On the gain of genes and gene function

Michael Behe recently published a review article in the Quarterly Review of Biology entitled Experimental evolution, loss-of-function mutations, and “the first rule of adaptive evolution” (subscription required), which consists largely of a review of laboratory experiments addressing the adaptive response of microorganisms to simple environmental changes. Behe generates a new definition – Functional Coded elemenTs (FCTs), essentially any segment of DNA that has a biological function, and a “rule”, the “first rule of adaptive evolution”, which essentially states that the majority of adaptive changes reflect mutational events are those which impair or eliminate FCT function.

Update: please note the first comment on this article, which outlines in more detail problems with Behe’s “first rule”.

My own view is firstly, that the data Behe relies on come largely from simple laboratory experiments on microbes (mostly bacteria) generally cultured as a monoculture away from other bacterial species and their bacteriophages (viruses), and secondly that the examples given for eukaryotic adaptation (of humans to endemic malaria) are peculiarly interpreted. Jerry Coyne has published several blog articles reflecting on this paper (Behe’s new paper; IDers already distorting Behe’s new paper; Casey Luskin distorts Behe’s paper; An experimental evolutionist replies to Behe), so there’s really no need to revisit it, other than to note the reservations I have.

What’s a bit more interesting is recently published evidence on the evolution of new genes in the fruit fly Drosophila (in fact these papers look as several species of Drosophila rather than just the common lab species Drosophila melanogaster).

In the first, Chen et al (2010) compared the genome sequences of different species of Drosophila. Again, Jerry Coyne’s beaten me to it with a detailed review of the paper (New genes arise quickly), but in essence, the authors investigated the gene differences between the species in the D. willistoni and D. melanogaster lineages, which diverged about 35 million years ago. Their aim was to evaluate how often genes appeared within the D. melanogaster lineage. In Behe’s new terminology, these would be gain-of-FCT. To summarise, Chen et al:

  • Identified 566 new genes in the D. melanogaster genome and dated their evolutionary ages through phylogenetic distributions.

  • Assayed the effects of loss of function by RNA interference – of 195 ‘young genes’ tested, 59 gave lethal phenotypes. In other words slightly more than 30%.

  • The frequency of young genes with essential function is not statistically different from the corresponding frequency of ‘old genes’, 35%.

Coyne notes in his blog article (New genes arise quickly) that

The presence of frequent gene duplications is supported by an independent study:  Emerson et al. (2008) found that in only fifteen lines of D. melanogaster from nature there were several hundred duplicate genes segregating as polymorphisms (that is, some individuals had one copy of a gene, some had two or more).  They estimated that 2% of the genome was tied up in this copy-number variation.  Clearly, there are a lot of duplicate genes variants floating around in nature.

Indeed, some years ago my laboratory identified a case of gene duplication in D. melanogaster that was presumably a recent event, being present in only some lab strains. It’s quite clear that these sorts of observations are widespread across genomes of species in which the genomes of many individuals have been looked at. Copy number variation is widespread among humans.  What is the usual fate of a duplicated gene?  In many cases, the duplicated gene may have lost vital elements required for correct expression (those sequences important for correct spatiotemporal expression patterns).  In such a circumstance it is likely to be non-functional (i.e. a pseudogene).  If the new copy has retained the capacity for expression, it may still acquire sequence changes which cause loss of function (i.e. it will become a pseudogene).  However, two other outcomes are possible: neofunctionalisation and subfunctionalisation.  In the former, one of the duplicate genes acquires a novel function, while in the latter, one of the genes performs a subset of the functions of the original gene.  Several mechanisms can lead to these outcomes.

In a second paper, Ding et al (2010) looked at the origins and function of young duplicated genes in Drosophila, and focusses on the members of the kep1 gene family, with particular reference to the appearance of new functions. In D. melanogaster, kep1 is a pre-mRNA splicing factor, influencing female fertility, eye development, and immune responses to bacterial infection.

The diagram shows the lineages of several Drosophila species (ana = anannasae; ere = erecta; yak = yakuba; sim = simulans; mel = melanogaster).  In these lineages, the points of origins of the members of the kep1 family are shown as horizontal bars.  Not all members of the gene have been named: those gene names in the form CGxxxx are working names allocated during the Drosophila genome project.

