Welcome to the Genome. Michael Yudell
that genes were real and led genetics and molecular biology into a new and exciting realm. With the basics of heredity worked out, molecular biology became a driving force in science as the working characteristics of the gene came under scrutiny and study.
To complicate matters, research on and expansion of ideas about how phenotypes might be generated in a heritable fashion apart from genetics first formulated by C. H. Waddington and called epigenetics have made the biology of genes and inheritance even more complex and interesting. Epigenetics is what its name from the Greek implies—“beside genetics”. More precisely it concerns the expression of heritable phenotypes without changes in the DNA of the genome. In other words, epigenetic effects are heritable phenotypic effects without changes in genotype. The most famous case used to demonstrate this phenomenon is the Dutch Hunger Winter. A follow‐up study done on women who suffered through all or part of this 5‐month‐long famine that occurred near the end of World War II (the cause of the famine—which killed 20,000—was a Nazi blockade of food and fuel) revealed some important “heritable” problems. (82) It was reported that during the height of the famine, average caloric intake was less than 400 calories per day (the equivalent of say four pieces of toast). After the war a long‐term study of people who survived the famine was undertaken to determine the impact of famine on the offspring of women whose children were exposed prenatally to famine. As Laura C. Schultz puts it “the Dutch Hunger Winter study, from which results were first published in 1976, provides an almost perfectly designed, although tragic, human experiment in the effects of intrauterine deprivation on subsequent adult health.” (83)
The sad but remarkable results were that diabetes, obesity, microalbuminuria (a kidney malfunction), psychological and cognitive problems, and cardiovascular disease were seen in higher frequency in the offspring of women who lived through the famine than in the offspring of children of their siblings who were not exposed to famine. More remarkable was that women whose fetuses experienced the famine later in prenatal development were affected more severely than fetuses who experienced the famine earlier in their prenatal development (those fetuses that were conceived close to the end of the famine). Researchers could clearly show that this phenomenon was not due to DNA sequence changes. What then could cause this drastic change in the susceptibility to the offspring of women exposed to famine?
To understand this phenomenon completely we need first to describe the structure of DNA as it resides on our chromosomes. The DNA of our chromosomes is wrapped into what is called chromatin. First, the double helix is wrapped twice around a protein complex called a histone core. The histone cores have short parts of their proteins that “tail” off of the wrapped DNA. These “histone tails” are where the epigenetic action takes place, because these parts of the histone proteins can easily be modified by chemical reactions like the addition of methyl groups or acetyl groups. If a histone tail is methylated (or phosphorylated, acetylated, ubiquitylated, or sumoylated) this modification changes the shape of the histone core and disrupts the tightly wound chromatin altering the availability of the DNA in that region to transcription and hence gene expression of that region of the chromosome. Methylation can also occur on the DNA strand itself and this alters the availability of the region of DNA that is methylated to transcription.
Researchers were able to examine the methylation patterns of the DNA in an important gene called insulin‐like growth factor II (IGF2) of women who suffered through the Dutch Hunger Winter. Six decades after the famine, women exposed to it had much less methylation of IGF2 than women who escaped the famine. The implication of the study is that early mammalian development is an incredibly important stage where DNA sequences are highly prone to methylation tags as a result of some environmental shock like famine. Such methylation alters the gene expression of important genes involved in many phenotypes. More importantly, these methylation patterns can persist for long periods of time.
The Dutch Hunger Winter case is only one of many where epigenetic factors like DNA methylation and histone modification have an impact on human health. Epigenetic factors are also important in other organisms and have been implicated in many evolutionary phenomena. (83)
Figure 1.12 The mechanisms of epigenetics.
Credit: National Institutes of Health
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