A Gene is Born

Yes, genes do develop out of nothing.

The "intelligent" design movement has long made a fetish of information. As science has found, life relies on encoded information for its genetic inheritance and the reliable expression of its physical manifestations. The ID proposition is, quite simply, that all this information could not have developed out of a mindless process, but only through "design" by a conscious being. Evidently, Darwinian natural selection still sticks on some people's craw. Michael Behe even developed a pseudo-mathematical theory about how, yes, genes could be copied mindlessly, but new genes could never be conjured out of nothing, due to ... information.

My understanding of information science equates information to loss of entropy, and expresses a minimal cost of the energy needed to create, compute or transmit information- that is, the Shannon limits. A quite different concept comes from physics, in the form of information conservation in places like black holes. This form of information is really the implicit information of the wave functions and states of physical matter, not anything encoded or transmitted in the sense of biology or communication. Physical state information may be indestructable (and un-create-able) on this principle, but coded information is an entirely different matter.

In a parody of scientific discussion, intelligent design proponents are hosted by the once-respectable Hoover Institution for a discussion about, well, god.

So the fecundity that life shows in creating new genes out of existing genes, (duplications), and even making whole-chromosome or whole-genome duplications, has long been a problem for creationists. Energetically, it is easy to explain as a mere side-effect of having plenty of energy to work with, combined with error-prone methods of replication. But creationistically, god must come into play somewhere, right? Perhaps it comes into play in the creation of really new genes, like those that arise from nothing, such as at the origin of life?

A recent paper discussed genes in humans that have over our recent evolutionary history arisen from essentially nothing. It drew on prior work in yeast that elegantly laid out a spectrum or life cycle of genes, from birth to death. It turns out that there is an active literature on the birth of genes, which shows that, just like duplication processes, it is entirely natural for genes to develop out of humble, junky precursors. And no information theory needs to be wheeled in to show that this is possible.

Yeast provides the tools to study novel genes in some detail, with rich genetics and lots of sequenced relatives, near and far. Here is portrayed a general life cycle of a gene, from birth out of non-gene DNA sequences (left) into the key step of translation, and on to a subject of normal natural selection ("Exposed") for some function. But if that function decays or is replaced, the gene may also die, by mutation, becoming a pseudogene, and eventually just some more genomic junk.

The death of genes is quite well understood. The databases are full of "pseudogenes" that are very similar to active genes, but are disabled for some reason, such as a truncation somewhere or loss of reading frame due to a point mutation or splicing mutation. Their annotation status is dynamic, as they are sometimes later found to be active after all, under obscure conditions or to some low level. Our genomes are also full of transposons and retroviruses that have died in this fashion, by mutation.

Duplications are also well-understood, some of which have over evolutionary time given rise to huge families of related proteins, such as kinases, odorant receptors, or zinc-finger transcription factors. But the hunt for genes that have developed out of non-gene materials is a relatively new area, due to its technical difficulty. Genome annotators were originally content to pay attention to genes that coded for a hundred amino acids or more, and ignore everything else. That became untenable when a huge variety of non-coding RNAs came on the scene. Also, occasional cases of very small genes that encoded proteins came up from work that found them by their functional effects.

As genome annotation progressed, it became apparent that, while a huge proportion of genes are conserved between species, (or members of families of related proteins), other genes had no relatives at all, and would never provide information by this highly convenient route of computer analysis. They are orphans, and must have either been so heavily mutated since divergence that their relationships have become unrecognizable, or have arisen recently (that is, since their evolutionary divergence from related species that are used for sequence comparison) from novel sources that provide no clue about their function. Finer analysis of ever more closely related species is often informative in these cases.

The recent paper on human novel genes makes the finer point that splicing and export from the nucleus constitute the major threshold between junk genes and "real" genes. Once an RNA gets out of the nucleus, any reading frame it may have will be translated and exposed to selection. So the acquisition of splicing signals is a key step, in their argument, to get a randomly expressed bit of RNA over the threshold.

A recent paper provided a remarkable example of novel gene origination. It uncovered a series of 74 human genes that are not shared with macaque, (which they took as their reference), have a clear path of origin from non-coding precursors, and some of which have significant biological effects on human development. They point to a gradual process whereby promiscuous transcription from the genome gave rise by chance to RNAs that acquired splice sites, which piped them into the nuclear export machinery and out to the cytoplasm. Once there, they could be translated, over whatever small coding region they might possess, after which selection could operate on their small protein products. A few appear to have gained enough function to encourage expansion of the coding region, resulting in growth of the gene and entrenchment as part of the developmental program.

Brain "organoids" grown from genetically manipulated human stem cells. On left is the control, in middle is where ENSG00000205704 was deleted, and on the right is where ENSG00000205704 is over-expressed. The result is very striking, as an evolutionarily momentous effect of a tiny and novel gene.

One gene, "ENSG00000205704" is shown as an example. Where in macaque, the genomic region corresponding to this gene encodes at best a non-coding RNA that is not exported from the nucleus, in humans it encodes a spliced and exported mRNA that encodes a protein of 107 amino acids. In humans it is also highly expressed in the brain, and when the researchers deleted it in embryonic stem cells and used those cells to grow "organoids", or clumps of brain-like tissue, the growth was significantly reduced by the knockout, and increased by the over-expression of this gene. What this gene does is completely unknown. Its sequence, not being related to anything else in human or other species, gives no clue. But it is a classic example of gene that arose from nothing to have what looks like a significant effect on human evolution. Does that somehow violate physics or math? Nothing could be farther from the truth.

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