Drosophila’s New Genes

An analysis of the transcriptomes of several fruit fly strains reveals dozens of possible de novo genes in each.

By Jef Akst | January 23, 2014

WIKIMEDIA, MUHAMMAD MAHDI KARIMIn the last few years, scientists have come to realize that genes really can arise from formerly noncoding regions of the genome. Indeed, comparing the genomes of related species has even suggested that such de novo gene formation may be quite common. Today, the first-ever within-population search for novel genes supports this idea. Publishing in Science, researchers at the University of California, Davis, present a total of 142 transcripts that are expressed in some or all six Drosophila melanogaster strains they examined, but that corresponded to intergenic sequences of the D. melanogaster reference genome.

“Until recently, de novo origin of genes was considered to be so unlikely as to be impossible,” comparative genomicist Aoife McLysaght of the Smurfit Institute of Genetics at Trinity College in Dublin, Ireland, who was not involved in the study, told The Scientist in an e-mail. “[T]his population level analysis is important because it gives a new insight into the very early stages of the origin and establishment of genes de novo.”

“To show [the formation of de novo genes] at the population genetics level is really a nice story,” agreed evolutionary biologist Diethard Tautz of the Max Planck Institute for Evolutionary Biology in Plön, Germany, who also did not participate in the research. “It shows the power of generating from nothing, so to speak.”

To search for de novo genes in the fruit fly, UC Davis’s David Begun and his colleagues analyzed the transcriptomes of the testes of six D. melanogaster strains, as well as three strains of D. simulans and two strains of D. yakuba. They specifically looked for transcripts that were expressed in at least one D. melanogaster strain, but not in the D. melanogaster reference strain (data generated by the modENCODE project), nor in any of the D. simulans or D. yakuba strains the researchers examined. This pattern would indicate that the transcripts have only recently evolved to be expressed—at some point in the last 2 million to 3 million years since D. melanogaster and D. simulans split. The researchers then compared the transcripts that fit this pattern to the D. melanogaster reference genome and eliminated any sequences that fell fewer than 500 base pairs away from known genes, minimizing the possibility that the sequences were simply part of the untranslated regions of existing genes. In the end, they found 142 de novo gene candidates.

“There are lots of genes that originated and [are] spreading in the D. melanogaster population,” said coauthor Li Zhao, a postdoc in Begun’s lab.

Looking more closely at these transcripts, the researchers found evidence that the majority of the de novo gene candidates were subject to cis-regulation, meaning that expression was controlled by regulatory elements just upstream of the new transcripts. Furthermore, the vast majority of the sequences contained open reading frames (ORFs)—regions that could theoretically produce proteins, as signified by start and stop codon sequences—of at least 150 base pairs. And looking at the ancestral sequence, as well as the sequences of the nonexpressing Drosophila strains, the researchers found these same ORFs, suggesting that the regulatory change alone is responsible for the expression of the new gene.

“The simplest model [of de novo gene formation] is that they have some mutation in the upstream regions, and those mutations somehow—it could be a binding region or some other regulation region—they somehow make the transcription machinery start,” Zhao said.

Finally, the researchers present preliminary data to suggest that these potential de novo genes may have been subject to natural selection. First, genes that were expressed at high frequencies in the population tended to be longer and more complex than those expressed at lower frequencies, pointing to a role for selection in their spread. Moreover, the researchers observed reduced heterozygosity, also consistent with patterns of selection. Whether these sequences are translated into proteins, or are otherwise functional, remains to be seen.

And of course, not all new genes are likely to be beneficial. In fact, theory would predict that the majority are actually harmful. But the idea that new genes are arising at such high frequencies would certain give natural selection plenty of raw material to work with. “You’ve got this constant churning of new regulatory mutations activating ancestrally unexpressed sequence, and a lot of them turn out to be deleterious, but some of them turn out to be functionally important and spread by selection,” Begun said. “We think we got a glimpse of that from this dataset.”

Though many questions remain, the study represented yet another advance in scientists’ understanding of a phenomenon that only a few years ago was thought impossible, said Tautz. “There has been a long tradition in biology to think that a gene can only arise due to duplication and diversions from another gene, and this is therefore a completely new story. It’s quite an exciting field.”

L. Zhao et al., “Origin and spread of de novo genes in Drosophila melanogaster populations,” Science, doi:10.1126/science.1248286, 2014.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 526

January 24, 2014

The de novo creation of genes has previously been reported to be the "holy grail" of evolutionary biology. If that is true, what's reported here exemplifies the fact that the "holy grail" involves only the direct olfactory/pheromonal link from the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man.

