Saturday, January 22, 2011

Baby genes take big steps

Fascinating insights from a study of recently evolved genes in fruit flies

The molecular revolution in biology has changed studies of evolution almost as much as it has changed mechanistic studies of how cells and bodies work. In both fields, the fruit fly (Drosophila) holds a central place as an experimental organism- for studies of development in molecular biology and genetics, and for studies of recent evolution among the many closely related species of its family. Several genomes have been sequenced, yielding ever more-detailed information about the path of evolution in relatively short times.

A recent paper asks whether we can identify genes born recently among the drosophilids, and if so, what kind of genes they are. Do they arise from duplication of an existing gene, or other mechanisms? Do they diverge rapidly from the parent they are copied from, or not? Do they tend to be unimportant or important?
" ... we identified 566 young genes that had originated within the past 35 million years (Myr) and 11,909 old genes that are shared by the 12 Drosophila genomes (>40 Myr)."
With genomes in hand, the lineage of individual genes can indeed be elucidated, up to a point. A gene might appear in one sub-lineage on the linear DNA where it was not before. It is new, and further (similarity) analysis can say whether it was duplicated from an existing older gene, or from some junky region of DNA, or has no visible source at all.

Lineage of the species used on left, and a diagrammatic example of one baby gene on right (yellow), appearing within a small aligned segment of each genome, top to bottom.

The authors find that 80% of the new genes arose from duplication of existing genes by DNA copying, 12% arose from duplication via an RNA intermediate, (the originating gene was transcribed, and its spliced mRNA was copied back into DNA by a reverse transcriptase), and 8% arose de novo from non-gene DNA regions. Needless to say, this process is totally uncontroversial among biologists, but represents the mythic "gain of information" that anti-evolutionists claim is patently impossible. This distribution of sources makes a great deal of sense, since it is easier for a gene to duplicate and then diverge, versus arising from some non-coding sequence which is typically full of stop codons and other serious barriers to encoding a sensible protein. Indeed, I am somewhat amazed that any genes could be classed as originating de novo in this way- they were probably originally very short, as shown in section E of the figure.

Mechanisms of gene birth.

After origination, the authors find that sequence divergence was typically rapid and extensive. Median divergence of the encoded protein sequences was 47%. Chimerism was common, with segments of the new genes expanding, disappearing, and rearranging (again, note E in the figure). Young genes also showed elevated rates of non-synonymous substitution (replacements in the three letter genetic code that change the coded amino acid, as opposed to synonymous substitutions which don't change the amino acid). This indicates positive selection, or an overall lack of selection for a time ... though not too long, or else the nascent gene would have caught a stop mutation and been inactivated. Genes normally show a strong bias to synonymous substitution, since other mutations tend to be deleterious or fatal.

Most interesting was the author's observation that young genes have virtually the same chance of being essential to the organism as older genes. They carried out a screen over ~200 genes of those identified above that were less then 35 million years old, with an RNAi knockout method, where an inactivating RNA matched to the selected gene is engineered into the flies, eliminating that gene's expression. 30% of these mutants ended up dead when gene expression was knocked down, the same rate as for all other genes in the fly. So it seems that not only can novel genes arise rapidly and take on enough function to be preserved by selection, but they can take on essential functions as well.

Why is that? The authors track down the parents of many of these young genes and ask whether they are also essential. No, they are not at a significantly higher rate than chance. The acquisition of essential function by a new gene seems largely independent of the role of the parent gene, though the numbers here are small. The fact that new genes not derived from duplications also acquired essential function at a lower, but still substantial rate (19%, vs 31%), indicates the same thing- that it isn't the origin of a gene that determines its importance to an organism, but the details of what process it happens to insinuate itself into and how it does so, which can range widely whatever a gene's origin.

"Our observation of lethal phenotypes caused by the knockdown of young genes suggested that essential vital genes have been frequently generated in recent evolutionary periods. A new gene might not have become essential immediately after its origination. It, however, can integrate into a vital pathway by interacting with existing genes, and such interaction would be optimized by mutation and selection. This coevolution may lead to the new gene becoming indispensable."
It is remarkable to see this data- one more payoff of the sequencing revolution. The surprising amount of change documented in young genes prompts the authors to claim that neofunctionalization is far more common than I would have thought. This means the adoption of new functions by a gene, as opposed to sub-functionalization, which is the splitting of existing functions between a parent gene and its offspring. For instance, if an important developmental gene functions in both early embryonic and later brain development, a duplication may allow the two copies to specialize/sub-functionalize for each role, each doubtless remaining highly important for the organism, but perhaps only the one functioning in early development being essential in laboratory conditions. Without further details on all the functions involved, it is hard to evaluate the author's claim, but there is no doubt that this form of molecular paleontology is an exciting frontier, taking us way beyond the interpretation of fossils.
"The prevalent gene structure renovation, together with the independence between parental gene essentiality and new gene essentiality, support the neofunctionalization origin of essentiality for most new protein-coding genes, many of which may contribute to the lineage-specific developmental program."

"Government debt, for example, can be thought of as a means for upward redistribution of income, from ordinary taxpayers to rich bond-holders."...
"Public debt is a powerful way of assuring that the state remains safely in capital’s hands. The higher a government’s debts, the more it must please its bankers."...
"But the violet of interest is no longer hidden behind graceless parts of speech alone; mathematics is now the preferred disguise."
  • A few notes on stuttering.
  • Remember that the rich supported the South in the Civil War.
  • Skidelsky on Keynes for today...
"A Keynesian analysis would put global imbalances at the heart of the current economic meltdown. Keynesian unemployment is triggered off by an imbalance between planned saving and investment that is liquidated by a fall in output. The imbalance can be initiated either by an increased desire to save or a reduced desire to invest, or by a mixture of both. An increased desire to save (by the Chinese) subjected the US economy to deflationary pressure."
"Rather, it comes from the feeling that Western civilization is increasingly unsatisfying, saddled with a system of incentives that are essential for accumulating wealth, but that undermine our capacity to enjoy it. "
"Judt considers the success of that welfare state was a double-edged sword. By reducing insecurity “their success would over time undermine their appeal”. In other words, we forget what we have and what our past generations fought for and why."

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