Darwin's pertubration - Intro to Methylation

This will be the kick off for Darwin's perturbation effect. The first section in a rundown of epigenetic research and its place in evolutionary context. Being that this is an open to everyone (even anonymous) commentators. I am hoping for all types of comments. Bash it, add to it, tell me if it makes sense. This will be a multi-part event, released every few weeks. I am not stupid enough to hold to a schedule I will apologize for not being able to make. On a positive note, I have had some people sign up as authors and we will hopefully see something from them soon.


Darwin’s Perturbation Effect: Natural Selection and the Field of Epigenetics

In 1859, with the publication of On the Origin of Species, Darwin was unsure of the mechanism for heredity. Had he lived to see Mendel’s particulate inheritance be incorporated into this position, eventually giving rise to the modern synthesis, he would have been fascinated by the implications. Over the course of 150 years these two theories have guided the course of research. They have prompted us to sift through the soil in search of ancestral forms, redefined what we know about medicine, and brought our search for origins to a simple four letter code from which variation blooms. Now, advances resulting directly from these lines of inquiry have moved us towards a technological sophistication that allows us to appreciate a new layer of complexity within the evolutionary framework: epigenetics. Paradigms are being refined by advances in methylation, histone modification, meiotic inheritance, imprinting and chromosomal positioning. These studies are currently being driven by new methods developed in order to understand the epigenetic phenomenon. Many of the developing methods within this new field are helping us to comprehend phenomena that are not well understood by classical concepts of genetics (Stam and Chandler, 2004). With this theoretical thrust firmly in mind, it should be noted that as the study of epigenetics expands, so does the definition. This was a central question at the conference held at the Académie des sciences in Paris in May of 2008.

At this conference it was suggested that the definition previously assigned: “the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence (Feil 2008 and Stam and Chandler, 2004).” This definition, though functional, fails on some accounts in the wake of new insights. At the conference a separate definition was suggested: ‘the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states’” (Feil 2008). At the heart of both of these definitions is the ability for genetic information to be “read” differently depending upon the context of a specific environment. The implication for such a phenomenon is that an environment could produce a phenotypic change by way of an alternate reading of genome depending upon the circumstances an organism is subjected to. This alternative interpretation leaves the genome unaltered and does not require a mutational event to produce variation within a species and could potentially be reversed through a similar epigenetic mechanism (Rassoulzadegan et al. 2007). Such a concept invokes the idea of a nature versus nurture dichotomy which is prevalent in popular media but truly has no bearing in the scientific community. What is apparent is that there is a demarcation problem surrounding which pole of the spectrum has the larger influence in ontogeny. Epigenetics, therefore, could be instrumental in broadening the point of consensus. Before such a revolution takes place, however, we must understand the way in which the genetic code is interpreted by those organelles responsible for transcription and overall phenotypic expression. The best understood method for a cell to achieve this select interpretation is DNA methylation.

A portion of a gene becomes methylated by the direction of the enzyme methyltransferases. Within this enzyme family are two different types, those that maintain methyl patterns and those that create new methyl patterns (Takashima et al. 2008). When a gene becomes methylated it becomes silent and transcription is thought to no longer be possible. It is of note that this pattern of gene deactivation in animals is only found on the dinucleotides Cytosine and Guanine and appears to be essential for the proper development of most eukaryotes. When the gene for methyltransferase Dnmt1, 2, or 3 is knocked out in mice, death or malformation occurs depending upon which combinations remain (Suzuki and Bird 2008). Furthermore, aberrant methylation patterns have been noted in a number of cancers, potentially by way of hypermethylation and oncogene activation (Takashima et al. 2008). Evidence such as this is strong support for the claim that the cause and effect of methylation patterns should be explored. From this several different patterns of methylation have been noted in a variety of organisms.
In invertebrates a ‘mosaic methylation’ pattern is noted. This pattern is characterized by areas of heavily methylated DNA spaced by those that are methylation free. This pattern is also seen in the plant Arabidopsis thaliana (Suzuki and Bird 2008). A separate pattern is evident within vertebrate genomes. This pattern is one of global methylation, where Cytosine and Guanine are universally methylated. This pattern is broken by large unmethylated islands of Cytosine and Guanine (CpG islands) that range from 300 to 3,000 base pairs (bp) long. Unmethylated domain areas account for about 2% of the total. This does not mean that these islands cannot become methylated. It has been observed that somatic tissue can vary in the level of CpG island methylation on genes that are central to development, such as homeobox and paired box (Suzuki and Bird 2008). Even the global methylation pattern remains causally ambiguous, but it is thought that it is established during the implantation and gametogenesis stages of ontogeny (Takashima et al. 2008). Although nothing in vertebrate DNA has yet been uncovered, a variety of non-vertebrate and plant genome assay have exposed a spatial dynamic in which methylation patterns are being revealed in actively transcribed genes, thus denying methylation’s sole property of silencing transcription (Suzuki and Bird 2008). Should this be discovered in vertebrate studies, an entirely new implication for globally methylated patterns could arise. Technological barriers revolving around the relatively large size of vertebrate genomes have thus far dispelled any hopes of mapping the methylated human genome in any great resolution. Still, simultaneous assay techniques and 454 sequencing in parallel with bisulphitetreated DNA are bridging this technological barrier (Suzuki and Bird 2008).

In DNA methylation landscapes-provocative insights from epigenomics by Miho Suzuki and Adrian Bird points out that the unique pattern of vertebrate global methylation landscapes could be a result of an immune system adaptation. It is not difficult to see that a select pressure could be so extreme that an organism could overcome the detrimental consequences of remapping the methylation patterns that are surely ancestral (Suzuki and Bird 2008). The hinge of their argument is that plasmacytoid cells, a type of B cell, can potentially trigger an innate immune response. Specifically “toll-like receptor 9 detects genomes of invading bacterial pathogens by recognizing DNA that is rich in unmethylated CpG moieties (Suzuki and Bird 2008).” Being that methylation is so prominent in vertebrate genomes it would then reduce the risk of an auto-immune response. Potentially lending support to this is the way in which the Epstein-Barr virus (EBV) is linked with auto-immune disorders such as Multiple Sclerosis. A demonstration of DNA methylation may affect B cell behavior in an attempt to evade destruction (Kurtuncu and Tuzun 2008 and Mehler et al. 2008). If this exploitation of epigenetic factors is the case for diseases, then certainly variation in methylation patterns should be a focus of human variation. Past studies, such as the one by Fraga et al. looked at the deviations between methylation patterns of monozygotic twins, demonstrating a significant gap between patterns relevant to age (Fraga et al. 2005). Another study the following year undertaken by Eckhardt et al., was aimed at generating a picture of methylation variance within a large sample size. Groups of people of varying age, between 22-30 and 60 and 76 were examined. The average difference in this group was only .275%, and .1% between the genders. When the cell types were examined in a similar goal a statistical difference did appear, CD4+ lymphocytes versus fibroblasts registering 7.1% (Eckhardt et al. 2006). The seemingly contradictory results of these studies will only be elucidated by improved techniques for mapping epigenetic changes, and better gauges for determining what a significant deviation is.