See, for example, our 1996 Hormones and Behavior review article: From Fertilization to Adult Sexual Behavior (e.g., the section on molecular epigenetics where TB wrote): "Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans..."

The alternative splicings are obviously nutrient-dependent and they lead to 1) de novo gene creation and 2) chromosomal rearrangements, which are exemplified in sex diffferences at the advent of sexual differentiation in the cell types of yeasts that sexually reproduce. The physiology of reproduction is controlled by the metabolism of nutrients to pheromones in species from microbes to man. That means de novo creation of genes probably occurs via conserved molecular mechanisms in all species (see: Organizational and activational effects of hormones on insect behavior).

Alternatively, mutation-driven evolution can be substituted for the nutrient-dependent pheromone-controlled ecological adaptations that enable species divergence. Theorists need only explain how natural selection for mutations occurs so that their theory can be compared to a model of ecological variation and natural selection of food.

The model incorporates what is required for the Creation of new genes that enable organismal complexity via ecological, social, neurogenic, and socio-cognitive niche construction. What's required is food and nutrient-dependent pheromone-controlled reproduction. See for example: Nutrient-dependent/pheromone-controlled adaptive evolution: a model

Avatar of: PastToTheFuture


Posts: 117

January 24, 2014

Zow! I'm not a master of this topic, but what I am seeing here is ... messing with some of my pre-conceptions. It seems that here, de novo mutations are considered to be epignetic effects where genes are arising "from formerly noncoding regions of the genome". I have to think that this is obscuring a point. "And of course, not all new genes are likely to be beneficial." These are not "fresh" as "de novo" translates. These are simply broken, probably during recombination processes. It is like a large scale mutation. It is impossible in a controlled/directed context, but not in a random context and that's what I am pretty sure it is. ... Scratching my head on this one. I do think that de novo mutations are going to be in the news big time in the context of humans.

Avatar of: Hugh Hall

Hugh Hall

Posts: 1

January 24, 2014

It has always been hard to believe that the non-coding DNA was merely packing. 

This only helps to strengthen my Primal Egg hypothesis, in which the first organisms to appear on earth were fully equipped to go through the evolutionary pathways that it has. I believe Evolution is directed on a macro level and Darwinian evolution merely tunes this during adaptive radiation.

This of course presupposes organisms such as ourselves "playing God"and spreading life around the universe. 



Avatar of: Wen Wang

Wen Wang

Posts: 1

January 24, 2014

The traditional view of evolution of genetic novelties holds that complete de novo gene origination from ancestral non-genic sequences is almost impossible. This view has been changed because many de novo genes have been identified in Drosophila, yeast, mice, rice and human etc. However, the dynamics of origin and subsequent spread within populations of such de novo genes remain obscure. Zhao and colleagues targeted one of the most interesting questions in evolutionary and population genomics: what are the properties and selective forces acting on novel genes that have just originated from non-coding DNA. They found a number of possible de novo genes were born through the activation of transcription of previously non-coding DNA. They found most of these gene may contain “pre-formed ORFs” and experienced natural selection. Most of the genes expression may due to cis-regulation, which brings up the simple but convincing model that mutation in the upstream flanking region may lead to activation of transcription of a de novo gene. These de novo genes already show signs of alternative splicing, which is also important for understanding evolution of alternative splicing in genes.

Avatar of: James V. Kohl

James V. Kohl

Posts: 526

Replied to a comment from Wen Wang made on January 24, 2014

January 24, 2014

Mutation-Driven Evolution p. 196 "...natural selection is an evolutionary process initiated by mutation. It does not have any creative power..."

It is interesting to see experimental evidence of epigenetically-effected de novo creation of genes reinterpreted as if the physical evidence in Drosophila or any other model organism could somehow be forced to fit back into the context of mutation-driven evolution.

I think that trying to make physical evidence from an experiment fit a theory that failed its only experimental test last year: An experimental test on the probability of extinction of new genetic variants attests to the overall ignorance of the basic principles of biology and levels of biological organization required to link sensory cause to behavioral affects via conserved molecular mechanisms in species from microbes to man.

So, I'll ask this: What experimental evidence suggests that mutation-initiated natural selection results in species divergence? Can it be compared to a model in which ecological variation leads to experience-dependent receptor-mediated species divergence in species from microbes to man via nutrient-dependent pheromone-controlled reproduction?

Avatar of: drwho


Posts: 1

Replied to a comment from PastToTheFuture made on January 24, 2014

March 19, 2014

No it cannot due to recombination, because all these genes seems to have unique orthologous region in the close related outgroup species. So that means by synteny relationship between sibling species, they could rule out the possibility of   recombination or "broken" assembly caused false transcripts.

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