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Epigenetics: Lamarckism revisited
« on: 2004-07-03 10:31:15 » |
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Among the several subtleties in the way from the genetic blueprint (the genotype) to the actual product (the phenotype), this one seems to be very interesting both in theory and in practice.
Among other things, it should make evolution theorists more cautious when talking about the genetic origins of some human traits.
http://www.the-scientist.com/yr2004/jul/feature_040705.html
(free registration required)
Epigenetics: Genome, Meet Your Environment.
As the evidence accumulates for epigenetics, researchers reacquire a taste for Lamarckism
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EPIGENETICS EXPLAINED This type of inheritance, the transmission of non-DNA sequence information through either meiosis or mitosis, is known as epigenetic inheritance. From the Greek prefix epi, which means "on" or "over", epigenetic information modulates gene expression without modifying actual DNA sequence. DNA methylation patterns are the longest-studied and best-understood epigenetic markers, although ethyl, acetyl, phosphoryl, and other modifications of histones, the protein spools around which DNA winds, are another important source of epigenetic regulation. The latter presumably influence gene expression by changing chromatin structure, making it either easier or more difficult for genes to be activated.
Because a genome can pick up or shed a methyl group much more readily than it can change its DNA sequence, Jirtle says epigenetic inheritance provides a "rapid mechanism by which [an organism] can respond to the environment without having to change its hardware." Epigenetic patterns are so sensitive to environmental change that, in the case of the agouti mice, they can dramatically and heritably alter a phenotype in a single generation. If you liken the genome to the hardware of a computer, Jirtle explains, then "epigenetics is the software. It's the grey area. It's just so darn beautiful if you think about it."
The environmental lability of epigenetic inheritance may not necessarily bring to mind Lamarckian images of giraffes stretching their necks to reach the treetops (and then giving birth to progeny with similarly stretched necks), but it does give researchers reason to reconsider long-refuted notions about the inheritance of acquired characteristics. Eighteenth-century French naturalist Jean Baptiste de Lamarck proposed that environmental cues could cause phenotypic changes transmittable to offspring. "He had a basically good idea but a bad example," says Rohl Oflsson, Uppsala University, Sweden.
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Terminology aside, biologists have long entertained the notion that certain types of cellular information can be transmitted from one generation to the next, even as DNA sequences stay the same. Bruce Stillman, director of Cold Spring Harbor Laboratory (CSHL), NY, traces much of today's research in epigenetics back to Barbara McClintock's discovery of transposons in maize. Methyl-rich transposable elements, which constitute over 35% of the human genome, are considered a classical model for epigenetic inheritance.
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One of the prominent features of DNA methylation is the faithful propagation of its genomic pattern from one cellular or organismal generation to the next. When a methylated DNA sequence replicates, only one strand of the next-generation double helix has all its methyl markers intact; the other strand needs to be remethylated.
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EPIGENETICS AND DISEASE More than two decades ago, anyone who proposed that epigenetic regulation played a role in carcinogenesis was a "lone prophet in the desert," explains Jaenisch. Researchers didn't seriously entertain the notion until Andy Feinberg and Bert Vogelstein, both at Johns Hopkins University, reported a link between human cancer cells and aberrant DNA methylation patterns.7 Even then, Feinberg says "the initial reaction was disbelief. I think that people ignored it. Now, everyone accepts that epigenetics is important in cancer." The etiological link between epigenetic change and cancer has fueled both academic and pharmaceutical interest in the field.
Methylation usually silences gene expression. Normally, about 70% of all CpG dinucleotides in the mammalian genome are methylated. The remainder, clusters near the 5' end of genes known as CpG islands, are protected from it. Too little methylation across the genome or too much methylation in the CpG islands can cause problems, the former by activating nearby oncogenes, and the latter by silencing tumor suppressor genes. When Feinberg and Vogelstein linked cancer to epigenetics in the early 1980s, they linked it specifically to genome-wide hypomethylation. A few years later, German and US research teams discovered connections between cancer and tumor- suppressing silencing caused by hypermethylation. Both hypo- and hypermethylation can play significant regulatory roles even in the same tumor.
It has taken more than correlations between methylation and cancer, however, to convince researchers that epigenetics is the cause, not consequence, of malignancy.
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Epigenetic inheritance has been associated with a number of other human health conditions, including some whose incidence is higher among babies born with the aid of assisted reproduction technology (ART). As Reik explains, embryos normally develop in a protective environment, the womb. When they are put into the suboptimal environment of a culture dish, many things can go wrong. Methylation sites initially established in the oocyte may not be maintained properly, and imprinting patterns may be lost during development.
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Epigenetic inheritance also may be the reason that human cloning is all but impossible. Indeed, Jaenisch considers cloning "the ultimate bioassay for epigenetic changes." When a differentiated somatic cell is put into an oocyte, its genome-wide epigenetic pattern must be reprogrammed in order to restore totipotency. The difficulties associated with reprogramming all the chromatin, histones, and methylation patterns along the entire length of the DNA sequence may explain why so many cloned embryos have so many developmental failures.
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