Re: Duplicate Genes

From: bivalve (bivalve@mail.davidson.alumlink.com)
Date: Thu Jan 09 2003 - 19:16:48 EST

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    >So a few offhand questions:
    >Can we really assess the genome and proclaim that it is filled with
    >junk (and "not optimally designed" as quoted from the News and Views
    >article) in light of this study?<

    Not unless there is some definition of what is being optimized.
    There is certainly a lot of DNA in most eukaryotic genomes that does
    not serve any known purpose, much of which is not duplicate genes.
    Many species have a lot more DNA than others, suggesting that much of
    it is extraneous. All of this extra DNA has some potential (though
    often rather low potential) of evolving into something useful.
    Major DNA duplication events (probable duplication of most if not all
    of the genome) are associated with the origins of some evolutionary
    lineages that went on to become quite succesful, e.g. the
    vertebrates. On the other hand, more DNA takes more copying time,
    limiting the rate of cell division and thus of reproduction.

    Thus, we can say that the genome does not look as though it were
    designed as a finished product, assembled for maximum efficiency of
    self-replication, with every gene individually optimized. The genome
    does appear to be quite good as a compromise between stability and
    adaptability, which is what it should be to be an evolutionary
    success.

    >Does the fact that duplicated genes contribute to genetic robustness
    >support the conclusion of design or evolution?<

    What definition of design is intended? By providing a useful backup
    system in case of deleterious mutation, duplications can provide an
    evolutionary advantage. Duplicated genes provide an important source
    of evolutionary raw material, which tends to be detrimental to
    arguments claiming the improbability of evolving a given sequence.
    Some ancient gene duplications suggest stepwise evolution of complex
    systems (which today require both copies), contrary to some design
    claims. A designer intending a system to be robust to mutation and
    able to evolve might include such features.

    >Taking this data into account does the presence of duplicated genes
    >by themselves indicate clearly that they must be products of
    >evolution?<
    It does not require it. Obviously the duplicate genes that I produce
    with a PCR machine are not products of evolution. However, there are
    numerous ready mechanisms for gene duplication in organisms, so the
    presence of gene duplications within a genome is no grounds for
    suspicion of outside imposition of design.

    >What does the fact that deleting one copy of a duplicate gene 12.4%
    >of the time causes lethality indicate about the purpose of duplicate
    >genes? Simply raw material for evolution, or perhaps requisite
    >components of a well-designed system needed for reasons not yet
    >determined?<

    If multiple truly identical gene copies are necessary for cell
    survival, this suggests that a single copy does not have a high
    enough level of expression. Cells have a variety of mechanisms for
    controlling the expression level of a gene, gene copy number being
    one. Thus, a designed system would not require duplicate genes;
    other methods would also work. They could be a means selected by a
    designer; they are also quite easily generated by ordinary processes.
    If a designer makes extensive use of evolutionary means, then he
    might want to design a good source of evolutionary raw material.
    However, such a designer is not the one envisioned by most ID
    advocates.

    >Consider also the comments concerning the growth conditions that the
    >authors make in the last paragraph of the original paper in regards
    >to this question.<

    It is actually detrimental to the claim that duplicates are an
    integral part of a functional genome, because in real life most
    organisms do not have to function in multiple, disparate growth
    conditions. The fact that a gene is necessary to survival under some
    condition contrived in the lab does not mean that a real organism out
    in the wild would have trouble without it. If the duplicate copy is
    vital only under certain conditions, then the duplicates are useful
    safety mechanisms but not essential.

    Another problem is the risk that similar independent genes are
    mistaken for duplicates in some cases, since the identified
    duplicates vary in the degree of similarity.

