"Epigenetics" drives phenotype?

Researchers have identified a possible mechanism by which DNA regions that don't encode proteins can still determine phenotypic traits such as a person's height or susceptibility to a particular disease, researchers report online in Science today. Image: WikipediaThe scientists found that certain chromatin modifications often considered to be epigenetic -- meaning, regulated by factors other than genetic sequence -- are in fact determined by a person's DNA. Moreover, they found that this c

By | March 18, 2010

Researchers have identified a possible mechanism by which DNA regions that don't encode proteins can still determine phenotypic traits such as a person's height or susceptibility to a particular disease, researchers report online in Science today.
Image: Wikipedia
The scientists found that certain chromatin modifications often considered to be epigenetic -- meaning, regulated by factors other than genetic sequence -- are in fact determined by a person's DNA. Moreover, they found that this chromatin variation is associated with distinct single nucleotide polymorphisms, suggesting that the variation may serve as a platform to enable these SNPs -- often found in non-coding regions of DNA -- to influence phenotype. "This is quite novel," said linkurl:Emmanouil Dermitzakis,;http://www.medecine.unige.ch/recherche/groupes/b_donnees/cv_892_4.html a geneticist at the University of Geneva Medical School, who was not involved in the study. "Epigenetics has been used as a term that is orthogonal to genetics. This study clearly shows it's not." Genome-wide association studies have linked single nucleotide polymorphisms (SNPs) to particular diseases or characteristics, but how SNPs relate to phenotype has been unclear. Because SNPs often occur in non-coding regions of the genome, researchers have generally thought that what links these regions to phenotype are processes that control how genes are regulated, but such a relationship has never been demonstrated. "What this paper really does is show this to be the case," said linkurl:Vishwanath Iyer;http://www.biosci.utexas.edu/mgm/people/faculty/profiles/iyer.htm of the University of Texas at Austin, one of study's three lead authors. The researchers examined two processes involved in gene regulation: chromatin structure -- in particular, whether or not chromatin is open, allowing genes to be transcribed -- and transcription factor binding. Both of these features can be regulated epigenetically -- that is, by factors such as DNA methylation and histone modifications. They used high-throughput sequencing to analyze cell lines taken from six individuals whose genomes had originally been sequenced within the 1000 Genomes Project -- two parents and their daughter from Utah, of northern and western European ancestry, and two parents and their daughter from Ibadan, Nigeria, of Yoruban ancestry. This pool of six people allowed them to compare these factors across both alleles of genes carried by single individuals, as well as examine familial heritability in the two daughters. "It's the first time someone has looked at chromatin structure throughout the genome in related individuals," Iyer said. In 10 percent of the sites they examined, they found that chromatin sites that tended to be open in the parents also tended to be open in their daughters, suggesting chromatin structure was heritable. Similarly, many differences in transcription factor binding were maintained across individuals. But these differences could still be the result of heritable changes in epigenetics, not genetics. So the authors also looked at these traits at at both alleles in single genes in the individuals' genomes. They found that, in a subset of sites, chromatin structure and transcription factor binding occurred differently at each allele, which suggested it was the genetic code at each allele that produced the difference. "We find that it is actually the sequence that matters," said Iyer. If a non-coding SNP leads to a difference in chromatin structure and/or transcription factor binding, that effect can indeed be inherited, thereby providing a potential mechanism for transmission of phenotypes like disease susceptibility, Iyer said. "What we have is a way to link polymorphisms to phenotypes via things like chromatin structure and transcription factor binding." He stressed that not all forms of chromatin-level regulation were dependent on the genome sequence. "We are looking at one transcription factor and one measure of chromatin structure," he said; other kinds of chromatin variation, however, may be due to mechanisms such as DNA methylation, which are independent of the sequence. "The paper in itself is not really surprising," said linkurl:Maxwell Lee,;http://ccr.cancer.gov/staff/staff.asp?profileid=5543 a geneticist at the National Cancer Institute, but the researchers examined variation at many more loci than previous studies have looked at, and also were able to examine variation both at the level of different chromosomes as well as different individuals. The study was done in the context of the linkurl:ENCODE Consortium,;http://www.genome.gov/10005107 a large-scale project conducted by the National Human Genome Research Institute that aims to understand all the functional elements in the human genome. The next step, said Iyer, is to examine this type of variation in a much larger set of people to determine when it is functional, and exactly how it drives phenotype.
**__Related stories:__***linkurl:Epigenetic suicide note;http://www.the-scientist.com/article/display/55843/
[August 2009]*linkurl:Burning chromatin at both ends;http://www.the-scientist.com/article/display/55468/
[March 2009]*linkurl:An epigenetic inheritance;http://www.the-scientist.com/blog/display/55342/
[January 19th 2009]
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Comments

Avatar of: Douglas Easton

Douglas Easton

Posts: 32

March 18, 2010

Criticism of ENCODE has been rampant and has even found its way into spirited discussion in the comments section of an article in the New York Times Health section. The topic was genome wide sequencing as a means to identify disease related genes. Leroy Hood and other proponents of genome wide approaches were quoted as having essentially given up on ENCODE for high throughput sequencing of whole genomes. Readers severely criticized the ENCODE project as a waste of money,ridiculing the project for having uncovered disease relationships to SNPs in non-protein-coding DNA.\n\nAs Yogi Berra said. "It ain't over til its over" Now ENCODE seems to have been serendipitous in identifying the kind of sites that may dictate chromatin structure. However I'm not holding my breath.There is much more to be learned than the Science article has uncovered. There is a lot at stake here. Reputations seem to be the most valuable chips on the table.
Avatar of: anonymous poster

anonymous poster

Posts: 1

March 18, 2010

I found this review to be very hard to follow. The distinction between the effect of SNYPS and epigenetic influences on chromatin structure was not clarified, nor how the data from the two families added to the conclusion that epigenetic modification of chromatin influenced a phenotype. It seemed like a lot of hand waving over complex analysis and techniques that would have been very informative.
Avatar of: Dov Henis

Dov Henis

Posts: 97

March 19, 2010

epigenetic = after or beside + genetic = something that affects a cell, organ or individual without directly affecting its DNA. An epigenetic change may indirectly influence the expression of the genome.\n\nEpigenetics are not the operators; they are the traffic signs/directions for the operators...\n\nDov Henis
Avatar of: Sergio Stagnaro

Sergio Stagnaro

Posts: 59

March 21, 2010

As incipit, the paper informs that DNA (I think, n-DNA) mutations bring about disorders. It is clear that oustanding Authors and Editors continue to ignore the existence and the importance of mit-DNA alterations, at the base of the common and severe diseases, today's growing epidemics, as diabetes, CVD, cancer, I demonstrated more than 30 years ago. In my opinion, the time has come to spread among physicians such as knowledge, new way in the war against common disorders is based on. Epigenesis is important, perhaps. However, since individual's birth, we can bedside recognized, i.e., with a stethoscope, an awfull lot of quantum biophysical semeiotic Constitutions "AND" related INHERITED Real Risks, now succesfully treated in a large majority of cases (Ask www.google.com)

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