As far back as the eighteenth and well into the twentieth century, biologists debated whether acquired (or adaptive) characters were heritable or not. Often they divided into the "naturalists," who believed that acquired characters were heritable, and the geneticists, who believed only in the inheritance of genetic variants through natural selection. Beginning around 1920, the views of naturalists began to decline while those of geneticists were ascendant, largely as a result of the pioneering studies of heredity in fruit flies by Thomas Hunt Morgan and his students. By the 1940s and 1950s, DNA had been demonstrated to be the genetic material by Oswald, Avery, and McCarty, and the double helix of DNA had been proposed as the molecular basis of modern genetics by Watson and Crick (Table 1.1 and Figure 1.1). During this revolutionary period of experimental biology, epigenetics emerged as a series of isolated observations in three disparate areas, developmental biology, chromosomal biology, and molecular biology, advancing along separate pathways before their convergence in the 1980s.
In attempting to understand how genotypes evolve, developmental biology studies in fruit flies in the 1940s by C.H. Waddington showed that a crossveinless phenotype induced by heat shock was assimilated and expressed in nearly 100% of progeny after several generations, even in the absence of heat shock. Waddington hypothesized that a genetic factor was responsible for the assimilation and transmission of this adaptive response.3 As Waddington's findings were confirmed in other studies (reviewed by Ruden et al.4), we next learned how a series of inquiries into chromosomal biology initiated during the 1940s and 1950s began to shed light on X chromosome inactivation and much later how X inac-tivation was related to the peculiar phenomenon of genomic imprinting. In 1949, Murray Barr demonstrated that a cellular organelle easily visible in male and female animal cells under an ordinary microscope, the so-called ''sex chromatin body,'' could be used to sort tissues and individuals into two groups according to gender.5 In 1959, Ohno explained that one of the X chromosome pair in female cells remained extended in mitosis while the other assumed a condensed state to form the sex chromatin (Barr) body.6 Within 2-3 years, Lyon7 and Beutler and colleagues8 independently documented the mosaicism of X chromosome expression in female cells, concluding that only one X chromosome was active in each cell of females. While these studies were ongoing, Crouse, in her studies of the mealy bug Sciara, discovered another phenomenon having a bearing on X chromosome mosaicism, which she called ''parental imprinting'' (later also called ''genomic imprinting'').9 She used ''imprinting'' to describe the change in behavior acquired by the chromosome on passing through the male germ line as exactly opposite the imprint conferred on the same chromosome by the female germline.
In 1961, in the course of molecular studies probing the mechanisms of enzymatic replication of DNA in Arthur Kornberg's laboratory, Josse and co-workers made a seminal contribution to the emergence of epigenetics.10 They found that cytosine in vertebrate genomes occurred at a much lower frequency, about a quarter of that expected from the overall base composition. But several years elapsed before Grippo in Scarano's laboratory clarified this finding. In 1968, Grippo observed the presence of methylases in sea urchin embryos and pointed out that 5-methylcytosine (5mC) was unique among DNA bases in that it was the only methylated base, and that 90% of the methylcytosine is nonrandomly distributed in CpG doublets in this model.11 Actually, Rollin Hotchkiss had reported the likely presence of methylcytosine in calf thymus DNA in 1948,12 although he called it "epicytosine." In 1971, Scarano13 suggested that 5mC was unstable, and would deaminate spontaneously to form thymine (Figure 6.1). Following this suggestion in 1977, Salser14 showed that the dinucleotide mCpG was indeed unstable, tending to deaminate to TpG. In 1980, Adrian Bird drew attention to the curious species difference in DNA methylation that ranged from very high to intermediate to low in vertebrates, nonarthropod invertebrates, and arthropods, respectively. Bird's analysis of nearest-neighbor dinucleotide frequencies also supported the suggestion that 5mC tended to mutate spontaneously to thy-mine, and that this tendency caused a CpG deficiency in heavily methylated genomes.15,16
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