         Dr. David Campbell
         Old Seashells
         University of Alabama
         Biodiversity & Systematics
         Dept. Biological Sciences
         Box 870345
         Tuscaloosa, AL 35487-0345 USA
         bivalve@mail.davidson.alumlink.com

    That is Uncle Joe, taken in the masonic regalia of a Grand Exalted
    Periwinkle of the Mystic Order of Whelks-P.G. Wodehouse, Romance at
    Droitgate Spa

    ---------- Original Message ----------------------------------
    From: "Josh Bembenek" <jbembe@hotmail.com>
    Date: Tue, 07 Jan 2003 18:48:31 +0000

    >
    >I wanted to stimulate some discussion regarding a recent article (and
    >corresponding News and Views) in Nature. Reference Gu et al., Nature 421,
    >63-66, and 31-32. Following excerpts (first two paragraphs followed by the
    >final paragraph of both articles) highlight the topic:
    >
    >Original Article:
    >"Deleting a gene in an organism often has little phenotypic effect, owing to
    >two mechanisms of compensation. The first is the existence of duplicate
    >genes: that is, the loss of function in one copy can be compensated by the
    >other copy or copies. The second mechanism of compensation stems from
    >alternative metabolic pathways, regulatory networks, and so on. The relative
    >importance of the two mechanisms has not been investigated except for a
    >limited study, which suggested that the role of duplicate genes in
    >compensation is negligible. The availability of fitness data for a nearly
    >complete set of single-gene-deletion mutants of the Saccharomyces cerevisiae
    >genome has enabled us to carry out a genome-wide evaluation of the role of
    >duplicate genes in genetic robustness against null mutations. Here we show
    >that there is a significantly higher probability of functional compensation
    >for a duplicate gene than for a singleton, a high correlation between the
    >frequency of compensation and the sequence similarity of two duplicates, and
    >a higher probability of a severe fitness effect when the duplicate copy that
    >is more highly expressed is deleted. We estimate that in S. cerevisiae at
    >least a quarter of those gene deletions that have no phenotype are
    >compensated by duplicate genes.
    >
    >No correlation was found between the sequence similarity of duplicate genes
    >and the fitness effect of a null mutation in one of the two duplicates when
    >functional data from the yeast S. cerevisiae was analysed previously10. It
    >was therefore concluded that gene duplications contribute little to the
    >ability of an organism to withstand mutations (genetic robustness), although
    >they may be responsible for a small fraction of weak, null-mutation
    >phenotypes12. Because this conclusion was based on only 45 duplicate genes,
    >however, the issue deserves further investigation. Indeed, this conclusion
    >is not supported by a limited analysis of a third of the genes in the yeast
    >genome1 and is contrary to the general observation of relaxed selective
    >constraints after gene duplication.
    >
    >Although our estimates are compatible with the view that interactions among
    >unrelated genes rather than duplicate genes are the main cause of genetic
    >robustness against mutations10, 18, two additional factors need to be
    >considered. First, because we have considered only five growth conditions,
    >it is possible that when a gene deletion showed no effect in any of these
    >conditions it was not due to compensation by other genes but was because the
    >gene deleted was not related to the growth conditions used. Intuitively,
    >when more growth conditions are studied, both the proportion of duplicate
    >genes and the proportion of singletons that show only a weak or no effect of
    >deletion on growth rate will decrease. Indeed, the two proportions were
    >70.9% and 49.2% when only the YPD growth condition was considered (data not
    >shown), but became 64.3% and 39.5% when the five growth conditions shown in
    >Fig. 1a were used. The decrease is larger for singletons than for duplicate
    >genes, probably because duplicate genes have on average a stronger overlap
    >in function than do singletons and so can compensate each other in a wider
    >range of conditions. For this reason, our lower bound of 23% for the
    >relative contribution of duplicate genes to compensation for null mutations
    >is likely to be an underestimate. Second, a singleton in this or other
    >studies could actually have one or more paralogues in the genome that cannot
    >be detected by the criteria used but still overlap in function. Thus, gene
    >duplication might be the ultimate origin of functional compensation for some
    >'singletons'. In conclusion, whether the contribution of gene duplication to
