Sydney Brenner is a well-known figure in genetics, having made major contributions to our understanding of gene function and establishing Caenorhabditis elegans as the enormously popular model organism that it is today. He shared the 2002 Nobel Prize for “discoveries concerning genetic regulation of organ development and programmed cell death'”. He was also outspoken about various topics relating to genes and genomes, and had various things to say on the topic of junk DNA. For example, he was fond of distinguishing between “junk DNA” and “garbage DNA” — the former of which accumulates while the latter is thrown away.
In June of 1989, Brenner participated in a conference held in Bern, Switzerland entitled “Human Genetic Information: Science, Law and Ethics”. His contribution, “The human genome: the nature of the enterprise” was subsequently published along with transcripts of the discussion that followed in Brenner (1990). Here are some relevant excerpts, which highlight some of the discussions that were going on around the time of the early development of the Human Genome Project with regard to junk DNA and whether to sequence it (Brenner thought it should be ignored in favour of focusing on the genes). His discussion includes classic arguments about the limits of how much of the genome can have an essential, sequence-specific function, and thoughts on the possible functions of non-genic DNA.
“Grasping the magnitude of the technical tasks involved [in genome sequencing and analysis] requires some understanding of the sizes of genomes. First, the range of variation is about a millionfold, from around 4 kb (kilobases, 103) in small viruses to 4 Gb (gigabase, 109) in the human genome, and with bacterial genomes at the geometrical average of about 4 Mb (megabases, 106). The nematode has about 100 megabases and the Drosophila genome is twice that size. Evidence suggests that, up to the level of bacteria, genetic information is densely packed on the genome. This is because these unicellular organisms do not have a separate germline and the time it takes to replicate the genome could become rate limiting for cell multiplication. There is therefore a selective advantage for streamlined genomes which have eliminated all useless DNA. Streamlining is also found in some unicellular lower eukaryotes, such as yeast, which have genome sizes a few times larger than those of bacteria. We can make a reasonable estimate of the number of genes in these organisms by assuming that all the genes code for polypeptide sequences, and that the average size of a gene is, very roughly, one kilobase. Thus viruses would have of the order of ten to a few hundred genes, depending on their genome sizes, which bacteria might have as many as a few thousand genes. These estimates are well supported by what we know about these organisms, either from complete DNA sequences in the cases of some viruses, or from genetic and biochemical studies of bacteria such as Escherichia coli. If we applied this calculation to the genomes of higher organisms we would conclude that Drosophila has more than one hundred thousand genes and man, four million. Genetic considerations suggest that these estimates are far too large. For example, if all the supposed four million human genes performed indespensible functions, then, at an average forward mutation rate of 10-5 per gene, some 40 lethal mutations would have been accumulated in each preceding generation and therefore by now we should all be dead.
This argument about an upper limit on the sustainable number of truly essential regions of the genome with sequence-specific functions was made by others, including Susumu Ohno, in the 1970s. It’s one of several classic arguments that modern opponents of the concept of junk DNA seem to be unaware of.
A consideration of the mutational load suggests that one hundred thousand genes is a more likely upper estimate for the human genome and ten thousand for that of Drosophila. We also know that the genomes of higher organisms contain large amounts of DNA that carry no coding information, and indeed may carry no sequence information at all. Thus we have the surprising result that most of the human genome is junk; junk, and not garbage, because there is a difference that everybody knows: junk is kept, while garbage is thrown away. In higher organisms, with their separate germlines, there is little selective pressure for reducing the amount of DNA, and this is especially true for those with long developmental cycles. Processes leading to an increase of DNA, such as transpositions and certain errors of replication and recombination, are not deleterious and will go unchecked, while those that lead to a reduction in the amount of DNA will not be especially selected for. Such organisms accumulate and retain junk, while in the streamlined unicellular microbes, the junk has become garbage and has been eliminated.”
Here, Brenner is arguing that much of the genome is junk that has accumulated because it is not deleterious. Given that there are many well-known mechanisms that can add DNA to a genome (transposable elements, gene duplication and pseudogenization, replication slippage, illegitimate recombination, etc.), this is a sensible default position to take. Note, however, that Brenner does not dismiss the possibility that some of this DNA may become essential (see below) — neither did Ohno, or the authors of the selfish DNA papers in 1980. Note, also, that there was opposition to this notion each time it was suggested in the 1970s, 1980s, and 1990s.
“It is these considerations that lead me to question the conclusion that there can be no case now to aim to get the entire sequence of the human genome. If something like 98% of the genome is junk, then the best strategy would be to find the important 2%, and sequence it first. Some have argued that since we do not know what there is in all of the junk DNA, we cannot dismiss it, and the only way to find out is to sequence all of the genome. The counter to this is to look at on the sequencing of junk like income tax; it cannot be evaded but there are ways of avoiding it, and, anyway, it is one of the problems that we can and should leave for our successors. If cheap and easy methods of DNA sequencing were available, it would obviously pay to sequence everything and pick out the significant parts by computer. Ultimately it may be done this way, but the technology does not yet exist.”
Brenner argues that it would be better to focus on sequencing libraries constructed using cDNA, so that there could be a focus on elements in the genome that are very likely to have functions. This is largely based on technological considerations based on what was considered feasible in 1990 and not a dismissal of possible functional elements apart from protein-coding exons.
As with Ohno (1973), the discussion that took place after the presentation by Brenner are particularly interesting as an indicator of the state of thinking about junk DNA at the time:
Kimura: “I was very impressed with the statement that 98% of the human genome is junk, rather than garbage. Our daily experience suggests that sometimes ‘junk’ is valuable. Is it possible that some of the so-called junk genes might be found to be valuable…? If the junk gene could become valuable genes, we would have to change our criteria for what is junk.”
Brenner: “Unfortunately the organism cannot plan that. But, in one sense, organisms are very much like us! You get a wooden box and decide to keep it to make a bookcase, but you never do because it’s much cheaper to buy a bookcase, and so the wooden box remains as junk. Organisms cannot plan; there is nothing in the genome that can say that a piece of junk might come in handy in some future era, so let’s hold on to it!”
Some weird distinctions between “organisms” and “us” aside, this highlights a nonsensical but all-too-common idea regarding junk DNA: that it is there because it may someday become useful. This has been addressed many times over the decades, but it persists. Even Francis Collins, former head of the Human Genome Project and now director of the NIH, has invoked it.
“Davis: Is it possible that some, or much, of the junk does not have quite as definable function as, say, making an enzyme, but has regulatory roles that will turn out to be more than junk?”
Brenner: “I would be a fool if I denied that; it is possible, but that is another question I am going to leave for our successors. I am certainly not going to try to prove or disprove it for every piece of junk, and I shall avoid it.”
But perhaps the most telling quote about whether non-genic DNA had been dismissed as useless junk in the late 1980s is the concluding remark made by Gustav Nossal:
Nossal: “You are of course not alluding to certain shortish stretches of DNA that are becoming of very great interest, and clearly do have regulatory promoting or silencing functions, and are now a major object of study. What percentage, on top of the 2%, they represent, we don’t know yet, but it is not a negligible proportion.”
Part of the Quotes of interest series.