Duplicate Genes

From: Josh Bembenek (jbembe@hotmail.com)
Date: Tue Jan 07 2003 - 13:48:31 EST

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    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? 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.

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