    >genetic robustness is really less important than interactions among
    >unrelated genes is an issue that remains to be resolved by further studies."
    >
    >News and Views:
    >"Duplicated genes are common in genomes, perhaps because they provide
    >redundancy: if one copy is inactivated, the other can still work. A new
    >study quantifies the effects of deleting 'singletons' and duplicated genes
    >in yeast.
    >
    >In fairy tales, things frequently come in twos: there are, for instance, two
    >witches ruling over different parts of the land of Oz, two ugly sisters
    >vying for the attention of Cinderella's prince, and so on and so on. And the
    >phenomenon of duplication is not restricted to stories. In eukaryotes
    >(loosely speaking, those organisms, such as humans, whose DNA is packaged
    >into cell nuclei), genomes seem to be far from optimally designed, in that
    >most stretches of DNA sequence do not code for proteins, and even those
    >small portions that do are often duplicated. Why do organisms tolerate such
    >apparent wastage? Gu and colleagues1 tackle this question on page 63 of this
    >issue, looking specifically at the effects of duplicated genes on the
    >'fitness' of individuals.
    >
    >An important line of thinking about why duplicated genes might arise goes
    >back 30 years to Susumo Ohno2, who stated that "natural selection merely
    >modified while redundancy created". Ohno reasoned that gene (and even
    >genome) duplications are not a burden on the organism, but rather the raw
    >material for evolutionary diversification in other words, duplication
    >allows new gene functions to evolve. One copy of a gene can carry out the
    >original task while the duplicate becomes free to accumulate mutations,
    >possibly developing new functions and allowing the big steps in evolution to
    >occur. In today's era of wholesale genome sequencing, Ohno's hypothesis has
    >gained many new adherents through the recognition that duplicate genes are
    >abundant in most genomes and that significant portions of genomes are
    >repeated. But, in general, the actual effects of 'singletons' and duplicated
    >genes on evolutionary fitness that is, on roughly how well different
    >individuals fare compared with others in terms of reproduction have not
    >been well studied at the whole-genome level.
    >
    >On the other side of the coin, gene duplicates appear to have another
    >important function: they can buffer the genome against environmental
    >perturbations and mutations, because if one copy of the gene is somehow
    >inactivated, another with the same or a similar function can be used
    >instead. Such genetic redundancy is a headache for researchers trying to
    >determine the role of a particular gene, because the standard technique of
    >knocking out that gene in an organism might not have a noticeable effect,
    >thanks to functional substitution by the duplicate. Gu et al.1 shed new
    >light on this issue.
    >
    >We are only now beginning to comprehend just how malleable genomes are, and
    >also how resilient they are in the face of so much genetic perturbation; for
    >instance, rearrangements and duplications of chromosomal segments are also
    >commonplace8, 9. Gu et al.1 have provided the first estimate (2359%) of the
    >contribution of duplicated genes to genetic robustness. This may be one
    >reason why duplicated genes do not diverge to produce pseudogenes, or 'die',
    >as quickly or as often as had been predicted on the basis of
    >population-genetics theory10. I would guess that the existence of multiple
    >gene functions and their recruitment into novel gene networks provide
    >another explanation. But more needs to be learned about the evolution of
    >gene networks, through comparisons of complete genome sequences and through
    >further functional-genomic analyses, before this question can be answered."
    >
    >
    >So a few offhand questions:
    >
    >Can we really assess the genome and proclaim that it is filled with junk
    >(and "not optimally designed" as quoted from the News and Views article) in
    >light of this study?
    >
    >Does the fact that duplicated genes contribute to genetic robustness support
    >the conclusion of design or evolution?
    >
    >Taking this data into account does the presence of duplicated genes by
    >themselves indicate clearly that they must be products of evolution?
    >
    >What does the fact that deleting one copy of a duplicate gene 12.4% of the
    >time causes leathality indicate about the purpose of duplicate genes?
    >Simply raw material for evolution, or perhaps requisite components of a
    >well-designed system needed for reasons not yet determined? >
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