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# Chargaff's Test of the Tetranucleotide Hypothesis

Module by: Laura Martin. E-mail the author

Scientists of the early 1900's recognized that if the tetranucleotide model was correct, then DNA could not differ sufficiently among species to explain the incredible diversity of heritable differences. From the biochemical perspective, proteins were a superior candidate because they were known to be both incredibly diverse and physically associated with DNA in the nucleus.

From the cell biology and genetics perspective, however, evidence continued to accumulate that DNA was responsible for heredity. One particularly significant discovery, published in 1944 by Oswald T. Avery, Colin MacLeod, and Maclyn McCarty, provided very strong evidence that DNA was responsible for inducing heritable changes in a species of bacteria (Avery et al., 1944).

While momentous in hindsight, Avery et al.’s discovery was not particularly illuminating to the generally protein-focused biochemistry community. The biochemist Erwin Chargaff, however, reacted differently. As he later wrote, Avery et al.’s results

...almost abruptly, appeared to foreshadow a chemistry of heredity and, moreover,
made probable the nucleic acid character of the gene.  It certainly made an impression
on a few, not many, but probably on nobody a more profound one than on me.  For I saw
before me in dark contours the beginning of a grammar of biology.(Chargaff, 1971, p.639)

The intellectual impact of Avery et al’s work was such that Chargaff abandoned all prior research (or completed it quickly) and refocused the efforts of his entire lab on the question of DNA. As he wrote in 1971,

I started from the conviction that, if different DNA species exhibited different
biological activities, there should also exist chemically demonstrable differences
between deoxyribonucleic acids. From the very beginning I drew an analogy to the
proteins in assuming that the biological activity of the nucleic acid probably rested
on the sequence specificity of its constituents – on the order in which the four
different nucleotides were arranged in the macromolecule – rather than on the
occurrence of new, as yet unrecognized constituents.(Chargaff, 1971, p.639)


Chargaff’s nearly 'insurmountable’ challenge was to develop an analytical technique to precisely and reliably quantify the nucleotide composition of DNA. Such a tool would allow him to test the idea that DNA of different species differed in nucleotide composition. Such a result would be consistent with Chargaff’s proposition, inspired by Avery et al.’s work, that DNA is biologically active, its biological activity differs among species (in that it is responsible for their different heritable phenotypes) and that its activity is conferred by the particular sequence of nucleotides.

Let’s consider what insights the ability to quantify the relative amounts of A, T, G and C provide in relation to both the tetranucleotide model and Chargaff’s proposition above.

1. Reconsider the tetranucleotide model.

a. If DNA is composed of serially repeated tetranucleotides and you precisely measure the relative quantities of A, T, C and G in an organism’s DNA, what do you expect to find? Why? Please explain.

b. If DNA is composed of tetranucleotides and you compare the relative quantities of A, T, C and G (for example, the ratios of A to G or T to C) among species what would you expect to find? Why? Please explain.

2. Now consider Chargaff’s hypothesis. If DNA is biologically active, its biological activity differs among species and its activity stems from the particular sequence of nucleotides, what would you expect to find if you precisely measure the relative quantities of A, T, C and G in a variety of species and compare them? Why? Please explain.

## Works Cited

• Avery, O.T., C.M. MacLeod, and M. McCarty. 1944. Studies on the chemical nature of the substance inducing transformation of Pneumococcal types.The Journal of Experimental Medicine. 79: 137-159.
• Chargaff, E. 1971. Preface to a grammar of biology. A hundred years of nucleic acid research.Science. 172:637-642.

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