study, according to an April 23, 2014 news release, "Quality control guidelines for genomics studies." Noteworthy in the research is how do physicians and/or geneticists pinpoint the genetic changes that really cause disease?

A policy paper proposes guidelines for researchers studying the effects of rare genetic variants. The recommendations focus on several key areas, such as study design, gene- and variant-level implication, databases and implications for diagnosis.

Quality control guidelines for genomics studies

A recent NHGRI-sponsored workshop for genomics researchers led to proposal for statistical and evidence standards, according to the April 23, 2014 news release, "Quality control guidelines for genomics studies." Sequencing an entire human genome is faster and cheaper than ever before, leading to an explosion of studies comparing the genomes of people with and without a given disease.

You may wish to check out the study or its abstract, "Guidelines for investigating causality of sequence variants in human disease." After all, this year's National DNA Day, you might think about what the wide-scale availability of high-throughput DNA sequencing technologies means. For example, data on genetic variation in human diseases are accumulating rapidly.

Meanwhile, according to the "Quality control guidelines for genomics studies" news release, scientists found that often clinicians and researchers studying genetic contributions to a certain disease encounter variations that appear to be responsible, only to find other people with the same mutation who don't have the disease or who are affected to a lesser degree. Who takes charge of quality control using what guidelines?

How do doctors pinpoint the genetic changes that really cause disease?

An open-access policy paper published Wednesday, April 23, 2014 in the journal Nature proposes guidelines for researchers studying the effects of rare genetic variants. The recommendations focus on several key areas, such as study design, gene- and variant-level implication, databases and implications for diagnosis.

Co-author Chris Gunter, PhD, associate director of research at Marcus Autism Center and associate professor of pediatrics at Emory Health Sciences, is one of the organizers of the 2012 workshop of leading genomics researchers, sponsored by the National Human Genome Research Institute, that led to the paper.

"Several of us had noticed that studies were coming out with wrong conclusions about the relationship between a specific sequence and disease, and we were extremely concerned that this would translate into inappropriate clinical decisions," she says, according to the news release.

Potentially, based on flawed results, physicians could order additional testing or treatments that are not truly supported by a link between a genetic variant and disease, and this paper could help prevent such inappropriate decisions, Gunter says in the news release

The group of 27 researchers proposes two steps for claiming that a genetic variation causes disease: detailed statistical analysis followed by an assessment of evidence from all sources supporting a role for the variant in that specific disease or condition. In addition, they highlight priorities for research and infrastructure development, including added incentives for researchers to share genetic and clinical data.

One case cited in the paper relates to autism

Researchers found four independent variations in a gene called TTN when they compared genomes between individuals with and without autism. However, the TTN gene encodes a muscle protein (titin) that is the largest known.

Variations are simply more likely to be found within its boundaries compared to those of other genes. Without applying the proper statistical corrections, researchers may have falsely concluded that TTN was worthy of further investigation in autism studies.

The authors note that many DNA variants "may suggest a potentially convincing story about how the variant may influence the trait," but few will actually have causal effects. So, using evidence-based guidelines such as the ones in the Nature paper will be crucial

"We believe that these guidelines will be particularly useful to scientists and clinicians in other areas who want to do human genomic studies, and need a defined starting point for investigating genetic effects, " Gunter says, according to the news release."Quality control guidelines for genomics studies." You also may be interested in another noteworthy study, "Medical genomics: Gather and use genetic data in health care." Or if you're enthusiastic about DNA-based genealogy and patrilineal genetics, check out, "Origins and functional evolution of Y chromosomes across mammals."

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