The idea that only a fraction of the human genome could be functional dates back to the late 1940s. The estimated
mutation rate in humans suggested that if a large fraction of those mutations were deleterious then the human species could not survive such a mutation load (
genetic load). This led to predictions in the late 1940s by one of the founders of
population genetics,
J.B.S. Haldane, and by Nobel laureate
Hermann Muller, that only a small percentage of the human genome contains functional DNA elements (genes) that can be destroyed by mutation. In 1966, Muller reviewed these predictions and concluded that the human genome could only contain about 30,000 genes based on the number of
deleterious mutations that the species could tolerate. Similar predictions were made by other leading experts in
molecular evolution who concluded that the human genome could not contain more than 40,000 genes and that less than 10% of the genome was functional. The size of genomes in various species was known to vary considerably and there did not seem to be a correlation between genome size and the complexity of the species. Even closely related species could have very different genome sizes. This observation led to what came to be known as the
C-value paradox. The paradox was resolved with the discovery of
repetitive DNA and the observation that most of the differences in genome size could be attributed to repetitive DNA. Some scientists thought that most of the repetitive DNA was involved in regulating gene expression but many scientists thought that the excess repetitive DNA was nonfunctional. (Tomoko Harada) developed the nearly neutral theory that led to an understanding of how slightly deleterious junk DNA could be maintained in the genomes of species with small effective population sizes. In 2015 she was awarded the
Crafoord Prize by the Royal Swedish Academy (with Richard Lewontin).At about the same time (late 1960s) the newly developed technique of
C0t analysis was refined to include RNA:DNA hybridization leading to the discovery that considerably less than 10% of the human genome was complementary to
mRNA and this DNA was in the unique (non-repetitive) fraction. This confirmed the predictions made from genetic load arguments and was consistent with the idea that much of the repetitive DNA is nonfunctional. The idea that large amounts of
eukaryotic genomes could be nonfunctional conflicted with the prevailing view of evolution in 1968 since it seemed likely that nonfunctional DNA would be eliminated by natural selection. The development of the
neutral theory and the
nearly neutral theory provided a way out of this problem since it allowed for the preservation of slightly deleterious nonfunctional DNA in accordance with fundamental principles of population genetics. The term "junk DNA" began to be used in the late 1950s but
Susumu Ohno popularized the term in a 1972 paper titled "So much 'junk' DNA in our genome" where he summarized the current evidence that had accumulated by then. • some organisms have a lot more DNA than they seem to require (C-value
paradox), • current estimates of the number of genes (in 1972) are much less than the number that can be accommodated, • the mutation load would be too large if all the DNA were functional, and • some junk DNA clearly exists. The discovery of
introns in the 1970s seemed to confirm the views of junk DNA proponents because it meant that genes were very large and even huge genomes could not accommodate large numbers of genes. The proponents of junk DNA tended to dismiss intron sequences as mostly nonfunctional DNA (junk) but junk DNA opponents advanced a number of hypotheses attributing functions of various sort to intron sequences. and others promoted the idea that transposons were examples of selfish DNA and were responsible for the proliferation of junk DNA.By 1980 it was apparent that most of the repetitive DNA in the human genome was related to
transposons. This prompted a series of papers and letters describing transposons as selfish DNA that acted as a parasite in genomes and produced no fitness advantage for the organism. Opponents of junk DNA interpreted these results as evidence that most of the genome is functional and they developed several hypotheses advocating that transposon sequences could benefit the organism or the species. The most important opponent of junk DNA at this time was
Thomas Cavalier-Smith who argued that the extra DNA was required to increase the volume of the
nucleus in order to promote more efficient transport across the
nuclear membrane. The positions of the two sides of the controversy hardened with one side believing that evolution was consistent with large amounts of junk DNA and the other side believing that natural selection should eliminate junk DNA. These differing views of evolution were highlighted in a letter from
Thomas Jukes, a proponent of junk DNA, to
Francis Crick on December 20, 1979: Dear Francis, I am sure that you realize how frightfully angry a lot of people will be if you say that much of the DNA is junk. The geneticists will be angry because they think that DNA is sacred. The Darwinian evolutionists will be outraged because they believe every change in DNA that is accepted in evolution is necessarily an adaptive change. To suggest anything else is an insult to the sacred memory of Darwin. The other point of view was expressed by
Roy John Britten and Kohne in their seminal paper on repetitive DNA. A concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert (on an evolutionary timescale). ==Junk DNA and non-coding DNA==