Loss of function mutants of each of the four functional additional members of the D. melanogaster kep1 family (CG4021, nsr, CG3927, CG33318) were analysed.  All of these mutant alleles involved deletion of some or all of the genes involved: two were obtained by targeted mutagenesis and two by imprecise excision of the transposable P element.  CR9337 is a pseudogene – a duplicated gene that has lost biological function.

Loss of nsr leads to almost complete male sterility (see Figure 3 for an illustration of the mutant alleles and the severely reduced fertility of nsr mutant males) – a phenotype distinct from that of kep1 mutants.  The authors analyse the biological function of nsr in considerable detail: it turns out to play its important role in male fertility by regulating several Y-linked genes that are known to be required for male fertility.  [In Drosophila, the Y chromosome does not itself specify male-ness as it does in humans: rather the primary sex determination signal is the ratio of X chromosomes to autosome sets.  Thus a fly with a single X chomosome will be male, though sterile because it lacks the Y chromosomal fertility factors.  The Y chromosome is also rather peculiar, both in terms of its gross structure but also in the structure of individual genes.]  Interestingly, loss of kep1 function leads to female, but not male fertility, while loss of CG4021 or CG3927 did not lead to male sterility.

So, do the analyses of nsr sequence and function suggest that it is derived from neofunctionalisation or subfunctionalisation forllowing the original duplication event?  Ding et al suggest their data point to the former, but do not exclude the latter.  In support of neofunctionalisation, they observe that:

  • kep1 is under strict purifying selection across the Drosophila lineage studied.
  • Comparative sequence analysis of nsr shows strong positive selection
  • kep1 expression in the testis could not be detected in D. yakuba, suggesting the ancestral function of kep1 did not involve testis development.

On the other hand, the conclusion that nsr may have arisen by subfunctionalisation is still possible.  For example, kep1 my have lost its male fertility role in the D. yakuba lineage.  In any event, during the evolution of the melanogaster subgroup, nsr has not only arisen through gene duplication, but has been integrated into some pretty important biological processes.

How do these two papers relate to Behe’s proposal?  They do illustrate the extent to which novel gene functions arise during evolution, and that newly duplicated genes can be integrated into fundamental biological processes.  It’s interesting to note that the kind of experimental evolution experiments conducted using microorganisms and as reviewed by Behe are difficult (or at least time consuming)  to perform in eukaryotic laboratory organisms.  It’s clear from these two papers (and many other examples in the literature) that the increasing quantity of genome sequence data, not only of different species but of multiple individuals within species, has provided us with significant insight into the origins and diversification of genes.

References

Chen et al (2010) New Genes in Drosophila Quickly Become Essential. Science 330; 1682-1685. doi:10.1126/science.1196380. [Subscription required]

Ding et al. 2010. A Young Drosophila Duplicate Gene Plays Essential Roles in Spermatogenesis by Regulating Several Y-Linked Male Fertility Genes. PLoS Genetics 6; e1001255. doi:10.1371/journal.pgen.1001255. [Open Access]

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2 comments

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  1. Paul Braterman’s avatar

    You are too kind.

    You say "Behe generates … a “rule”, the “first rule of adaptive evolution”, which essentially states that the majority of adaptive changes reflect mutational events are those which impair or eliminate TCT function."

    I fear you have yourself fallen for Behe's trademark bait-and-switch. This is what he pretends he said in interviews with his allies, but his "First Rule" merely says, to quote his actual text,

    "Break or blunt any functional coded element whose loss would yield a net fitness gain…other circumstances being equal, this is what is usually to be expected in adaptive evolution… It is a heuristic, useful generalization, rather than a strict law"

    In other words, when the loss of an element would increase fitness, there is a tendency for it to be lost. No more than this, but the ambiguous expression "usually to be expected" creates the totally false impression that he has established a significant fact about the relative frequencies of different kinds of change.

    Reply

    1. GrumpyBob’s avatar

      Thanks for this Paul. I've added a note directing the reader to your comment. Rather than falling for Behe's bait and switch, I was writing this article more about the two Drosophila papers than pointing out the fallacies associated with Behe's 'rule'. Behe's first rule essentially says nothing.

      Reply

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